Home Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
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Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis

  • Ximin Wang , Dongxu Zheng EMAIL logo , Changting Wang and Wanhua Chen
Published/Copyright: May 9, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Radiotherapy resistance is a challenge for colorectal cancer (CRC) treatment. Circular RNAs (circRNAs) play vital roles in the occurrence and development of CRC. This study aimed to investigate the role of circ_0005615 in regulating the radiosensitivity of CRC. The levels of circ_0005615, microRNA-665 (miR-665), and notch receptor 1 (NOTCH1) were detected by quantitative real-time PCR or western blot. The radiosensitivity of CRC cells was assessed by colony formation assay. Cell viability, apoptosis, and colony formation were assessed by Cell Counting Kit-8 assay, flow cytometry, and colony formation assay. Cell migration and invasion were confirmed by transwell assay and scratch assay. The binding relationship between miR-665 and circ_0005615 or NOTCH1 was verified by dual-luciferase reporter assay. Xenograft assay was used to test the effect of circ_0005615 on radiosensitivity in vivo. circ_0005615 and NOTCH1 were up-regulated, and miR-665 was down-regulated in CRC tissues and cells. Radiation decreased circ_0005615 and NOTCH1 levels and increased miR-665 level. Knockdown of circ_0005615 enhanced radiosensitivity of CRC cells. Moreover, circ_0005615 sponged miR-665 to regulate the radioresistance of CRC cells. Besides, miR-665 targeted NOTCH1 to mediate the radiosensitivity of CRC cells. Furthermore, circ_0005615 depletion increased CRC radiosensitivity in vivo. circ_0005615 silencing elevated radiosensitivity of CRC by regulating miR-665/NOTCH1 axis.

Keywords: circular RNAs; circ_0005615; miR-665; NOTCH1; colorectal cancer; radiosensitivity

1 Introduction

Colorectal cancer (CRC) is a common malignancy, ranking third in cancer incidence and second in mortality [1]. Unfortunately, CRC is usually asymptomatic in the early stage, and diagnosis often occurs in the advanced stage [2]. Surgery combined with adjuvant chemotherapy and radiotherapy is the preferred choice for CRC patients [3]. Additionally, a combination of radiotherapy and chemotherapy is considered a common treatment for locally advanced CRC [4]. Nevertheless, acquired or inherent drug resistance and radioresistance lead to limited therapeutic effects [5]. Therefore, revealing the molecular regulation of drug resistance and radioresistance is crucial for CRC treatment.

Circular RNAs (circRNAs) are single-stranded molecules with covalent closed-loop structures and no 5′ to 3′ polarity [6,7]. Mounting evidence has elucidated that circRNAs are abnormally expressed in cancer and are strongly related to tumor progression [8]. Besides, numerous investigations have highlighted that circRNA dysregulation exerts a crucial regulatory effect on the radiosensitivity of solid tumor cells [9–11]. For instance, circRNA_0000285 was prominently up-regulated in patients with radioresistant nasopharyngeal carcinoma, indicating that circRNA_0000285 might participate in radiosensitivity [12]. In addition, circ_VCAN in cancer cells was significantly down-regulated after irradiation, and circ_VCAN accelerated glioma progression and decreased radiosensitivity of glioma via combining with microRNA-1183 [13]. Moreover, circRNA_014511 facilitated carcinogenesis and reduced the radiosensitivity of bone marrow mesenchymal stem cells via absorbing microRNA-29b-2-5p [14]. Besides, interference of circ_0007031 suppressed tumor cell growth and reduced chemoradiotherapy resistance in CRC [15]. A recent research revealed that circ_0005615 derived from the nuclear factor of activated T cells 3 was highly expressed in CRC, and circ_0005615 silencing impeded cell proliferation and accelerated cell cycle arrest [16]. However, the role of circ_0005615 in radiotherapy has not been studied.

Furthermore, mounting evidence has demonstrated that circRNAs competitively bind to microRNAs (miRNAs), thereby indirectly regulating mRNA expression [17]. Additionally, substantial studies have suggested that some miRNAs can serve as detection factors for the radiosensitivity of cancer [18]. For example, miR-122-5p targeted CCAR1 to accelerate radiation-induced rectal injury and functioned as a radiosensitizer [19]. Chen et al. unveiled that miR-450a-5p restrained autophagy and elevated radiosensitivity in esophageal squamous cell carcinoma through inhibition of DUSP10 [20]. Also, Huang et al. discovered that miR-181a enhanced the radioresistance of nasopharyngeal carcinoma via negatively regulating RKIP [21]. Previous research showed that miR-665 was strikingly down-regulated in CRC [22]. Nonetheless, the function of miR-665 in CRC radiotherapy remains unknown. Apart from that, previous research indicated that notch receptor 1 (NOTCH1) is an oncogene and is corrected with radio-resistance in various cancers [23,24]. Herein, according to bioinformatics analysis, miR-665 was found to possess some binding sites with circ_0005615 or NOTCH1. Therefore, we hypothesized that the regulatory role of circ_0005615 on radio-resistance in CRC might be mediated by the miR-665/NOTCH1 axis.

