Startseite circ_0005962 functions as an oncogene to aggravate NSCLC progression
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circ_0005962 functions as an oncogene to aggravate NSCLC progression

  • Zhihong Zhang , Zhenxiu Shan , Rubin Chen , Xiaorong Peng , Bin Xu , Liang Xiao und Guofei Zhang EMAIL logo
Veröffentlicht/Copyright: 2. Juli 2021
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Open Medicine
Aus der Zeitschrift Open Medicine Band 16 Heft 1

Abstract

Background

Non-small cell lung cancer (NSCLC) is a leading threat to human lives with high incidence and mortality. Circular RNAs were reported to play important roles in human cancers. The purpose of this study was to investigate the role of circ_0005962 and explore the underlying functional mechanisms.

Methods

The protein levels of Beclin 1, light chain3 (LC3-II/LC3-I), Pyruvate dehydrogenase kinase 4 (PDK4), Cleaved Caspase 3 (C-caspase 3), and proliferating cell nuclear antigen were examined using western blot analysis. Glycolysis was determined according to the levels of glucose consumption and lactate production. Xenograft model was constructed to investigate the role of circ_0005962 in vivo.

Result

circ_0005962 expressed with a high level in NSCLC tissues and cells. circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but promoted apoptosis in NSCLC cells. miR-382-5p was targeted by circ_0005962, and its inhibition reversed the role of circ_0005962 knockdown. Besides, PDK4, a target of miR-382-5p, was regulated by circ_0005962 through miR-382-5p, and its overexpression abolished the effects of miR-382-5p reintroduction. circ_0005962 knockdown suppressed tumor growth in vivo.

Conclusion

circ_0005962 knockdown restrained cell proliferation, autophagy, and glycolysis but stimulated apoptosis through modulating the circ_0005962/miR-382-5p/PDK4 axis. Our study broadened the insights into understanding the mechanism of NSCLC progression.

Keywords: circ_0005962; miR-382-5p; PDK4; NSCLC

1 Introduction

Lung cancer is a leading cause of cancer-related death worldwide [1]. Lung cancer is the second most common cancer among men and women: second only to prostate cancer in men, and second only to breast cancer in women [2]. Non-small cell lung cancer (NSCLC) and small cell lung cancer are two types of lung cancer, and NSCLC accounts for about 85% of all lung cancer cases [3]. NSCLC, including large cell carcinoma, squamous cell carcinoma, and adenocarcinoma, is associated with high incidence and mortality [4,5]. Clinically, treatment modalities, including chemotherapy and surgery, are used to treat NSCLC, but the 5-year overall survival rate for all stages of NSCLC patients is only 16% [2,6]. The severe situation of NSCLC treatment makes it urgent to further explore the mechanism of occurrence and development of NSCLC to establish novel therapeutic strategies.

Circular RNAs (circRNAs) belong to non-coding RNAs and derive from precursor mRNAs by “back-splicing.” circRNAs are mostly detected in the cytoplasm and function as competing endogenous RNAs (ceRNAs) to work as microRNA (miRNA) sponges [7,8,9]. Advances of high-throughput RNA sequencing in the identification of circRNAs hinted that circRNAs participated in the pathogenesis of cancers [10]. Recent studies stated that circRNAs played vital roles in the development of NSCLC. For example, circ_100146 functioned as an oncogene, and its suppression hindered cell proliferation and invasion [11]. circP4HB overexpression promoted epithelial–mesenchymal transition (EMT), thus inducing metastatic ability in NSCLC [12]. circRNA F-circEA-2a contributed to cell migration and invasion but had little role in cell proliferation [13]. A former study obtained dozens of circRNAs through the circBase database and CSCD database for comparison between lung adenocarcinoma tissues and paired non-tumor tissues [14], and circ_0005962, back-spliced from tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), was one of the significantly upregulated circRNAs and had valuable prognostic significance. However, the understanding of the specific roles of circ_0005962 in NSCLC remained lacking and requires further exploration.

miRNAs are known as small non-coding RNAs with 18–23 nucleotides [15]. It is well documented that circRNAs played functions by acting as miRNA sponges [9]. Interestingly, bioinformatics analysis found that miR-382-5p was a potential target of circ_0005962. miR-382-5p was frequently mentioned in different cancers, including glioma, oral squamous cell carcinoma, and breast cancer [16,17,18]. Unfortunately, the role of miR-382-5p in NSCLC was largely unknown, and the interactions between circ_0005962 and miR-382-5p had not been declared.

One of the important functions of pyruvate dehydrogenase kinase (PDK) is to regulate the metabolic conversion from mitochondrial respiration to cytoplasmic glycolysis [19]. Glycolysis is a preferential way for tumor cells to obtain energy [20]. Pyruvate dehydrogenase kinase 4 (PDK4), one of the PDK family protein kinases, is located on chromosome 7q21.3 [21]. PDK4 was reported to be implicated in numerous cellular activities, such as cell proliferation, metastasis, drug resistance, glycolysis, and autophagy in different types of cancers [21,22,23]. Intriguingly, bioinformatics analysis discovered that PDK4 was a putative target of miR-382-5p, which was further clarified in NSCLC development in our study.

