Startseite circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
Artikel Open Access

circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma

  • Wei Li , Wancheng Wei , Dingyin Hu , Rutong Tang und Zikang Hu EMAIL logo
Veröffentlicht/Copyright: 11. Januar 2023
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Open Medicine
Aus der Zeitschrift Open Medicine Band 18 Heft 1

Abstract

Circular RNAs have been reported to be widely involved in cancer cell tumorigenesis and drug resistance; here, the aim of this study was to investigate whether circRNA Integrin Subunit Alpha 7 (ITGA7) (circ_ITGA7) was associated with the tumor growth and radiosensitivity of colorectal cancer (CRC). We found that circ_ITGA7 expression was lower in CRC tissues and cells than those in the normal tissues and cell lines according to quantitative real-time polymerase chain reaction. As shown by cell counting kit-8 assay, flow cytometry, colony formation assay, and xenograft experiment, ectopic overexpression of circ_ITGA7 remarkably restrained CRC tumor growth and enhanced radiosensitivity in vitro and in vivo. Mechanistically, circ_ITGA7 could target microRNA (miR)-766 to prevent the degradation of its target gene mothers against decapentaplegic homolog 4 (SMAD4), the binding between miR-766 and circ_ITGA7 or SMAD4 was first verified by dual-luciferase activity assay. Additionally, miR-766 up-regulation reversed the inhibitory effects of circ_ITGA7 on CRC growth and radiosensitivity. Besides that, inhibition of miR-766 reduced CRC cell growth and sensitized cells to radiotherapy, and these effects mediated by miR-766 inhibitor were rescued by the silencing of SMAD4. In all, circ_ITGA7 suppressed CRC growth and enhanced radiosensitivity by up-regulating SMAD4 through sequestering miR-766, providing an insight for the further development of CRC treatment.

Keywords: circ_ITGA7; miR-766; SMAD4; tumorigenicity; radioresistance

1 Introduction

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies throughout the world. Attributing to the technological advances in early detection and intervention, the overall survival of CRC has partially improved; however, patients with advanced stage are difficult to completely eliminate with high frequency of metastasis and recurrence [1,2]. Radiotherapy (RT) is a commonly used nonsurgical modality for both curative and palliative therapies of many types of malignancies; moreover, RT alone or along with surgery is an important treatment option for CRC patients [3,4]. Unfortunately, the intrinsic and acquired radioresistance among a good deal of CRC patients limits the efficacy of RT [5,6]. Thus, further investigations on the molecular mechanisms of CRC tumor growth and radiosensitivity are helpful for improving CRC therapy.

Circular RNAs (circRNAs) are non-coding transcripts with a 3′,5′-phosphodiester bond at the junction site, they are widespread and abundant in eukaryotic transcriptome, and show high conservation across species [7]. Increasing studies have revealed that circRNAs play a significant role in numerous biological processes [8]. Importantly, dysregulation of circRNAs in many diseases including cancer has been observed [9,10], besides that, circRNAs are widely reported to involve in cancer cell tumorigenesis and drug resistance [11]. circRNA Integrin Subunit Alpha 7 (ITGA7) (circ_ITGA7, ID: hsa_circ_0026782) is derived from the ITGA7 gene and located at chr12:56094682–56094938. Li et al. showed that circ_ITGA7 was decreased in CRC; importantly, circ_ITGA7 overexpression repressed CRC growth and metastasis via blocking the Ras signaling pathway and up-regulating ITGA7 expression [12]. Besides, another study showed that circ_ITGA7 increased ASXL1 expression level by absorbing miR-3187-3p to reduce the proliferation rate of CRC cells [13]. Although these findings support the notion that abnormal expression of circ_ITGA7 is implicated in CRC tumorigenic molecular pathway, the function of circ_ITGA7 in radioresistance remains unclear.

Herein, the purpose of this study was to elucidate the expression profile of circ_ITGA7 in CRC, and investigate the action and mechanism of circ_ITGA7 in CRC tumor growth and RT sensitization.

2 Materials and methods

2.1 Clinical samples

Fifty-one pairs of CRC tissues and adjacent normal tissues were collected from patients who underwent surgical resection at Gaozhou People’s Hospital. All patients were newly diagnosed as CRC by pathological examination and received radiation therapy alone. All tissue samples were stored in −80°C until RNA extraction.

  1. Ethical approval and consent to participate: The present study was approved by the ethical review committee of Gaozhou People’s Hospital. Written informed consent was obtained from all enrolled patients.

  2. Consent for publication: Patients agree to participate in this work.

2.2 Cell culture

Human CRC cell lines HCT116 and DLD1, and normal colonic cell line FHC were provided by Cedarlane (Burlington, NC, USA). HCT116 and DLD1 cells were cultured in the Dulbecco’s Modified Eagle’s Medium (DMEM; Life Technologies, Scotland, UK) with 100 U/mL of penicillin and streptomycin (HyClone, Logan, UT, USA) and 10% fetal bovine serum (FBS; Hyclone). FHC cells were cultured in DMEM/F-12 (Life Technologies) plus 10% FBS, 10 ng/mL cholera toxin, 5 μg/mL insulin, 5 μg/mL transferrin, 100 ng/mL hydrocortisone, and 10 mM Hanks’ balanced salt solution. All cells were maintained in a humidified 5% CO2 incubator at 37°C.