2 Materials and methods

2.1 Clinical specimens

Thirty CRC tissues and matched adjacent normal tissues were collected from 30 CRC patients, containing 14 patients with primary CRC (the less-radiosensitive group) and 16 with recurrent CRC (the high-radiosensitive group) after radiation treatment, recruited at the Second Affiliated Hospital of Fujian Medical University. All tissue samples were stored at −80°C immediately after resection. The clinicopathological parameters of CRC patients are presented in Table 1.

Table 1

Correlation between circ_0005615 expression and clinicopathological parameters of CRC patients

Parameter Case circ_0005615 expression P valuea
Low (n = 15) High (n = 15)
Age (years) 0.273
 ≤50 15 9 6
 >50 15 6 9
Gender 0.269
 Female 13 8 5
 Male 17 7 10
Tumor size 0.001*
 ≤5 cm 15 12 3
 >5 cm 15 3 12
TNM stage 0.003*
 I–II 18 13 5
 III 12 2 10
Lymphatic metastasis 0.003*
 Negative 16 12 4
 Positive 14 3 11

Note: *P < 0.05, aChi-square test.

  1. Ethical approval: All participants carefully read and signed the written informed consent. This research was ratified by the Ethics Committee of the Second Affiliated Hospital of Fujian Medical University. The research has been carried out in accordance with the World Medical Association Declaration of Helsinki, and all subjects provided written informed consent.

2.2 Cell culture and radiation treatment

CRC cell lines (LOVO and SW480) were purchased from the American Type Culture Collection (cat. nos. CCL-229 and CCL-228; ATCC, Manassas, VA, USA). Normal colonic epithelial cells (NCM460) were bought from Fuyuanbio (Shanghai, China). All cells were cultured in RPMI-1640 medium (Hyclone, Logan, UT, USA) supplemented with 10% fetal bovine serum (FBS; Hyclone) and maintained in an incubator with 5% CO2 at 37°C.

To maintain the radioresistance phenotype, LOVO and SW480 cells were exposed to different doses of 6 MV X-ray (0, 2, 4, 6 and 8 Gy) using a linear accelerator (Varian, Palo Alto, CA, USA). Also, the resistant cells were cultured in a medium containing 6 Gy 6 MV X-ray. After 24 h of irradiation, RNA was collected and used in subsequent experiments.

2.3 Cell transfection

circ_0005615 small interfering RNA (si-circ_0005615; 5′-ATTTCGATCTTGAGCCAGA-3′) and the control (si-NC; 5′-CGTTATTACTTGAGCCAGA-3′), miR-665 mimic and negative control (miRNA NC), miR-665 inhibitor and negative control (inhibitor NC), NOTCH1 overexpression vector (pc-NOTCH1) and the control (pc-NC) were purchased from Genechem (Shanghai, China). The oligonucleotides or vectors were introduced into LOVO and SW480 cells at 60% confluency using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA).

2.4 Quantitative real-time PCR (qRT-PCR)

RNA isolation was performed using Trizol reagent (Solarbio, Beijing, China). Then, the complementary DNA (cDNA) was synthesized using the specific reverse transcription kit (Vazyme, Nanjing, China). Subsequently, the RNA level was examined via AceQ qPCR SYBR Green Master Mix (Vazyme) and quantified via the 2−ΔΔCt method. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) acted as the internal reference to normalize the expression of circ_0005615 and NOTCH1, and U6 was used as the endogenous control to normalize the expression of miR-665. All primers were shown: circ_0005615-F: 5′-TCACCCTTTACCTGGAGCAAA-3′, circ_0005615-R: 5′-GAGCTGAAACGATGGTGACAAA-3′; miR-665-F: 5′-ACCAGGAGGCTGAGGC-3′, miR-665-R: 5′-GAACATGTCTGCGTATCTC-3′; NOTCH1-F: 5′-GAGGCGTGGCAGACTATGC-3′, NOTCH1-R: 5′-CTTGTACTCCGTCAGCGTGA-3′; GAPDH-F: 5′-GAAGGTGAAGGTCGGAGT-3′, GAPDH-R: 5′-GATGGCAACAATATCCACTT-3′; and U6-F: 5′-CTCGCTTCGGCAGCACA-3′, U6-R: 5′-ACGCTTCACGAATTTGCGT-3′.

2.5 Nuclear and cytoplasmic fraction assay

The subcellular localization of circ_0005615 was evaluated using mirVanaTM PARIS Kit (Invitrogen). GAPDH and U6 were regarded as positive controls for cytoplasmic and nuclear fractions, respectively.