In the present study, we measured the expression of circ_0005962 in NSCLC tissues and cells. Functional analyses revealed the role of circ_0005962 in cell proliferation, autophagy, glycolysis, and apoptosis. Besides, we constructed circRNA–miRNA–mRNA regulatory axis to expound the potential mechanism of circ_0005962 in NSCLC. Our study aimed to provide new sights for the understanding of NSCLC development and supply promising biomarkers.

2 Materials and methods

2.1 Tissues and cell lines

A total of 45 tumor tissues and adjacent normal tissues from NSCLC patients were collected from Gong’an County People’s Hospital. Informed consent was signed by each subject. All tissues were immediately placed into liquid nitrogen and stored at −80°C ultra low-temperature refrigerator. This research obtained the approval of the Ethics Committee of Gong’an County People’s Hospital.

NSCLC cell lines (A549 and HCC827) and human bronchial epithelial cells (BEAS-2B) were purchased from Zishi Biotechnology (Shanghai, China). A549 and HCC827 cells were maintained in 90% Roswell Park Memorial Institute 1640 (RPMI 1640; Sigma, St. Louis, MO, USA) containing 10% fetal bovine serum (FBS; Sigma). BEAS-2B cells were cultured in 90% Dulbecco’s Modified Eagle Medium (DMEM; Sigma) containing 10% FBS (Sigma). All mediums were placed at 37°C containing 5% CO2.

2.2 Quantitative real-time polymerase chain reaction (qPCR)

Trizol reagent (Beyotime, Shanghai, China) was utilized to isolate total RNA from tissues and cells. The complementary DNA (cDNA) was assembled using the riboSCRIPT Reverse Transcription Kit (Ribobio, Guangzhou, China). Then the amplification reaction was carried out using SYBR Green Master PCR mix (Beyotime) through the ABI 7900 system (Applied Biosystems, Foster City, CA, USA). The relative expression was normalized using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or small nuclear RNA U6 and calculated using 2−ΔΔCt method. The primers used were listed as below:

circ_0005962, F: 5′-AACTCCCCAGAGAAAGCCTGC-3′ and R: 5′-TGCTTGTGAAGCATTGGGGAT-3′; YWHAZ, F: 5′-ACTTTTGGTACATTGTGGCTTCAA-3′ and R: 5′-CCGCCAGGACAAACCAGTAT-3′; PDK4, F: 5′-GGAGCATTTCTCGCGCTACA-3′ and R: 5′-ACAGGCAATTCTTGTCGCAAA-3′; GAPDH, F: 5′-CTGGGCTACACTGAGCACC-3′ and R: 5′-AAGTGGTCGTTGAGGGCAATG-3′; miR-382-5p, F: 5′-ATCCGTGAAGTTGTTCGTGG-3′ and R: 5′-TATGGTTGTAGAGGACTCCTTGAC-3′; U6, F: 5′-CTCGCTTCGGCAGCACATATACT-3′ and R: 5′-ACGCTTCACGAATTTGCGTGTC-3′.

2.3 Chromogenic in situ hybridization (CISH) assay

Digoxigenin (DIG)-labeled circ_0005962 probe at the 5′ and 3′ ends was synthesized by Sangon Biotech (Shanghai, China). Tissue microarray which contained 45 cases with paired tumor tissues and non-tumor tissues was used to perform CISH analysis. In brief, paraffin tissue slides were incubated with proteinase K (20 µg/mL; Servicebio, Wuhan, China; 37°C, 30 min). The slides were then used for prehybridization in a hybridization solution (Servicebio) at 37°C for 1 h, followed by incubation with fresh hybridization solution containing 500 nM of the corresponding probe at 4°C overnight. Slides were washed and blocked in serum-containing BSA for 30 min. The immunological reaction was carried out using anti-DIG-AP antibody (Roche, Basel, Switzerland) according to the manufacturer’s protocol. The expression of circ_0005962 was detected by the BCIP/NBT substrates (Boster, Wuhan, China), and the stained specimens were observed using a bright field microscopy.

2.4 RNase R treatment

To confirm the stability and tolerance of circ_0005962, the RNA extraction was probed with or without RNase R (Applied Biological Materials Inc., Vancouver, Canada) at 37°C for 10 min. Then, the qPCR analysis was conducted as described above.

2.5 Cell transfection

Small interference RNA against circ_0005962 and negative control were synthesized by Sangon Biotech (Shanghai, China). The mimics of miR-382-5p (miR-382-5p), the inhibitor of miR-382-5p (anti-miR-382-5p), and respective negative control (NC or anti-NC) were purchased from Ribobio (Shanghai, China). The overexpression of circ_0005962 (circ_0005962) was performed as the previous study described [24] and constructed by Genechem (Shanghai, China), while the specific plasmid without the circ_0005962 cDNA was served as a control (circ-NC). The vector pcDNA3.1-PDK4 for the overexpression of PDK4 and the control pcDNA empty vector (vector) were constructed by Sangon Biotech. Lentiviral vector (Lenti-short hairpin) for stable NEAT1 downregulation (Lv-sh-circ_0005962) and the corresponding negative control (Lv-sh-NC) were obtained from Genechem. Cell transfection was conducted using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA). Transfection efficiency and the following experiments were implemented after 48 h of transfection.