2.3 Quantitative real-time PCR (qRT-PCR)

Nuclear and cytoplasmic separation was performed using RNA Subcellular Isolation Kit (Life Technologies) following the manufacturer’s instructions. For Actinomycin D treatment, cells were incubated with 2 μg/mL Actinomycin D or dimethylsulfoxide (as control) (Sigma-Aldrich, St. Louis, MO, USA) to block transcription at indicated time points. Total RNA from the tissues and cultured cells was prepared using RNeasy Mini Kit (Life Technologies). The single-stranded CDNA was synthesized in 25 µL reactions using SuperScriptIII reverse transcriptase (Takara Biotech, Otsu, Japan) with 2 µg of RNA. Then qRT-PCR was conducted using SYBR QPCR Mix (Toyobo, Tokyo, Japan). The level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or U6 was simultaneously detected for normalization of circ_ITGA7, linear ITGA7 (Integrin Subunit Alpha 7) mRNA, miR-766, and SMAD4 (mothers against decapentaplegic homolog 4) mRNA expression employing the comparative Ct method. The primer sequences for qRT-PCR are:

circ_ITGA7: F 5′-GTGTGCACAGGTCCTTCCAA-3′, R 5′-TGGAAGTTCTGTGAGGGACG-3′;

ITGA7: F 5′-TATTGACTCGGGGAAAGGTCT-3′, R 5′-CCAGCCATCACTGTTGAGG-3′;

SMAD4: F 5′-CTCATGTGATCTATGCCCGTC-3′, R 5′-AGGTGATACAACTCGTTCGTAGT-3′;

miR-766: F 5′-CAATCCTTACTCCAGCCAC-3′, R 5′-GTGTCTTAAGGCTAGGCCTA-3′;

GAPDH: F 5′-GCACCGTCAAGGCTGAGAAC-3′, R 5′-TGGTGAAGACGCCAGTGGA-3′;

U6: F 5′-GCAGACCGTTCGTCAACCTA-3′, R 5′-AATTCTGTTTGCGGTGCGTC-3′.

2.4 Cell transfection

The pLC5-ciR-circ_ITGA7 overexpression plasmid (circ_ITGA7) and plasmid containing scrambled sequences (Vector), SMAD4-specific siRNA (si-SMAD4), and negative control siRNA (si-NC) were obtained from Genechem (Shanghai, China). Mature miR-766 mimics (miR-766), inhibitors (anti-miR-766), and the negative control miR (anti-NC or anti-miR-NC) were provided by GenePharma (Shanghai, China). Then transient transfections with 2 μg of circ_ITGA7, Vector, or 50 nM of si-SMAD4, si-NC, miR-766, anti-miR-766, or the negative control miR were performed using LipofectamineTM 3000 reagent (Thermo Fisher Scientific). Lentivirus particles encoding circ_ITGA7 (Lenti-circ_ITGA7) or Vector (Lenti-NC) were purchased from Genechem and then stably transfected into HCT116 cells at a multiplicity of infection of 25. After 2 weeks of screening with puromycin, stably expressed cells were selected for subsequent analysis.

2.5 Cell counting kit-8 (CCK-8) assay

Transfected HCT116 and DLD1 cells (1 × 104/well) were seeded into 96-well plates, then cultured for 0, 1, 2, or 3 days before the addition 10 μL of CCK-8 (5 mg/mL) to the culture medium in each well. One hour after CCK-8 addition, cell proliferation was analyzed by reading the absorbances at 570 nm with a Viktor X3 reader (PerkinElmer, Turku, Finland).

2.6 Flow cytometry

For cell cycle analysis, transfected HCT116 and DLD1 cells were collected and fixed in 70% ethanol. After rinsing with phosphate-buffered saline (PBS), fixed cells were stained with propidium iodide (PI) (Life Technologies). Finally, cell cycle distribution was evaluated using a FACS Calibur flow cytometer (BD Biosciences, San Diego, CA, USA).

After assigned transfection, HCT116 and DLD1 cells were exposed to 0 or 6 Gy irradiation for 48 h. Then cells were harvested by trypsin, resuspended by 1× binding buffer and then stained orderly with fluorescein isothiocyanate-Annexin V (BD Biosciences) and PI (Life Technologies) for 15 min. Then cell apoptosis was determined using a BD Biosciences flow cytometer.

2.7 Colony formation assay

Transfected HCT116 and DLD1 cells were seeded into a six-well plate at 1 × 103 cells per well and then irradiated with 0, 2, 4 or 6 Gy for 48 h. After incubation for 14 days at 37°C, cells were fixed with 4% paraformaldehyde (Sigma-Aldrich) for 30 min and then stained with 0.5% crystal violet (Sigma-Aldrich) for 15 min. Number of viable cells in five randomly selected fields were assayed. The survival fraction was calculated according to the formula: (number of colonies/number of cells plated)irradiated/(number of colonies/number of cells plated)non-irradiated.