2.6 Colony formation assay

Treated LOVO and SW480 cells were maintained in six-well plates and cultured for 48 h. Subsequently, the cells were treated with various doses of irradiation (0, 2, 4, 6, and 8 Gy). Then, the cells were incubated for 2 weeks at 37°C. After staining with 1% crystal violet (Beyotime, Shanghai, China), the colonies were counted under a microscope.

2.7 Cell viability assay

To detect cell viability, Cell Counting Kit-8 (CCK-8) kit (Beyotime) was used in this study. Treated LOVO and SW480 cells (2.0 × 103) were injected into 96-well plates. After incubation at 37°C for 24 h, the cells were reacted with 10 µL CCK-8 solution (Beyotime) for 4 h. Then, cell viability was evaluated by measuring optical density using a Microplate Reader (BioTek, Burlington, VT, USA).

2.8 Flow cytometry

Cell apoptosis was monitored using Annexin V-FITC/propidium iodide (PI) Apoptosis Detection kit (Vazyme) according to the manufacturer’s instructions. After LOVO and SW480 cells were treated with 6 Gy irradiation alone or combined with transfection, the cells were stained with Annexin V-FITC and PI. Subsequently, the apoptosis rate was tested by FACScan Flow Cytometer (BD Biosciences, San Diego, CA, USA).

2.9 Transwell assay

Cell migration and invasion were assessed using 24-transwell plates with 8 μm pore inserts (Corning, Corning, NY, USA) and transwell chambers with Matrigel (Corning)-precoated inserts, respectively. In short, treated LOVO and SW480 cells were seeded into the upper chamber, and the lower chamber was filled with RPMI-1640 medium containing 10% FBS (Hyclone). After incubation for 24 h, the cells migrated/invaded into the lower surface of the membranes were fixed with methanol and stained with 0.5% crystal violet (Beyotime). Then, the stained cells were counted under a microscope at 100× magnification.

2.10 Scratch assay

To check tumor cell migration ability, treated LOVO and SW480 cells (5 × 105) were plated in six-well plates. Subsequently, the cells were scratched with a sterilized pipette tip and the floating cells were removed with PBS (Hyclone). After culturing for 0 or 24 h, the images were taken under a microscope at 100× magnification, and the migrated distance was calculated using ImageJ 1.8.0 software (National Institutes of Health, Bethesda, MD, USA). The migration rate was calculated using the following formula: Migration rate (%) = (S0 h – S24 h)/S0 h × 100. S0 h represents the distance of the scratch at 0 h and S24 h represents the distance at 24 h.

2.11 Dual-luciferase reporter assay

To verify the interaction between miR-665 and circ_0005615 or NOTCH1, dual-luciferase reporter assay was conducted. The sequences of circ_0005615 or NOTCH1 3′-UTR harboring miR-665 wild-type or mutant binding sites were cloned into the pmirGLO vector (LMAI Bio, Shanghai, China) to form WT-circ_0005615, MUT-circ_0005615, WT-NOTCH1-3′-UTR, or MUT-NOTCH1-3′-UTR, respectively. Then, the luciferase reporter and miRNA NC or miR-665 mimic were introduced into LOVO and SW480 cells. The luciferase intensity was determined via Dual-Lucy Assay Kit (Solarbio).

2.12 Western blot assay

Protein was extracted using RIPA buffer (Solarbio). Then, equal amounts of protein samples were separated by polyacrylamide gel electrophoresis and transferred onto polyvinylidene fluoride membranes (Millipore, Billerica, MA, USA). After blocking with 5% skimmed milk for 2 h, the membranes were probed with primary antibodies against NOTCH1 (ab52627, 1:1,500; Abcam, Cambridge, UK) or GAPDH (ab9485, 1:2,500; Abcam) at 4°C overnight. Afterward, the membranes interacted with a secondary antibody (ab205718, 1:20,000; Abcam) for 2 h at room temperature. Finally, the signal intensity was measured by ECL reagent (Millipore).

2.13 Xenograft assay

The experiment was approved by the Animal Ethics Committee of the Second Affiliated Hospital of Fujian Medical University. LOVO cells (5 × 106) stably transfected with sh-NC or sh-circ_0005615 (Genechem) were subcutaneously injected into the right back of BALB/c nude mice (5-week-old; n = 10). Nude mice were divided into two groups. One week after injection, the mice received 6 Gy irradiation every 2 days. Tumor volume was monitored once a week. Four weeks later, the mice were sacrificed and the xenograft tumors were weighed. In addition, the levels of circ_0005615, miR-665, and NOTCH1 in xenograft tissues were measured using qRT-PCR and western blot. Animal studies were performed in compliance with the ARRIVE guidelines and the Basel Declaration. All animals received humane care according to the National Institutes of Health (USA) guidelines.