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

Cell proliferation was investigated using CCK-8 assay. A549 or HCC827 cells with different transfection were seeded into 96-well plates (5 × 103 cells/well). Then, cells interacted with CCK-8 solution (Beyotime) continuously for 2 h at 24, 48, and 72 h. The absorbance at 450 nm was measured using a microplate reader (Bio-Rad, Hercules, CA, USA).

2.7 Flow cytometry assay

Flow cytometry was applied to monitor cell apoptosis. After 48 h, A549 or HCC827 cells with different transfection were washed with phosphate buffer saline (PBS), probed with 0.25% trypsin, and resuspended in binding buffer. Afterward, the Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit (Sigma) was used to doubly stain cells for 15 min in the dark. Eventually, the apoptotic cells were sorted using CellQuest software under a flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA).

2.8 Western blot

The western blot analysis was performed in line with a previous study described [25]. In brief, total proteins were separated and transferred into polyvinylidene fluoride (PVDF) membranes (Bio-Rad). After the block, the membranes were incubated with the primary antibodies and the secondary antibodies. Finally, the seeking proteins were visualized using the enhanced chemiluminescent reagent (Beyotime) through an imaging system (Bio-Rad). The antibodies used were listed as follows: anti-Beclin 1 (1:1,000; cat. no. ab210498; Abcam, Cambridge, MA, USA), anti-light chain3 (LC3) (1:2,000; cat. no. ab192890), anti-PDK4 (1:1,000; cat. no. ab89295), anti-Cleaved Caspase 3 (C-caspase 3) (1:1,000; cat. no. ab2302), anti- proliferating cell nuclear antigen (PCNA) (1:1,000; cat. no. ab92552), anti-GAPDH (1:1,000; cat. no. ab8245), and the horseradish peroxidase-conjugated secondary antibodies (1:5,000; cat. no. ab205718).

2.9 Detection of glucose consumption and lactate production

A549 or HCC827 cells with different transfection were planted into 96-well plates. After 48 h, cells were collected, washed three times with PBS, and then used for the detection of glucose consumption and lactate production using the Glucose Uptake Colorimetric Assay Kit and Lactate Assay Kit (Sigma) in agreement with the manufacturer’s instructions.

2.10 Bioinformatics analysis

The targets of circRNA and miRNA were forecasted, and their binding sites were analyzed by the online bioinformatics tool circInteractome (https://circinteractome.nia.nih.gov/) and starbase (http://starbase.sysu.edu.cn/).

2.11 Dual-luciferase reporter assay

The dual-luciferase reporter assay was carried out for the verification of the relationship between miR-382-5p and circ_0005962 or PDK4. The partial frame of circ_0005962 containing the binding site or mutant binding site (wild-type or mutant-type) with miR-382-5p was amplified and cloned into the downstream of pGL4 vector (Promega, Madison, WI, USA) to generate circ_0005962-wt and circ_0005962-mut fusion plasmids. Likewise, the 3′UTR sequences of PDK4 harboring the binding site with miR-382-5p or mutant binding site (wild-type or mutant-type) were also amplified and inserted into the downstream of pGL4 vector to generate PDK4-wt and PDK-mut fusion plasmids. Subsequently, these fusion plasmids and miR-382-5p or NC were co-transfected into A549 and HCC827 cells, respectively. After 48 h, the cells were collected and detected using the Dual-luciferase assay system (Promega). The firefly luciferase activity was normalized by Renilla luciferase activity.

2.12 RNA immunoprecipitation (RIP) assay

RIP assay was executed to further confirm the relationship between miR-382-5p and circ_0005962 or PDK4. In one case, A549 and HCC827 cells were harvested and incubated with RNA lysis buffer. Then, cell lysate was incubated with RIP binding buffer containing magnetic beads coated with human Ago2 antibody or mouse IgG antibody (control) (Millipore, Billerica, MA, USA). Subsequently, the levels of circ_0005962 and miR-382-5p enriched in the beads were detected by qPCR. In another case, A549 and HCC827 cells transfected with miR-382-5p were lysed in RIP buffer with anti-Ago2- or IgG-bound magnetic beads. Next, the mRNA level of PDK4 enriched in the beads was examined by qPCR.

2.13 In vivo experiment

The mice experiment was approved by the Animal Care and Use Committee of Gong’an County People’s Hospital. A total of 10 BALB/c nude mice (5-week-old, male) were purchased from HFK Bioscience (Beijing, China). A549 cells with Lv-sh-circ_0005962 or Lv-sh-NC transfection were subcutaneously injected into the back right flank of nude mice, dividing into the Lv-sh-circ_0005962 and Lv-sh-NC groups. Tumor volume was observed and recorded once a week following the algorithm (length × width2 × 0.5), lasting 5 weeks. In the end, the mice were killed, and tumor samples were removed for weighting and further molecular studies.

2.14 Data analysis

The data were obtained from at least three times independent experimental analyses and conducted using SPSS 18.0 software (SPSS, Inc., Chicago, IL, USA). The survival curve was depicted via the Kaplan–Meier method. The correlation analysis was performed based on Spearman’s correlation coefficient. Differences between the two groups were analyzed by Student’s t-test or one-way analysis of variance among multiple groups. The data after processing were presented as the mean ± standard deviation, and P < 0.05 was considered to be statistically significant.