2.8 Western blot

Cultured cells and tissues were disrupted by RIPA lysis and then quantified with the Bio-Rad protein assay kit (Bio-Rad, Richmond, CA, USA). Equivalent amounts of protein (50 µg per lane) were separated by 10% SDS-poly acrylamide gel electrophoresis and transferred to Clear Blot membrane-p (ATTO, Tokyo, Japan). Then primary antibody incubation and secondary antibody incubation were performed, membranes carrying protein blots were visualized by enhanced chemiluminescence detection system (Life Technologies). The antibodies used in this study included B-cell lymphoma-2 (Bcl-2; 1:1,000, ab194583), GAPDH (1:5,000, ab181602), Bcl-2-associated X protein (Bax; 1:1,000, ab32503), Vimentin (1:2,000, ab92547), E-cadherin (1:2,000, ab15148), and SMAD4 (1:5,000, ab40759) (Abcam, Cambridge, MA, USA).

2.9 Dual-luciferase activity assay

The pGL3-Basic Vector harboring the mutated (MUT) or wild-type (WT) miR-766 binding sequences in the 3′-UTR of circ_ITGA7 or SMAD4 was constructed by GenePharma. Then HCT116 and DLD1 cells were co-transfected with 50 ng pGL3 Vector and 10 ng pRL-TK Renilla together with miR-766 mimic or mimic control when cells reached 70% confluence. Cells were lysed 36 h later, and 20 µL of cell lysates were used to evaluate the luciferase activity.

2.10 Tumor xenografts in vivo

This animal study was approved by the animal care and experiment committee of Gaozhou People’s Hospital. Five-week-old BALB/c nude mice (N = 24) purchased from Charles River Labs (Beijing, China) were used in this study. Twenty days after injection of Lenti-circ_ITGA7 or Lenti-NC-infected HCP116 cells (2 × 106/0.2 mL PBS) in mice (N = 6/each group), the mice were irradiated with 6 Gy once per day for the following 5 days. The tumor volume was assayed every 5 days using the formula: (length  ×  width2)/2. At Day 40, mice were sacrificed, the tumors were excised, and the tumor weights were recorded. The expression levels of circ_ITGA7, miR-766, and SMAD4 in tumors of mice were then examined, respectively.

2.11 Statistical analyses

All experiments were conducted in three independent biological replicate, and data were plotted as mean  ±  standard deviation. Group comparison was conducted using Student’s t-test (two-tailed) or one-way analysis of variance. The survival rates were evaluated by Kaplan–Meier method and tested by log-rank test. The relationship between two variables was evaluated using Pearson’s correlation coefficient. P < 0.05 indicated significantly difference.

3 Results

3.1 circ_ITGA7 expression is decreased in CRC tissues and cells

The expression profile of circ_ITGA7 was first investigated. As shown in Figure 1a and b, circ_ITGA7 expression was lower in CRC tissues and cell lines (HCT116 and DLD1) compared with the normal tissues and normal FHC cells, suggesting the involvement of circ_ITGA7 in CRC progression. Furthermore, the overall survival of CRC patients was analyzed based on the medium of circ_ITGA7 expression. Patients in high circ_ITGA7 group showed a remarkably longer overall survival than that in the low circ_ITGA7 group (Figure 1c). After that, through the use of cellular RNA fractionation, circ_ITGA7 was found to be predominately distributed in the cytoplasm of HCT116 and DLD1 cells (Figure 1d and e). Moreover, we adopted Actinomycin D to block transcription and then detected the half-life of circ_ITGA7 and ITGA7 mRNA in HCT116 and DLD1 cells. The results exhibited that circ_ITGA7 was more stable than ITGA7 mRNA (Figure 1f and g). These data demonstrated that a relatively stable cytoplasmic transcript is decreased in CRC.

Figure 1 circ_ITGA7 is highly expressed in CRC tissues and cells. (a and b) Expression level of circ_ITGA7 in CRC tissues and matched normal tissues, as well as in CRC cell lines and normal FHC cells were analyzed using qRT-PCR. (c) Kaplan–Meier overall survival curve for CRC patients classified according to relative circ_ITGA7 expression level. (d and e) Cellular distribution of circ_ITGA7 was analyzed by cellular RNA fractionation assays in HCT116 and DLD1 cells. (f and g) Relative RNA levels of circ_ITGA7 and ITGA7 were measured by qRT-PCR in HCT116 and DLD1 cells after treatment with Actinomycin D at the indicated time points. *P < 0.05.
Figure 1

circ_ITGA7 is highly expressed in CRC tissues and cells. (a and b) Expression level of circ_ITGA7 in CRC tissues and matched normal tissues, as well as in CRC cell lines and normal FHC cells were analyzed using qRT-PCR. (c) Kaplan–Meier overall survival curve for CRC patients classified according to relative circ_ITGA7 expression level. (d and e) Cellular distribution of circ_ITGA7 was analyzed by cellular RNA fractionation assays in HCT116 and DLD1 cells. (f and g) Relative RNA levels of circ_ITGA7 and ITGA7 were measured by qRT-PCR in HCT116 and DLD1 cells after treatment with Actinomycin D at the indicated time points. *P < 0.05.