2.14 Statistical analysis

All data were displayed as mean ± standard deviation (SD) in three independent replicates by using Graphpad Prism 7.0 software (GraphPad, San Diego, CA, USA). Student’s t-test and one-way analysis of variance were utilized to assess statistical differences. P < 0.05 was considered statistically significant.

3 Results

3.1 circ_0005615 is up-regulated in CRC tissues and cells

To explore the role of circ_0005615 in CRC, we first determined the expression of circ_0005615 in CRC tissues and normal tissues. As depicted in Figure 1a, circ_0005615 level was increased in CRC tissues compared with normal tissues. In order to check the function of circ_0005615 in radioresistance, its expression was measured in the less-radiosensitive group (n = 14) or the high-radiosensitive group (n = 16). Compared with the less-radiosensitive group, circ_0005615 level was apparently enhanced in the high-radiosensitive group (Figure 1a). Similarly, circ_0005615 expression was strikingly higher in LOVO (2.32-fold) and SW480 cells (2.98-fold) than that in NCM460 cells (Figure 1b). In addition, nuclear and cytoplasmic fraction assay suggested that circ_0005615 was mainly distributed in the cytoplasm (Figure 1c and d). As shown in Table 1, circ_0005615 expression was not associated with age and gender but was related to tumor size, TNM stage, and lymphatic metastasis. These data hinted that circ_0005615 might play an oncogene role in CRC.

Figure 1 circ_0005615 is up-regulated in CRC tissues and cells. (a) circ_0005615 expression in normal tissues (n = 30), the less-radiosensitive group (n = 14), and the high-radiosensitive group (n = 16) was examined by qRT-PCR. (b) The level of circ_0005615 was measured in NCM460, LOVO, and SW480 cells (n = 3). (c and d) Levels of circ_0005615, GAPDH, and U6 were detected in nuclear and cytoplasmic fractions (n = 3). Data are shown as mean ± SD. *P < 0.05.
Figure 1

circ_0005615 is up-regulated in CRC tissues and cells. (a) circ_0005615 expression in normal tissues (n = 30), the less-radiosensitive group (n = 14), and the high-radiosensitive group (n = 16) was examined by qRT-PCR. (b) The level of circ_0005615 was measured in NCM460, LOVO, and SW480 cells (n = 3). (c and d) Levels of circ_0005615, GAPDH, and U6 were detected in nuclear and cytoplasmic fractions (n = 3). Data are shown as mean ± SD. *P < 0.05.

3.2 Depletion of circ_0005615 enhances the radiosensitivity of CRC cells

To illuminate the function of circ_0005615 in radiosensitivity, loss-of-function experiments were carried out in LOVO and SW480 cells transfected with si-NC or si-circ_0005615. First, qRT-PCR confirmed that the knockdown efficiency of circ_0005615 was significant in LOVO (with a 70% reduction) and SW480 (with a 79% reduction) cells (Figure 2a). Moreover, colony formation assay showed that circ_0005615-silenced CRC cells were more sensitive to X-ray irradiation (Figure 2b and c). Meanwhile, radiation reduced the expression of circ_0005615 in a dose-dependent manner (Figure 2d and e). Next, LOVO and SW480 cells were treated with 6 Gy irradiation alone or together with si-circ_0005615. CCK-8 analysis showed that radiation treatment remarkably reduced the viability of LOVO and SW480 cells, and si-circ_0005615 transfection enhanced this effect (Figure 2f). Flow cytometry suggested that circ_0005615 knockdown strengthened the promotion of cell apoptosis caused by radiation alone (Figure 2g). Colony formation assay exhibited that radiation significantly decreased the number of colonies in LOVO and SW480 cells, and this change was enhanced after the introduction of si-circ_0005615 (Figure 2h). Besides, transwell and scratch assays showed that circ_0005615 silence aggravated the inhibitory effect of radiation on cell migration and invasion (Figure 2i–k). Collectively, these data evidenced that circ_0005615 knockdown increased the radiosensitivity of CRC cells.

Figure 2 Depletion of circ_0005615 enhances the radiosensitivity of CRC cells. (a) Transfection efficiency of si-circ_0005615 in LOVO and SW480 cells was determined by qRT-PCR. (b and c) Colony formation assay was performed in LOVO and SW480 cells transfected with si-NC or si-circ_0005615 exposed to different doses of X-ray. (d and e) Expression of circ_0005615 was examined in LOVO and SW480 cells treated with various doses of X-ray. After LOVO and SW480 cells were exposed to 6 Gy irradiation alone or in combination with si-circ_0005615, cell viability (f), apoptosis (g), colony number (h), migration and invasion (i and j), and migratory rate (k) were detected by CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay. Data are shown as mean ± SD, n = 3. *P < 0.05.
Figure 2