3 Result

3.1 High expression of circ_0005962 was observed in NSCLC tissues and cells and predicted the low survival rate of NSCLC patients

The expression of circ_0005962 was detected in NSCLC tissues and cell lines to observe whether circ_0005962 was aberrantly regulated in NSCLC. As shown in Figure 1a, the expression of circ_0005962 was significantly higher in tumor tissues (n = 45) than that in adjacent normal tissues (n = 45), and the data of circ_0005962 expression from CISH analysis was consistent with the data from qPCR. Besides, the expression of circ_0005962 was abundant in A549 and HCC827 cells relative to BEAS-2B cells (Figure 1b). Moreover, the survival curve was depicted utilizing Kaplan–Meier survival rate analysis according to the living status of NSCLC patients, and we found that the survival rate of patients with high expression of circ_0005962 was notably weaker compared with patients with low circ_0005962 expression (Figure 1c). Additionally, the result of qPCR showed that the expression of circ_0005962 decreased a little with the treatment of RNase R, while the expression of the parental linear mRNA (YWHAZ) was significantly reduced with the treatment of RNase R, indicating that circ_0005962 was resistant to RNase R (Figure 1d). The data indicated that circ_0005962 was aberrantly upregulated in NSCLC.

Figure 1 circ_0005962 was highly expressed in NSCLC tissues and cells. (a) The expression of circ_0005962 in tumor tissues (n = 45) and adjacent normal tissues (n = 45) was detected by qPCR. (b) The expression of circ_0005962 in NSCLC cell lines (A549 and HCC827) and normal cells (BEAS-2B) was detected by qPCR. (c) The survival curve was depicted according to the Kaplan–Meier plot and analyzed by the log-rank test. (d) The tolerance of circ_0005962 and corresponding linear RNA to RNase was measured according to their mRNA levels. *P < 0.05.
Figure 1

circ_0005962 was highly expressed in NSCLC tissues and cells. (a) The expression of circ_0005962 in tumor tissues (n = 45) and adjacent normal tissues (n = 45) was detected by qPCR. (b) The expression of circ_0005962 in NSCLC cell lines (A549 and HCC827) and normal cells (BEAS-2B) was detected by qPCR. (c) The survival curve was depicted according to the Kaplan–Meier plot and analyzed by the log-rank test. (d) The tolerance of circ_0005962 and corresponding linear RNA to RNase was measured according to their mRNA levels. *P < 0.05.

3.2 circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but promoted apoptosis in NSCLC cells

The endogenous level of circ_0005962 was knocked down to investigate the role of circ_0005962 in NSCLC cells. Si-circ_0005962 was inserted into the mature sequence of circ_0005962 to reduce circ_0005962 expression, with si-NC as a control (Figure 2a). Then, the knockdown efficiency was examined by qPCR, and the result showed that the expression of circ_0005962 in A549 and HCC827 cells with si-circ_0005962#1, si-circ_0005962#2, and si-circ_0005962#3 transfection was notably decreased compared to si-NC, and the knockdown efficiency in the si-circ_0005962#1 group was the highest (Figure 2b). Hence, si-circ_0005962#1 was chosen for the following analyses. The result of CCK-8 assay revealed that cell proliferation was prominently suppressed in A549 and HCC827 cells transfected with si-circ_0005962#1 (Figure 2c). On the contrary, flow cytometry assay presented that the apoptosis rate in A549 and HCC827 cells with si-circ_0005962#1 transfection was inversely enhanced (Figure 2d). Besides, the protein levels of autophagy-related markers were quantified to assess the change of autophagy, and we found that the levels of Beclin 1 and LC3-II/LC3-I were declined with circ_0005962 knockdown (Figure 2e and f). Moreover, the level of glucose in the culture medium and the production of lactate were checked to assess glycolysis progression, and we noticed that the level of existing glucose in A549 and HCC827 cells with si-circ_0005962#1 transfection was higher than that with si-NC transfection, suggesting that the consumptive glucose was reduced (Figure 2g). The level of lactate production was significantly blocked in A549 and HCC827 cells with si-circ_0005962#1 transfection relative to si-NC (Figure 2h). All data clarified that circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but induced apoptosis in NSCLC cells.

Figure 2 circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but contributed to apoptosis in NSCLC cells. (a) The diagram of circ_0005962 knockdown. (b) The efficiency of circ_0005962 knockdown in different transfection lines was detected by qPCR. A549 and HCC827 cells were transfected with si-circ_0005962#1 or si-NC. (c) Cell proliferation was assessed by CCK-8 assay. (d) Cell apoptosis was executed by flow cytometry assay. (e and f) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (g and h) The glycolysis progression was evaluated according to the level of glucose in culture medium and lactate production. *P < 0.05.
Figure 2

circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but contributed to apoptosis in NSCLC cells. (a) The diagram of circ_0005962 knockdown. (b) The efficiency of circ_0005962 knockdown in different transfection lines was detected by qPCR. A549 and HCC827 cells were transfected with si-circ_0005962#1 or si-NC. (c) Cell proliferation was assessed by CCK-8 assay. (d) Cell apoptosis was executed by flow cytometry assay. (e and f) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (g and h) The glycolysis progression was evaluated according to the level of glucose in culture medium and lactate production. *P < 0.05.