3.2 circ_ITGA7 overexpression suppresses cell growth and enhances radiosensitivity in CRC in vitro

To underlie the effects of circ_ITGA7 on CRC cell growth and radiosensitivity, circ_ITGA7 overexpressing vector was designed and transfected into HCT116 and DLD1 cells. qRT-PCR analysis showed a significant elevation of circ_ITGA7 expression level in HCT116 and DLD1 cells after circ_ITGA7 transfection compared with Vector transfection (Figure 2a and b). Then CCK-8 assay suggested that circ_ITGA7 up-regulation led to a decrease of cell proliferation rate in HCT116 and DLD1 cells (Figure 2c and d). Cell cycle analysis showed that overexpression of circ_ITGA7 caused CRC cell arrest at G0/G1 phase, accompanied by the decreased percentage of cells in S phase, suggesting the inhibition of cell cycle in HCT116 and DLD1 cells (Figure 2e and f). We then explored the role of circ_ITGA7 in irradiation sensitivity of CRC cells. Transfected HCT116 and DLD1 cells were treated with different doses of irradiation (0, 2, 4, or 6 Gy). It was manifested that the transfection of circ_ITGA7 into HCT116 and DLD1 cells markedly decreased cell survival fraction with the increase of radiotherapy dose (Figure 2g and h). In addition, the irradiation treatment of 6 Gy had high-efficiency effects on the two cells. Therefore, 6 Gy dose was selected as the treatment dose. Radiosensitivity is often related to cell apoptosis, thus cell apoptosis was then analyzed. Flow cytometry suggested that circ_ITGA7 overexpression dramatically reinforced irradiation-induced apoptosis in HCT116 and DLD1 cells reflected with decreased apoptosis rate and Bcl-2 expression as well as increased Bax expression (Figure 2i–l). Besides, the action of epithelial–mesenchymal transition (EMT) in cancer drug resistance has been increasingly recognized, cells undergoing EMT exhibit a feature similar to cancer stem cells, such as an increase in drug efflux pumps and anti-apoptotic effects [14]. It has been identified that EMT can endow the cancer cells with radioresistance [15]. Then, the inhibition of Vimentin and promotion of E-cadherin mediated by irradiation were enhanced by circ_ITGA7 overexpression (Figure 2m and n), indicating that circ_ITGA7 enhanced radiosensitivity by suppressing EMT process. Taken together, circ_ITGA7 suppressed CRC cell growth and induced irradiation sensitivity in vitro.

Figure 2 circ_ITGA7 overexpression suppresses cell growth and enhances radiosensitivity in CRC in vitro. (a–l) HCT116 and DLD1 cells were transfected with Vector or circ_ITGA7. (a and b) qRT-PCR analysis of circ_ITGA7 expression in HCT116 and DLD1 cells. (c and d) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (e and f) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (g and h) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (i and j) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (k–n) Western blot analysis of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. *P < 0.05.
Figure 2

circ_ITGA7 overexpression suppresses cell growth and enhances radiosensitivity in CRC in vitro. (a–l) HCT116 and DLD1 cells were transfected with Vector or circ_ITGA7. (a and b) qRT-PCR analysis of circ_ITGA7 expression in HCT116 and DLD1 cells. (c and d) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (e and f) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (g and h) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (i and j) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (k–n) Western blot analysis of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. *P < 0.05.

3.3 miR-766 is a target of circ_ITGA7

Since circ_ITGA7 was distributed predominantly in the cell cytoplasm, we hypothesized that circ_ITGA7 might act as a miRNA sponge to exert its biological functions. Through the circInteractome database (https://circinteractome.nia.nih.gov/), we identified that miR-766 might be a target of circ_ITGA7 (Figure 3a). To validate our speculation, dual-luciferase activity assay was performed. The results showed that miR-766 overexpression greatly reduced the luciferase activity in HCT116 and DLD1 cells transfected with circ_ITGA7-WT vector, while no significant effect was observed in cells transfected with circ_ITGA7-MUT vector (Figure 3b and c). Besides that, it was also found that circ_ITGA7 overexpression decreased miR-766 expression in HCT116 and DLD1 cells (Figure 3d). Therefore, we confirmed that circ_ITGA7 directly targeted miR-766 and repressed its expression. Meanwhile, miR-766 was found to be highly expressed in CRC tissues (Figure 3e), which was negatively correlated with circ_ITGA7 expression (Figure 3f). Similarly, miR-766 expression was also increased in CRC cells (Figure 3g), suggesting the potential implication in CRC progression.