Depletion of circ_0005615 enhances the radiosensitivity of CRC cells. (a) Transfection efficiency of si-circ_0005615 in LOVO and SW480 cells was determined by qRT-PCR. (b and c) Colony formation assay was performed in LOVO and SW480 cells transfected with si-NC or si-circ_0005615 exposed to different doses of X-ray. (d and e) Expression of circ_0005615 was examined in LOVO and SW480 cells treated with various doses of X-ray. After LOVO and SW480 cells were exposed to 6 Gy irradiation alone or in combination with si-circ_0005615, cell viability (f), apoptosis (g), colony number (h), migration and invasion (i and j), and migratory rate (k) were detected by CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay. Data are shown as mean ± SD, n = 3. *P < 0.05.

3.3 circ_0005615 directly interacts with miR-665

The online database circinteractome predicted that circ_0005615 contained a possible miR-665 binding site (Figure 3a). Subsequently, the miR-665 level was prominently increased in LOVO (16.39-fold) and SW480 (21.25-fold) cells transfected with miR-665 mimic compared to the control group (Figure 3b). Dual-luciferase reporter assay was performed to verify the relationship between circ_0005615 and miR-665, and the results showed that miR-665 mimic overtly reduced the luciferase activity of WT-circ_0005615 reporter (Figure 3c and d). Compared with the control group, miR-665 expression was strikingly decreased in CRC tissues (with a 65% reduction) and cells (LOVO cells with a 55% decrease, SW480 cells with a 67% reduction) (Figure 3e and f). Next, the knockdown efficiency of miR-665 was determined by transfecting miR-665 inhibitor into LOVO (with a 70% decrease) and SW480 cells (with an 80% reduction) (Figure 3g). Furthermore, silencing of circ_0005615 remarkably increased miR-665 level, while the change was abrogated after transfection with the miR-665 inhibitor (Figure 3h). In addition, 6 Gy irradiation elevated miR-665 expression in LOVO (2.51-fold) and SW480 (2.36-fold) cells (Figure 3i).

Figure 3 circ_0005615 directly interacts with miR-665. (a) Putative binding site of miR-665 in circ_0005615 is shown. (b) Overexpression efficiency of miR-665 was detected using qRT-PCR (n = 3). (c and d) Luciferase activity was tested in LOVO and SW480 cells co-transfected with WT-circ_0005615 or MUT-circ_0005615 and miRNA NC or miR-665 mimic (n = 3). (e) miR-665 level was determined in CRC tissues and adjacent normal tissues (n = 30). (f) miR-665 level was examined in NCM460, LOVO, and SW480 cells (n = 3). (g) Transfection efficiency of miR-665 inhibitor was detected by qRT-PCR (n = 3). (h) miR-665 level was measured in LOVO and SW480 cells transduced with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor (n = 3). (i) Expression of miR-665 was detected in LOVO and SW480 cells treated with 6 Gy irradiation (n = 3). Data are shown as mean ± SD. *P < 0.05.
Figure 3

circ_0005615 directly interacts with miR-665. (a) Putative binding site of miR-665 in circ_0005615 is shown. (b) Overexpression efficiency of miR-665 was detected using qRT-PCR (n = 3). (c and d) Luciferase activity was tested in LOVO and SW480 cells co-transfected with WT-circ_0005615 or MUT-circ_0005615 and miRNA NC or miR-665 mimic (n = 3). (e) miR-665 level was determined in CRC tissues and adjacent normal tissues (n = 30). (f) miR-665 level was examined in NCM460, LOVO, and SW480 cells (n = 3). (g) Transfection efficiency of miR-665 inhibitor was detected by qRT-PCR (n = 3). (h) miR-665 level was measured in LOVO and SW480 cells transduced with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor (n = 3). (i) Expression of miR-665 was detected in LOVO and SW480 cells treated with 6 Gy irradiation (n = 3). Data are shown as mean ± SD. *P < 0.05.

3.4 circ_0005615 affects the radiosensitivity of CRC cells via regulating miR-665

To investigate whether circ_0005615 targeted miR-665 to modulate the radiosensitivity of CRC cells, LOVO and SW480 cells were introduced with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor, followed by 6 Gy radiation treatment. CCK-8 and flow cytometry assays exhibited that circ_0005615 knockdown inhibited cell viability and induced apoptosis in LOVO and SW480 cells, whereas these effects were partially alleviated by down-regulating miR-665 (Figure 4a and b). Moreover, transfection with miR-665 inhibitor partially attenuated the reduction in colony number caused by circ_0005615 silencing (Figure 4c). Additionally, down-regulation of circ_0005615 impeded the migration and invasion of LOVO and SW480 cells, while these impacts were overturned by inhibiting miR-665 (Figure 4d–f). Overall, these data indicated that circ_0005615 depletion increased the radiosensitivity of CRC cells by modulating miR-665.