3.3 miR-382-5p was a target of circ_0005962

To determine whether circ_0005962 functioned by acting as a ceRNA to modulate the expression of target miRNAs, the putative target miRNAs were predicted by the online tool circInteractome. The analysis showed that miR-382-5p was one of target miRNAs of circ_0005962 with specific binding sites (Figure 3a). To ascertain the relationship between circ_0005962 and miR-382-5p, dual-luciferase reporter assay and RIP assay were performed. The luciferase activity in A549 and HCC827 cells with circ_0005962-wt and miR-382-5p transfection was substantially decreased compared with circ_0005962-wt and NC transfection, while the luciferase activity in A549 and HCC827 cells with circ_0005962-mut and miR-382-5p transfection was unchanged compared with circ_0005962-mut and NC transfection (Figure 3b). RIP analysis presented that both circ_0005962 and miR-382-5p were significantly enriched in the Ago2 pellet of A549 and HCC827 lysate compared to IgG control (Figure 3c). Moreover, qPCR analysis exhibited that the expression of miR-382-5p was notably declined with circ_0005962 overexpression but improved with circ_0005962 knockdown in A549 and HCC827 cells (Figure 3d). Additionally, the expression of miR-382-5p in NSCLC tumor tissues (n = 45) was markedly weaker than that in normal tissues (n = 45) (Figure 3e). The expression of miR-382-5p was also lower in A549 and HCC827 cells than that in BEAS-2B cells (Figure 3f). Spearman’s correlation coefficient revealed that circ_0005962 expression was negatively correlated with miR-382-5p expression in NSCLC tissues (Figure 3g). These analyses maintained that miR-382-5p was a target of circ_0005962, and its expression was suppressed by circ_0005962.

Figure 3 miR-382-5p was a target of circ_0005962. (a) The binding sites between circ_0005962 and miR-382-5p were analyzed by the online tool circInteractome. (b) The relationship between circ_0005962 and miR-382-5p was verified by dual-luciferase reporter assay. (c) The relationship between circ_0005962 and miR-382-5p was further confirmed by RIP assay. (d) The expression of miR-382-5p in A549 and HCC827 cells transfected with circ_0005962 or si-circ_0005962 was detected by qPCR. (e and f) The expression of miR-382-5p in NSCLC tissues and cell lines was detected by qPCR. (g) The correlation between circ_0005962 and miR-382-5p was analyzed by Spearman’s correlation coefficient. *P < 0.05.
Figure 3

miR-382-5p was a target of circ_0005962. (a) The binding sites between circ_0005962 and miR-382-5p were analyzed by the online tool circInteractome. (b) The relationship between circ_0005962 and miR-382-5p was verified by dual-luciferase reporter assay. (c) The relationship between circ_0005962 and miR-382-5p was further confirmed by RIP assay. (d) The expression of miR-382-5p in A549 and HCC827 cells transfected with circ_0005962 or si-circ_0005962 was detected by qPCR. (e and f) The expression of miR-382-5p in NSCLC tissues and cell lines was detected by qPCR. (g) The correlation between circ_0005962 and miR-382-5p was analyzed by Spearman’s correlation coefficient. *P < 0.05.

3.4 Inhibition of miR-382-5p reversed the role of circ_0005962 knockdown in NSCLC cells

A549 and HCC827 cells were introduced with si-circ_0005962#1, si-NC, si-circ_0005962#1 + anti-miR-382-5p and si-circ_0005962#1 + anti-NC, respectively. First, the expression of miR-382-5p in these transfected cells was checked, and we found that the expression of miR-382-5p was enhanced in the si-circ_0005962#1 group but inhibited in the si-circ_0005962#1 + anti-miR-382-5p group (Figure 4a). Cell proliferation inhibited by si-circ_0005962#1 transfection was recovered in A549 and HCC827 cells with si-circ_0005962#1 + anti-miR-382-5p transfection (Figure 4b). The elevated apoptosis rate of cells with si-circ_0005962#1 transfection was suppressed in cells with si-circ_0005962#1 + anti-miR-382-5p transfection (Figure 4c). The protein levels of Beclin 1 and LC3-II/LC3-I were depleted in A549 and HCC827 cells transfected with si-circ_0005962#1 but restored in cells transfected with si-circ_0005962#1 + anti-miR-382-5p (Figure 4d and e). The level of existing glucose in medium in the si-circ_0005962#1 + anti-miR-382-5p group was declined than that in the si-circ_0005962#1 group (Figure 4f). The level of lactate production inhibited in the si-circ_0005962#1 group was largely promoted in the si-circ_0005962#1 + anti-miR-382-5p group (Figure 4g). These results indicated that circ_0005962 knockdown inhibited proliferation, autophagy, and glycolysis but induced apoptosis by enhancing the expression of miR-382-5p.