Figure 3 miR-766 is a target of circ_ITGA7. (a) Schematic diagram representing the predicted binding sites for miR-766 in circ_ITGA7. (b and c) Dual-luciferase activity assay for the detection of the relative luciferase activity of wild and mutated circ_ITGA7 reporter after miR-766 up-regulation in HCT116 and DLD1 cells. (d) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells transfected with Vector or circ_ITGA7. (e) qRT-PCR analysis of miR-766 expression in CRC tissues and matched normal tissues. (f) Pearson’s correlation coefficient analysis for the correlation between miR-766 in circ_ITGA7 expression in CRC tissues. (g) qRT-PCR analysis of miR-766 expression in CRC cell lines and normal FHC cells. *P < 0.05.
Figure 3

miR-766 is a target of circ_ITGA7. (a) Schematic diagram representing the predicted binding sites for miR-766 in circ_ITGA7. (b and c) Dual-luciferase activity assay for the detection of the relative luciferase activity of wild and mutated circ_ITGA7 reporter after miR-766 up-regulation in HCT116 and DLD1 cells. (d) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells transfected with Vector or circ_ITGA7. (e) qRT-PCR analysis of miR-766 expression in CRC tissues and matched normal tissues. (f) Pearson’s correlation coefficient analysis for the correlation between miR-766 in circ_ITGA7 expression in CRC tissues. (g) qRT-PCR analysis of miR-766 expression in CRC cell lines and normal FHC cells. *P < 0.05.

3.4 circ_ITGA7 suppresses cell growth and enhances radiosensitivity in CRC via regulating miR-766

To investigate whether miR-766 was responsible for circ_ITGA7-mediated growth and radiosensitivity of CRC cells, miR-766 mimic was transfected into circ_ITGA7-increased HCT116 and DLD1 cells, as expected, miR-766 mimic rescued circ_ITGA7-induced decrease of miR-766 expression level (Figure 4a). Thereafter, the results of CCK-8 assay and flow cytometry exhibited that introduction of miR-766 mimic reversed circ_ITGA7-mediated inhibition of HCT116 and DLD1 cell growth by increasing cell proliferation (Figure 4b and c) and inducing cell cycle progression (Figure 4d and e). Colony formation assay indicated that miR-766 mimic resulted in an increase of cell survival fraction in circ_ITGA7-increased HCT116 and DLD1 cells with the increase of radiotherapy dose (Figure 4f and g). Additionally, circ_ITGA7 promoted irradiation-induced apoptosis in HCT116 and DLD1 cells accompanied by the decrease of Bcl-2 expression and the increase of Bax expression, which were abolished by miR-766 mimic (Figure 4h–k). Moreover, miR-766 overexpression reversed circ_ITGA7-caused arrest of EMT process under irradiation treatment, evidenced by the increased Vimentin and decreased E-cadherin (Figure 4l and m). Altogether, miR-766 was a functional target of circ_ITGA7 and involved in circ_ITGA7-mediated growth inhibition and radiosensitivity in CRC cells.

Figure 4 circ_ITGA7 suppresses cell growth and enhances radiosensitivity in CRC via regulating miR-766. (a–k) HCT116 and DLD1 cells were transfected with Vector, circ_ITGA7, circ_ITGA7 + miR-NC, or circ_ITGA7 + miR-766. (a) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells. (b and c) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (d and e) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (f and g) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (h and i) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (j–m) Detection of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation using western blot. *P < 0.05.
Figure 4

circ_ITGA7 suppresses cell growth and enhances radiosensitivity in CRC via regulating miR-766. (a–k) HCT116 and DLD1 cells were transfected with Vector, circ_ITGA7, circ_ITGA7 + miR-NC, or circ_ITGA7 + miR-766. (a) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells. (b and c) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (d and e) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (f and g) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (h and i) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (j–m) Detection of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation using western blot. *P < 0.05.

3.5 SMAD4 is a target of miR-766

Based on the prediction of miRDB database (http://www.mirdb.org/), we inferred SMAD4 transcript might be a potential target of miR-766 (Figure 5a). The results of dual-luciferase activity assay exhibited that miR-766 mimic reduced the luciferase activity of SMAD4-WT vector but not the mutated one in HCT116 and DLD1 cells (Figure 5b and c). In addition, after confirming the transfection efficiency of miR-766 mimic or inhibitor in HCT116 and DLD1 cells, it was observed that SMAD4 expression both at mRNA and protein levels was decreased in miR-766-overexpressed cells, while it was increased in miR-766-down-regulated cells (Figure 5e and f). Afterward, the expression profile of SMAD4 was determined. SMAD4 mRNA and protein levels were decreased in CRC tissues compared with the normal tissues (Figure 5g and h), which was negatively correlated with miR-766 (Figure 5i) and positively correlated with circ_ITGA7 expression at the mRNA level (Figure 5j). Also, a decreased SMAD4 expression was detected in CRC cells both at mRNA and protein levels (Figure 5k and l). Therefore, these results verified that miR-766 targeted SMAD4 and negatively regulated its expression in a targeted manner.