Figure 4 circ_0005615 affects the radiosensitivity of CRC cells via regulating miR-665. LOVO and SW480 cells were transfected with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor and then exposed to 6 Gy irradiation. Cell viability (a), apoptosis (b), colony number (c), migration and invasion (d and e), and migratory rate (f) were examined using CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay, respectively. Data are shown as mean ± SD, n = 3. *P < 0.05.
Figure 4

circ_0005615 affects the radiosensitivity of CRC cells via regulating miR-665. LOVO and SW480 cells were transfected with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor and then exposed to 6 Gy irradiation. Cell viability (a), apoptosis (b), colony number (c), migration and invasion (d and e), and migratory rate (f) were examined using CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay, respectively. Data are shown as mean ± SD, n = 3. *P < 0.05.

3.5 NOTCH1 is a target of miR-665

TargetScan prediction software showed that miR-665 and NOTCH1 3′-UTR had an assumed binding site (Figure 5a). Next, dual-luciferase reporter assay suggested that miR-665 mimic significantly decreased the luciferase activity of WT-NOTCH1 3′-UTR reporter (Figure 5b and c). As shown in Figure 5d, the NOTCH1 mRNA level in CRC tissues (1.51-fold) was markedly higher than that in normal tissues. Also, the NOTCH1 protein level in LOVO (1.96-fold) and SW480 (2.26-fold) cells was overtly increased in comparison with NCM460 cells (Figure 5e). Western blot assay exhibited that the overexpression efficiency of NOTCH1 was significant (Figure 5f). Moreover, the introduction of miR-665 mimic suppressed the expression of NOTCH1, while co-transfection of miR-665 mimic and pc-NOTCH1 mitigated the inhibitory effect (Figure 5g). Furthermore, inhibition of miR-665 reversed the decline in NOTCH1 protein level caused by circ_0005615 knockdown (Figure 5h). Besides, NOTCH1 protein expression was strikingly repressed in LOVO (with a 43% decrease) and SW480 cells (with a 54% reduction) exposed to 6 Gy irradiation (Figure 5i).

Figure 5 NOTCH1 is a target of miR-665. (a) Putative binding site of miR-665 in NOTCH1 3′-UTR was displayed. (b and c) Luciferase activity was detected in LOVO and SW480 cells co-transfected with WT-NOTCH1-3′-UTR or MUT-NOTCH1-3′-UTR and miRNA NC or miR-665 mimic (n = 3). (d) NOTCH1 mRNA level was examined in CRC tissues and adjacent normal tissues (n = 30). (e) NOTCH1 protein level was measured in NCM460, LOVO, and SW480 cells (n = 3). (f) NOTCH1 protein expression was determined in LOVO and SW480 cells transfected with pc-NC or pc-NOTCH1 (n = 3). (g) NOTCH1 protein level was detected in LOVO and SW480 cells transfected with miRNA NC, miR-665 mimic, miR-665 mimic + pc-NC, or miR-665 mimic + pc-NOTCH1 (n = 3). (h) NOTCH1 protein level was measured in LOVO and SW480 cells transfected with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor (n = 3). (i) NOTCH1 protein level was detected in LOVO and SW480 cells treated with 6 Gy irradiation (n = 3). Data are shown as mean ± SD. *P < 0.05.
Figure 5

NOTCH1 is a target of miR-665. (a) Putative binding site of miR-665 in NOTCH1 3′-UTR was displayed. (b and c) Luciferase activity was detected in LOVO and SW480 cells co-transfected with WT-NOTCH1-3′-UTR or MUT-NOTCH1-3′-UTR and miRNA NC or miR-665 mimic (n = 3). (d) NOTCH1 mRNA level was examined in CRC tissues and adjacent normal tissues (n = 30). (e) NOTCH1 protein level was measured in NCM460, LOVO, and SW480 cells (n = 3). (f) NOTCH1 protein expression was determined in LOVO and SW480 cells transfected with pc-NC or pc-NOTCH1 (n = 3). (g) NOTCH1 protein level was detected in LOVO and SW480 cells transfected with miRNA NC, miR-665 mimic, miR-665 mimic + pc-NC, or miR-665 mimic + pc-NOTCH1 (n = 3). (h) NOTCH1 protein level was measured in LOVO and SW480 cells transfected with si-NC, si-circ_0005615, si-circ_0005615 + inhibitor NC, or si-circ_0005615 + miR-665 inhibitor (n = 3). (i) NOTCH1 protein level was detected in LOVO and SW480 cells treated with 6 Gy irradiation (n = 3). Data are shown as mean ± SD. *P < 0.05.