Figure 4 Inhibition of miR-382-5p reversed the role of circ_0005962 knockdown. A549 and HCC827 cells were introduced with si-circ_0005962#1, si-NC, si-circ_0005962#1 + anti-miR-382-5p or si-circ_0005962#1 + anti-NC. (a) The transfection efficiency was examined by qPCR. (b) Cell proliferation was assessed by CCK-8 assay. (c) Cell apoptosis was executed by flow cytometry assay. (d and e) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (f and g) The glycolysis progression was evaluated according to the levels of glucose in culture medium and lactate production. *P < 0.05.
Figure 4

Inhibition of miR-382-5p reversed the role of circ_0005962 knockdown. A549 and HCC827 cells were introduced with si-circ_0005962#1, si-NC, si-circ_0005962#1 + anti-miR-382-5p or si-circ_0005962#1 + anti-NC. (a) The transfection efficiency was examined by qPCR. (b) Cell proliferation was assessed by CCK-8 assay. (c) Cell apoptosis was executed by flow cytometry assay. (d and e) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (f and g) The glycolysis progression was evaluated according to the levels of glucose in culture medium and lactate production. *P < 0.05.

3.5 PDK4 was a target of miR-382-5p

The circRNA–miRNA–mRNA regulatory network is an important mechanism in the development of human cancers. The target mRNAs of miR-382-5p were analyzed to observe whether circ_0005962 played functions following this mechanism. Online bioinformatics tool starbase predicted that PDK4 was one of the targets of miR-382-5p with a specific binding site at its 3′UTR (Figure 5a). Besides, miR-382-5p overexpression predominantly inhibited the luciferase activity in A549 and HCC827 cells transfected with PDK4-wt but not PDK4-mut (Figure 5b). Moreover, the enrichment of PDK4 was notably elevated in the miR-382-5p-transfected group compared with that in the NC group after Ago2 RIP, while enrichment of PDK4 after IgG RIP showed no efficacy (Figure 5c). Next, western blot analysis monitored that the level of PDK4 was weakened in A549 and HCC827 cells with miR-382-5p transfection but elevated in cells with circ_0005962 + miR-382-5p transfection (Figure 5d). Also, the expression of PDK4 was detected in NSCLC tumor tissues, and the result presented that the expression of PDK4 at both mRNA and protein levels was abnormally higher in NSCLC tumor tissues (n = 45) relative to normal tissues (n = 45) (Figure 5e and f). Likewise, the protein level of PDK4 in A549 and HCC827 cells was also enhanced compared to BEAS-2B cells (Figure 5g). Furthermore, the mRNA level of PDK4 was positively correlated with circ_0005962 level but negatively correlated with the miR-382-5p level in NSCLC tissues (Figure 5h and i). All data suggested that PDK4 was a target of miR-382-5p, and circ_0005962 regulated the expression of PDK4 by targeting miR-382-5p.

Figure 5 PDK4 was a target of miR-382-5p. (a) The binding sites between PDK4 3′UTR and miR-382-5p were analyzed by online tool starbase. (b) The relationship between PDK4 and miR-382-5p was verified by dual-luciferase reporter assay. (c) The relationship between PDK4 and miR-382-5p was further confirmed by RIP assay. (d) The expression of PDK4 at the protein level in A549 and HCC827 cells transfected with miR-382-5p or circ_0005962 + miR-382-5p was detected by western blot. (e and f) The expression of PDK4 at mRNA and protein levels in NSCLC tissues was detected by qPCR and western blot. (g) The protein level of PDK4 in NSCLC cell lines was detected by western blot. (h and i) The correlation between PDK4 and circ_0005962 or miR-382-5p was analyzed by Spearman’s correlation coefficient. *P < 0.05.
Figure 5

PDK4 was a target of miR-382-5p. (a) The binding sites between PDK4 3′UTR and miR-382-5p were analyzed by online tool starbase. (b) The relationship between PDK4 and miR-382-5p was verified by dual-luciferase reporter assay. (c) The relationship between PDK4 and miR-382-5p was further confirmed by RIP assay. (d) The expression of PDK4 at the protein level in A549 and HCC827 cells transfected with miR-382-5p or circ_0005962 + miR-382-5p was detected by western blot. (e and f) The expression of PDK4 at mRNA and protein levels in NSCLC tissues was detected by qPCR and western blot. (g) The protein level of PDK4 in NSCLC cell lines was detected by western blot. (h and i) The correlation between PDK4 and circ_0005962 or miR-382-5p was analyzed by Spearman’s correlation coefficient. *P < 0.05.

3.6 PDK4 overexpression abolished the role of miR-382-5p reintroduction in NSCLC cells

A549 and HCC827 cells were introduced with miR-382-5p, NC, miR-382-5p + PDK4 and miR-382-5p + vector, respectively. The expression of PDK4 was examined to assess transfection efficiency, and the result showed that the level of PDK4 was obviously reduced in cells transfected with miR-382-5p but regained in cells transfected with miR-382-5p + PDK4 (Figure 6a). In function, cell proliferation was inhibited by the reintroduction of miR-382-5p but promoted by the combination of miR-382-5p reintroduction and PDK4 overexpression (Figure 6b). The apoptosis rate was elevated by miR-382-5p reintroduction but restrained by the combination of miR-382-5p reintroduction and PDK4 overexpression (Figure 6c). Moreover, the levels of Beclin1 and LC3-II/LC3-I were weakened in A549 and HCC827 cells transfected with miR-382-5p but rescued in cells transfected with miR-382-5p + PDK4 (Figure 6d and e). The existing glucose level was abundant in the miR-382-5p group but reduced in the miR-382-5p + PDK4 group, suggesting that PDK4 overexpression enhanced the level of glucose consumption inhibited by miR-382-5p reintroduction (Figure 6f). The level of lactate production was blocked by miR-382-5p reintroduction but recovered by the combination of miR-382-5p reintroduction and PDK4 overexpression (Figure 6g). These data hinted that miR-382-5p attenuated cell proliferation, autophagy, and glycolysis but contributed to apoptosis by inhibiting the expression of PDK4.