Figure 5 SMAD4 is a target of miR-766. (a) Schematic diagram representing the predicted binding sites for miR-766 in SMAD4. (b and c) Dual-luciferase activity assay for the detection of the relative luciferase activity of wild and mutated SMAD4 reporter after miR-766 up-regulation in HCT116 and DLD1 cells. (d–f) HCT116 and DLD1 cells were transfected with miR-766 mimic, inhibitor, or their negative control. (d) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells. (e and f) qRT-PCR and western blot analysis of SMAD4 levels in HCT116 and DLD1 cells. (g) qRT-PCR of SMAD4 mRNA levels in CRC tissues and matched normal tissues. (h) Western blot analysis of SMAD4 protein levels in three pairs of CRC tissues (T1–T3) and matched normal tissues (N1–N3). (i and j) Pearson’s correlation coefficient analysis for the correlation between SMAD4 and miR-766 or circ_ITGA7 expression in CRC tissues. (k and l) qRT-PCR and western blot analysis of SMAD4 levels in CRC cell lines and normal FHC cells. *P < 0.05.
Figure 5

SMAD4 is a target of miR-766. (a) Schematic diagram representing the predicted binding sites for miR-766 in SMAD4. (b and c) Dual-luciferase activity assay for the detection of the relative luciferase activity of wild and mutated SMAD4 reporter after miR-766 up-regulation in HCT116 and DLD1 cells. (d–f) HCT116 and DLD1 cells were transfected with miR-766 mimic, inhibitor, or their negative control. (d) qRT-PCR analysis of miR-766 expression in HCT116 and DLD1 cells. (e and f) qRT-PCR and western blot analysis of SMAD4 levels in HCT116 and DLD1 cells. (g) qRT-PCR of SMAD4 mRNA levels in CRC tissues and matched normal tissues. (h) Western blot analysis of SMAD4 protein levels in three pairs of CRC tissues (T1–T3) and matched normal tissues (N1–N3). (i and j) Pearson’s correlation coefficient analysis for the correlation between SMAD4 and miR-766 or circ_ITGA7 expression in CRC tissues. (k and l) qRT-PCR and western blot analysis of SMAD4 levels in CRC cell lines and normal FHC cells. *P < 0.05.

3.6 Inhibition of miR-766 suppresses cell growth and enhances radiosensitivity in CRC via SMAD4

We then elucidated whether miR-766/SMAD4 axis was engaged in CRC growth and radiosensitivity. HCT116 and DLD1 cells were co-transfected with si-NC, si-SMAD4, anti-miR-766 + si-NC, or anti-miR-766 + si-SMAD4, then we found that si-SMAD4 introduction markedly reduced SMAD4 expression, and co-transfection of anti-miR-766 + si-SMAD4 caused a decrease of the mRNA and protein level of SMAD4 in cells relative to anti-miR-766 + si-NC transfection (Figure 6a and b). The results showed that SMAD4 knockdown led to the promotion of the proliferation rate (Figure 6c and d) and cell cycle process (Figure 6e and f) in HCT116 and DLD1 cells. Besides that, with different doses of irradiation (0, 2, 4, or 6 Gy), SMAD4 knockdown markedly increased cell survival fraction (Figure 6g and h). Further, flow cytometry analysis showed that SMAD4 silencing reversed irradiation-induced apoptosis in HCT116 and DLD1 cells (Figure 6i and j) accompanied with increased Bcl-2 and decreased Bax (Figure 6k and l). In addition, western blot analysis also showed that knockdown of SMAD4 attenuated irradiation-induced EMT arrest (Figure 6m and n). Thereafter, SMAD4 might have anti-cancer effects and sensitized CRC to irradiation treatment.

Figure 6 Inhibition of miR-766 suppresses cell growth and enhances radiosensitivity in CRC via SMAD4. (a–l) HCT116 and DLD1 cells were co-transfected with anti-miR-NC, anti-miR-766, anti-miR-766 + si-NC, or anti-miR-766 + si-SMAD4. (a and b) qRT-PCR and western blot analysis of SMAD4 expression in HCT116 and DLD1 cells. (c and d) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (e and f) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (g and h) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (i and j) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (k–n) Western blot analysis of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. *P < 0.05.
Figure 6

Inhibition of miR-766 suppresses cell growth and enhances radiosensitivity in CRC via SMAD4. (a–l) HCT116 and DLD1 cells were co-transfected with anti-miR-NC, anti-miR-766, anti-miR-766 + si-NC, or anti-miR-766 + si-SMAD4. (a and b) qRT-PCR and western blot analysis of SMAD4 expression in HCT116 and DLD1 cells. (c and d) CCK-8 assay for the proliferation of HCT116 and DLD1 cells. (e and f) Flow cytometry for cell cycle distribution in HCT116 and DLD1 cells. (g and h) Colony formation assay for survival fraction in transfected HCT116 and DLD1 cells exposed to various doses of irradiation (0, 2, 4, or 6 Gy). (i and j) Flow cytometry for the apoptosis of transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. (k–n) Western blot analysis of Bax, Bcl-2, E-cadherin, and Vimentin protein levels in transfected HCT116 and DLD1 cells exposed to 0 or 6 Gy irradiation. *P < 0.05.