3.6 miR-665 mimic increases the radiosensitivity of CRC cells by targeting NOTCH1

To elucidate the association between miR-665 and NOTCH1 in the radiosensitivity of CRC cells, LOVO and SW480 cells transfected with miRNA NC, miR-665 mimic, miR-665 mimic + pc-NC, or miR-665 mimic + pc-NOTCH1 were treated with 6 Gy radiation. First, CCK-8 and flow cytometry assays revealed that miR-665 overexpression repressed cell viability and triggered apoptosis in LOVO and SW480 cells, while these changes were abolished after transfection with pc-NOTCH1 (Figure 6a and b). In addition, up-regulation of NOTCH1 alleviated the inhibition of miR-665 mimic on the proliferation of LOVO and SW480 cells (Figure 6c). Furthermore, transwell and scratch assays suggested that NOTCH1 overexpression attenuated the inhibitory effect of miR-665 mimic on the migration and invasion of LOVO and SW480 cells (Figure 6d–f). Collectively, these data evidenced that overexpression of miR-665 enhanced the radiosensitivity of CRC cells by regulating NOTCH1.

Figure 6 miR-665 mimic increases the radiosensitivity of CRC cells by targeting NOTCH1. LOVO and SW480 cells were introduced with miRNA NC, miR-665 mimic, miR-665 mimic + pc-NC, or miR-665 mimic + pc-NOTCH1 and then treated with 6 Gy irradiation. Cell viability (a), apoptosis (b), colony number (c), migration and invasion (d and e), and migratory rate (f) were detected using CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay, respectively. Data are shown as mean ± SD, n = 3. *P < 0.05.
Figure 6

miR-665 mimic increases the radiosensitivity of CRC cells by targeting NOTCH1. LOVO and SW480 cells were introduced with miRNA NC, miR-665 mimic, miR-665 mimic + pc-NC, or miR-665 mimic + pc-NOTCH1 and then treated with 6 Gy irradiation. Cell viability (a), apoptosis (b), colony number (c), migration and invasion (d and e), and migratory rate (f) were detected using CCK-8 assay, flow cytometry, colony formation assay, transwell, and scratch assay, respectively. Data are shown as mean ± SD, n = 3. *P < 0.05.

3.7 circ_0005615 silencing increases radiosensitivity in vivo

To explore the influence of circ_0005615 on radiosensitivity in vivo, we constructed a xenograft model. As illustrated in Figure 7a, tumor volume in the 6 Gy + sh-circ_0005615 group was markedly decreased compared to the 6 Gy + sh-NC group. Four weeks later, tumor weight in the 6 Gy + sh-circ_0005615 group was significantly reduced relative to the control group (Figure 7b). Additionally, silencing of circ_0005615 inhibited the expression of circ_0005615 and NOTCH1 and induced the expression of miR-665 (Figure 7c–e). These data indicated that circ_0005615 knockdown elevated radiosensitivity in vivo.

Figure 7 circ_0005615 silencing increases the radiosensitivity in vivo. Transfected LOVO cells with sh-circ_0005615 or sh-NC were subcutaneously injected into the nude mice. One week after injection, the tumors of the mice were exposed to 6 Gy radiation. (a) Tumor volume was measured once a week. (b) Mice were sacrificed 4 weeks later, and the tumors were removed and weighed. (c–e) Levels of circ_0005615, miR-665, and NOTCH1 in xenograft tumors were measured by qRT-PCR or western blot assay. Data are shown as mean ± SD, n = 5. *P < 0.05.
Figure 7

circ_0005615 silencing increases the radiosensitivity in vivo. Transfected LOVO cells with sh-circ_0005615 or sh-NC were subcutaneously injected into the nude mice. One week after injection, the tumors of the mice were exposed to 6 Gy radiation. (a) Tumor volume was measured once a week. (b) Mice were sacrificed 4 weeks later, and the tumors were removed and weighed. (c–e) Levels of circ_0005615, miR-665, and NOTCH1 in xenograft tumors were measured by qRT-PCR or western blot assay. Data are shown as mean ± SD, n = 5. *P < 0.05.

4 Discussion

Conventional surgical treatment combined with chemotherapy and radiotherapy has become the preferred strategy for the CRC [25]. Stereotactic body radiotherapy is a novel and effective therapy in the treatment of metastatic CRC [26]. Adjuvant radiotherapy reduces CRC recurrence rate and improves the survival rate [27]. Nonetheless, the emergence of radioresistance has become a huge obstacle to cancer therapy [28,29]. Radiation contributes to cancer cell death by regulating cell proliferation and apoptosis through the modulation of signaling pathways [30]. In-depth exploration of the molecular regulation of radioresistance is essential to improve the efficacy of radiotherapy. In recent years, some studies have manifested that not only lncRNAs and miRNAs, but also circRNAs are implicated in radiotherapy resistance of various cancers. It has been reported that dysregulated circ_0005615 was closely associated with the formation and development in different tumors [31,32], containing CRC [16]. However, the role and mechanism of circ_0005615 on radioresistance in CRC is still unclear. In the current research, our data first exhibited a competing endogenous RNAs (ceRNAs) network of circ_0005615/miR-665/NOTCH1 that was correlated with the radiosensitivity of CRC cells.