Figure 6 PDK4 overexpression abrogated the role of miR-382-5p reintroduction. A549 and HCC827 cells were transfected with miR-382-5p, NC, miR-382-5p + PDK4, or miR-382-5p + vector. (a) The transfection efficiency was checked according to the expression level of PDK4 using western blot. (b) Cell proliferation was assessed by CCK-8 assay. (c) Cell apoptosis was monitored by flow cytometry assay. (d and e) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (f and g) The glycolysis progression was evaluated according to the level of glucose in culture medium and lactate production. *P < 0.05.
Figure 6

PDK4 overexpression abrogated the role of miR-382-5p reintroduction. A549 and HCC827 cells were transfected with miR-382-5p, NC, miR-382-5p + PDK4, or miR-382-5p + vector. (a) The transfection efficiency was checked according to the expression level of PDK4 using western blot. (b) Cell proliferation was assessed by CCK-8 assay. (c) Cell apoptosis was monitored by flow cytometry assay. (d and e) The protein levels of Beclin 1 and LC3-II/LC3-I were quantified by western blot. (f and g) The glycolysis progression was evaluated according to the level of glucose in culture medium and lactate production. *P < 0.05.

3.7 circ_0005962 knockdown inhibited tumor growth in vivo

A549 cells with stable Lv-sh-circ_0005962 transfection were subcutaneously injected into the groin of nude mice to determine the role of circ_0005962 in vivo. As shown in Figure 7a and b, circ_0005962 knockdown remarkably reduced tumor volume and tumor weight. After injection for 5 weeks, all mice were killed, and the tumors were removed for expression analysis. The expression of circ_0005962 and PDK4 mRNA were noticeably declined in the Lv-sh-circ_0005962 group, while the expression of miR-382-5p was conspicuously strengthened in the Lv-sh-circ_0005962 group (Figure 7c). Besides, the protein level of PDK4 was consistent with its mRNA level. Additionally, the levels of apoptosis-related marker (C-caspase 3), proliferation-related marker (PCNA), and autophagy-related markers (Beclin 1 and LC3-II/LC3-I) were monitored, and we discovered that the level of C-caspase 3 was notably reinforced, while the levels of PCNA, Beclin 1, and LC3-II/LC3-I were notably impaired in the Lv-sh-circ_0005962 group (Figure 7d). Collectively, circ_0005962 knockdown impeded tumor growth in vivo.

Figure 7 circ_0005962 knockdown depleted tumor growth in vivo. (a) The tumor volume was recorded once a week, lasting 5 weeks. (b) The tumor weight was measured after 5 weeks. (c) The expression of circ_0005962, miR-382-5p, and PDK was examined in excised tumor tissues by qPCR. (d) The protein levels of PDK4, C-caspase 3, and PCNA were quantified by western blot. *P < 0.05.
Figure 7

circ_0005962 knockdown depleted tumor growth in vivo. (a) The tumor volume was recorded once a week, lasting 5 weeks. (b) The tumor weight was measured after 5 weeks. (c) The expression of circ_0005962, miR-382-5p, and PDK was examined in excised tumor tissues by qPCR. (d) The protein levels of PDK4, C-caspase 3, and PCNA were quantified by western blot. *P < 0.05.

4 Discussion

NSCLC is a severe burden to people’s lives, and the prognosis of NSCLC patients is still unsatisfactory. The responses to existing standard therapies are poor, except for the most localized cancers [26]. Hence, more novel mechanisms of NSCLC progression need to be explored to develop aimed therapeutic strategies for NSCLC. Here, we investigated the role of circ_0005962 in NSCLC for the first time. circ_0005962 was observed to be aberrantly overexpressed in NSCLC tissues and cells. Functional analysis concluded that circ_0005962 knockdown blocked NSCLC progression in vitro and in vivo. Stepwise identification manifested that circ_0005962 could directly bind to miR-382-5p, leading to an increase of PDK4 expression, thereby contributing to the development of NSCLC. Our study illustrated the importance and carcinogenesis of circ_0005962 in NSCLC.

circRNAs were documented to be dysregulated in numerous human cancers, their dysfunction took effects on apoptosis, autophagy, chemoresistance, metastasis, and glycolysis [27,28,29,30]. Up to now, dozens of NSCLC-related circRNAs were screened and identified, such as circ_100146, circ-PRMT5, and circ_0026134 [11,31], leading to the malignant progression of NSCLC via acting as oncogenes. On the contrary, certain circRNAs, such as circPTPRA, circ_0001946, and circSMARCA5 were maintained as tumor suppressors to block NSCLC deterioration [28,32,33]. These data suggested the diverse roles of circRNAs in cancer development. Despite the fact that the role of several circRNAs was partly characterized, numerous circRNAs were lacking functional exploration. A previous study predicted differentially expressed circRNAs in lung adenocarcinoma using Gene Expression Omnibus (GEO) dataset and found that circ_0005962 was highly expressed in lung adenocarcinoma plasma and cells [14]. In view of this finding, we speculated that dysregulation of circ_0005962 might be associated with the malignant progression of NSCLC. Interestingly, we discovered that circ_0005962 knockdown inhibited cell proliferation, autophagy, and glycolysis but accelerated cell apoptosis in vitro. The aggressive growth of cancer cells was satisfied by the enhanced glycolysis metabolism, and the inhibition of glycolysis was served as a strategy for cancer treatment [34]. Autophagy contributes to nutrient recycling and metabolic adaptation and plays a dichotomous role in cancer development, inhibiting tumor inhibition or promoting tumor progression [35]. Accumulating evidence suggests that autophagy inhibition is a promising approach for the treatment of advanced cancer [36]. Our findings showed that glycolysis and autophagy were blocked by circ_0005962 knockdown, strongly suggesting that circ_0005962 might function as an oncogene at least in NSCLC progression.