Then rescue assay was conducted. miR-766 inhibitor suppressed cell proliferation (Figure 6c and d) and resulted in cell cycle arrest (Figure 6e and f) in HCT116 and DLD1 cells, while these effects were attenuated by SMAD4 knockdown (Figure 6c–f). Then transfected cells were exposed to various doses of irradiation (0, 2, 4, or 6 Gy). It was discovered that miR-766 inhibitor promoted the inhibitory effect of irradiation on HCT116 and DLD1 cell survival, evidenced by the decreased cell survival fraction, which was rescued by SMAD4 silencing (Figure 6g and h). Moreover, inhibition of miR-766 combined with irradiation elevated cell apoptosis rate in HCT116 and DLD1 cells, while co-transection of miR-766 inhibitor and SMAD4 siRNA showed decreased ratio of apoptotic HCT116 and DLD1 cells (Figure 6i–l). Conclusively, we conducted western blot analysis and showed that miR-766 inhibitor combined with irradiation suppressed EMT process, which were reversed by SMAD4 silencing (Figure 6m and n). Collectively, these data demonstrated that inhibition of miR-766 could suppress cell growth and enhance radiosensitivity in CRC in a SMAD4-dependent manner.

3.7 circ_ITGA7/miR-766 axis mediates SMAD4 expression

We have shown that SMAD4 was involved in the tumorigenesis of CRC, and a potent transcription target of miR-766. Thus, we validated that circ_ITGA7/miR-766 axis indeed affected the SMAD4 expression by the competing endogenous RNA hypothesis. As shown in Figure 7a and b, it was observed that circ_ITGA7 could up-regulate SMAD4 mRNA and protein expression levels in HCT116 and DLD1 cells, which were reduced by miR-766 overexpression. Therefore, we concluded that circ_ITGA7 could regulate SMAD4 expression via sponging miR-766.

Figure 7 circ_ITGA7/miR-766 axis mediates SMAD4 expression. (a and b) qRT-PCR and western blot analysis of SMAD4 levels in HCT116 and DLD1 cells transfected with Vector, circ_ITGA7, circ_ITGA7 + miR-NC, or circ_ITGA7 + miR-766. *P < 0.05.
Figure 7

circ_ITGA7/miR-766 axis mediates SMAD4 expression. (a and b) qRT-PCR and western blot analysis of SMAD4 levels in HCT116 and DLD1 cells transfected with Vector, circ_ITGA7, circ_ITGA7 + miR-NC, or circ_ITGA7 + miR-766. *P < 0.05.

3.8 circ_ITGA7 impedes tumor growth and enhances irradiation sensitivity in vivo

We further clarified the role of circ_ITGA7 in vivo. A xenograft model was established by injecting Lenti-circ_ITGA7 or Lenti-NC-infected HCT116 cells into mice. Consistent with in vitro results, circ_ITGA7 overexpression reduced tumor volume and weight; moreover, circ_ITGA7 overexpression combined with irradiation led to a synergistic inhibition on tumor growth (Figure 8a and b). After that, molecular analysis was performed. As exhibited in Figure 8c–f, we found that circ_ITGA7 and SMAD4 expression levels were increased and miR-766 expression was decreased in circ_ITGA7-overexpressed tumor group; importantly, these effects could be enhanced by irradiation treatment. Besides that, western blot analysis also showed that circ_ITGA7 overexpression led to the decrease of PCNA, a key factor in DNA replication and cell cycle regulation, combined with Bcl-2 decrease and Bax up-regulation, two pro-apoptosis markers, in xenograft tumors, and these effects mediated by circ_ITGA7 were reinforced by irradiation treatment (Figure 8g). These data suggested in vivo that the up-regulation of circ_ITGA7 was sufficient to sensitize CRC xenografts to irradiation and suppressed CRC xenograft growth.

Figure 8 circ_ITGA7 impedes tumor growth and enhances irradiation sensitivity in vivo. (a) Tumor volume of each group was measured every 5 days starting 10 days after inoculation. (b) Tumor weight of each group was analyzed at Day 40 and the representative images of xenografts are shown. (c–f) qRT-PCR and western blot analysis of circ_ITGA7, miR-766, and SMAD4 expression levels in tumors isolated from mice of each group. (g) Western blot analysis of PCNA, Bcl-2, and Bax protein levels in tumors isolated from mice of each group. *P < 0.05.
Figure 8

circ_ITGA7 impedes tumor growth and enhances irradiation sensitivity in vivo. (a) Tumor volume of each group was measured every 5 days starting 10 days after inoculation. (b) Tumor weight of each group was analyzed at Day 40 and the representative images of xenografts are shown. (c–f) qRT-PCR and western blot analysis of circ_ITGA7, miR-766, and SMAD4 expression levels in tumors isolated from mice of each group. (g) Western blot analysis of PCNA, Bcl-2, and Bax protein levels in tumors isolated from mice of each group. *P < 0.05.