Here, we found that circ_0005615 content was obviously upregulated in CRC tissues and cell lines, consistent with a previous report [16]. Interestingly, our results identified high-level circ_0005615 might be associated with radioresistance in CRC for the first time, implying the positive effect of circ_0005615 in CRC. We inferred that the exact roles of circRNAs in cancers might be induced owing to the alteration of the tumor microenvironment. Under 6 Gy irradiation, circ_0005615 absence might improve radiosensitivity in CRC cells with the decrease in cell proliferation, migration, invasion, and increase in apoptosis. In addition, the radioresistence of circ_0005615 was verified on CRC xenografts in nude mice. These findings indicated the inimical function of circ_0005615 in radiotherapy for CRC patients.

In terms of mechanism, circRNAs regulate tumor progression by participating in many pathways, including serving as miRNA sponges [33]. For instance, circPITX1 silencing sensitized glioma to irradiation by declining glycolysis via competitively binding miR-329-3p to up-regulate NEK2 [34]. Liu et al. showed that circRNA_100367 strengthened the radioresistance of esophageal squamous cell carcinoma through functioning as a ceRNA for miR-217 and elevating Wnt3 [35]. Chen et al. disclosed that circRNA_000543 alleviated the radiosensitivity of nasopharyngeal carcinoma via sponging miR-9 and increasing PDGFRB expression [36]. In this research, we verified that circ_0005615 sponged miR-665 in CRC cells. Additionally, previous studies unveiled that miR-665 plays opposite roles in different cancers due to the differences in the tumor microenvironment. For example, miR-665 aggravated the malignancy of ovarian cancer via repressing SRCIN1 [37]. In gastric cancer, miR-665 hindered tumor growth and metastasis through down-regulating PPP2R2A [38]. In hepatocellular carcinoma, miR-665 facilitated cell proliferation and mobility via modulating PTPRB to inactivate Hippo signaling [39]. Hence, we selected miR-665 as the miRNA target of circ_0005615 for research. In the current research, rescue experiments suggested miR-665 knockdown abolished the effect of circ_0005615 silencing on CRC radiosensitivity.

Furthermore, substantial evidence has highlighted that miRNAs contribute to gene silencing via base-pairing with 3′-UTR of target genes [40]. Therefore, we searched the downstream target genes of miR-665 in the prediction database and identified NOTCH1 as the research object. Notch signaling exerts a crucial effect on tumorigenesis by regulating cell growth and development [41]. Revealing the interaction between Notch receptors and other pathways in CRC contributed to the exploration of the pathogenesis of CRC [42]. Besides, NOTCH1 is closely associated with radiation resistance in several cancers, including glioma [43], adenoid cystic carcinoma [44], and lung cancer [45]. Zhang et al. revealed that the depletion of NOTCH1 enhanced the radiosensitivity of CRC cells [46]. In this report, NOTCH1 up-regulation abrogated the effect of miR-665 mimic on CRC radiosensitivity.

In conclusion, our findings unveiled that circ_0005615 elevated NOTCH1 expression by acting as a ceRNA for miR-665. Also, circ_0005615 strengthened the radioresistance of CRC via regulating miR-665/NOTCH1 signaling (Figure 8), suggesting that circ_0005615 might be a promising biomarker for CRC radiotherapy.

Figure 8 Schematic diagram of the regulation of circ_0005615/miR-665/NOTCH1 signaling pathway in colorectal cancer.
Figure 8

Schematic diagram of the regulation of circ_0005615/miR-665/NOTCH1 signaling pathway in colorectal cancer.

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Acknowledgement

Not applicable.

  1. Funding information: This work was supported by Shaanxi Provincial Key Research and Development Program 2021SF-125.

  2. Author contributions: Conceptualization and methodology: Dongxu Zheng and Changting Wang; formal analysis and data curation: Changting Wang and Wanhua Chen; validation and investigation: Ximin Wang and Dongxu Zheng; writing – original draft preparation and writing – review and editing: Ximin Wang, Dongxu Zheng and Changting Wang; approval of final manuscript: all authors.

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

  4. 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: 2022-04-16
Revised: 2023-01-27
Accepted: 2023-02-07
Published Online: 2023-05-09

© 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-2023-0678
Keywords for this article
circular RNAs; circ_0005615; miR-665; NOTCH1; colorectal cancer; radiosensitivity
Creative Commons
BY 4.0

Articles in the same Issue

  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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