4 Discussion

CRC is the fourth most common cause of cancer death in the world with a high rate of incidence [16]. Preoperative RT is the primary treatment modality for CRC patients, which leads to DNA double-stranded breaks via direct DNA ionization or indirect reactive oxygen species stimulation [3]. Moreover, increasing evidence reports that neoadjuvant chemoradiotherapy benefits in controlling the local recurrence and improving the outcome of rectal cancer [17,18]. However, the occurrence of therapy resistance has been found in CRC patients which causes the failure in improving the outcomes.

Recently, it has been revealed that circRNAs have roles in regulating tumorigenesis and RT sensitization in CRC through modulating biological behaviors including cell cycle, proliferation, and apoptosis [19,20]. For instance, Bian’s team showed that hsa_circRNA_103809 impaired CRC cell migration and growth via increasing FOXO4 level through miR-532-3p [8]. Knockdown of hsa_circ_0001313 enhanced radiosensitivity by reducing cancer cell proliferation and promoting cell apoptosis through miR-338-3p [21]. Thus, targeting circRNAs may be an innovative anti-tumor approach for CRC treatment. In this study, we found that circ_ITGA7 expression was lower in CRC. Functional studies suggested the anti-cancer roles of circ_ITGA7 in restraining cell proliferation and cell cycle progression. In addition, it was also confirmed that circ_ITGA7 combined with irradiation treatment significantly reduced CRC cell survival, enhanced cell apoptosis, and arrest EMT process. Besides that, xenograft formation assay revealed that circ_ITGA7 suppressed CRC tumor growth and sensitized the CRC xenografts to irradiation in vivo. Besides, we also observed that radiation treatment could increase circ_ITGA7 level in CRC tumors; however, the mechanism is still unknown, and it shall be explored in future studies.

Previous studies have documented that circRNAs located in the cytoplasm can participate in gene regulation at the posttranscriptional level by acting as miRNA sponges [22,23]. This study confirmed that circ_ITGA7 was preferentially localized in the cytoplasm; therefore, the direct miRNAs interacted by circ_ITGA7 were then investigated. We confirmed that circ_ITGA7 directly targeted miR-766. Besides that, we also verified that SMAD4 was a target of miR-766; moreover, circ_ITGA7 could competitively bind with miR-766 to prevent the degradation of SMAD4. Collectively, a circ_ITGA7/miR-766/SMAD4 regulatory network was identified in CRC cells.

miR-766 is a functional miRNA, and has been demonstrated to be associated with diverse cancers. However, the action of miR-766 is complicated. It was identified to act as tumor suppressor in triple negative breast cancer [24] and papillary thyroid cancer [25], or function as onco-miR in hepatocellular carcinoma [26] and lung adenocarcinoma [27]. In CRC, Li et al. showed that miR-766 served as an oncogene to promote CRC cell growth by increasing cyclin D1 and decreasing p21 through SOX6 [28]. However, whether miR-766 was involved in therapeutic resistance remained unknown. SMDA4 is a member signal transduction protein family, phosphorylated and activated by transmembrane serine–threonine receptor kinases [29]. It is a central mediator of TGF-β signaling, which plays significant roles in cancer occurrence and progression [30]. The loss of SMAD4 was related to the recurrence, immune infiltrate, and chemoresistance in CRC [31]. Besides, loss of SMAD4 led to the poor outcome in CRC and contributed to CRC metastasis by regulating CCL15-CCR1 signaling [32]. Moreover, SMAD4 inactivation increased malignancy and chemoradiation resistance in CRC [33,34]. In the current review, we demonstrated that miR-766 promoted CRC cell growth and reduced irradiation sensitization, which was attenuated by SMAD4 knockdown. Importantly, miR-766 overexpression abolished the effects of circ_ITGA7 on CRC cell growth and RT sensitivity.

In conclusion, this study demonstrated that circ_ITGA7 suppressed CRC growth and enhanced RT sensitization by miR-766/SMAD4 axis (Figure 9), providing a new insight into the enhancement of irradiation therapy efficacy in CRC therapy.

Figure 9 A schematic diagram illustrating how the circ_ITGA7/miR766/SMAD4 axis regulates CRC cell growth and radiosensitivity.
Figure 9

A schematic diagram illustrating how the circ_ITGA7/miR766/SMAD4 axis regulates CRC cell growth and radiosensitivity.

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Acknowledgement

Not applicable.

  1. Funding information: No funding was received.

  2. Conflict of interest: The authors declare that they have no competing interest.

  3. Data availability statement: The analyzed datasets generated during the present study are available from the corresponding author on reasonable request.

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Received: 2022-01-18
Revised: 2022-09-23
Accepted: 2022-10-18
Published Online: 2023-01-11

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2022-0604
Schlagwörter für diesen Artikel
circ_ITGA7; miR-766; SMAD4; tumorigenicity; radioresistance
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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Heruntergeladen am 8.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2022-0604/html
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