In our study, miR-382-5p was identified as a target of circ_0005962. The role of miR-382 in NSCLC was gradually clear to function as a tumor suppressor. For example, miR-382 suppressed proliferation and migration of NSCLC cells by binding to the 3′UTR of LMO3 [37]. Besides, miR-382 was significantly downregulated in NSCLC tissues and cells, and enrichment of miR-382 depleted cell proliferation, migration, and invasion through targeting SETD8 [38]. Consistent with these findings, we also detected that miR-382-5p was weakly expressed in NSCLC cells, and reintroduction of miR-382-5p inhibited proliferation, autophagy, and glycolysis of NSCLC cells. Besides, miR-382-5p inhibition reversed the regulatory effects of circ_0005962 knockdown.

Considering the habitual action mode of miRNAs, we further analyzed the potential target mRNAs of miR-382-5p to establish a detailed action mechanism of circ_0005962 in NSCLC. Among the mRNAs whose levels were increased in A549 and HCC827 cells, the increase of PDK4 expression was the most significant. Similarly, PDK4 has been reported to be highly expressed in cisplatin-resistant lung adenocarcinoma [39]. Besides, oncogene LINC00243 contributed to proliferation and glycolysis in NSCLC by positively regulating PDK4 [23]. Consistently, we also noticed that PDK4 overexpression eliminated the role of miR-382-5p reintroduction, leading to the malignant activities of NSCLC cells. These data indicated that PDK4 played a carcinogenic role in NSCLC.

Taken together, the expression of circ_0005962 was increased in NSCLC tissues and cell lines. Knockdown of LINC00243 blocked cell proliferation, autophagy, and glycolysis but accelerated cell apoptosis in vitro and weakened tumor growth in vivo. Moreover, circ_0005962 played these functions in NSCLC progression by activating the expression of PDK4 via sponging miR-382-5p. Our results not only corroborate the role of circ_0005962 in NSCLC but also provide the circ_0005962/miR-382-5p/PDK4 regulatory axis, which may be promising to develop novel therapeutic approaches for NSCLC.

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  1. Funding information: This work was supported by study on the sensitization effect of EGFR inhibitors on radiotherapy combined with PD-L1 inhibitor to stimulate the remote effect (WJ2019H173).

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

  3. Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Received: 2020-07-30
Revised: 2021-02-19
Accepted: 2021-02-26
Published Online: 2021-07-02

© 2021 Zhihong Zhang et al., published by De Gruyter

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

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  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
https://doi.org/10.1515/med-2021-0255
Schlagwörter für diesen Artikel
circ_0005962; miR-382-5p; PDK4; NSCLC
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Artikel in diesem Heft

  1. Research Articles
  2. Identification of ZG16B as a prognostic biomarker in breast cancer
  3. Behçet’s disease with latent Mycobacterium tuberculosis infection
  4. Erratum
  5. Erratum to “Suffering from Cerebral Small Vessel Disease with and without Metabolic Syndrome”
  6. Research Articles
  7. GPR37 promotes the malignancy of lung adenocarcinoma via TGF-β/Smad pathway
  8. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  9. Additional baricitinib loading dose improves clinical outcome in COVID-19
  10. The co-treatment of rosuvastatin with dapagliflozin synergistically inhibited apoptosis via activating the PI3K/AKt/mTOR signaling pathway in myocardial ischemia/reperfusion injury rats
  11. SLC12A8 plays a key role in bladder cancer progression and EMT
  12. LncRNA ATXN8OS enhances tamoxifen resistance in breast cancer
  13. Case Report
  14. Serratia marcescens as a cause of unfavorable outcome in the twin pregnancy
  15. Spleno-adrenal fusion mimicking an adrenal metastasis of a renal cell carcinoma: A case report and embryological background
  16. Research Articles
  17. TRIM25 contributes to the malignancy of acute myeloid leukemia and is negatively regulated by microRNA-137
  18. CircRNA circ_0004370 promotes cell proliferation, migration, and invasion and inhibits cell apoptosis of esophageal cancer via miR-1301-3p/COL1A1 axis
  19. LncRNA XIST regulates atherosclerosis progression in ox-LDL-induced HUVECs
  20. Potential role of IFN-γ and IL-5 in sepsis prediction of preterm neonates
  21. Rapid Communication
  22. COVID-19 vaccine: Call for employees in international transportation industries and international travelers as the first priority in global distribution
  23. Case Report
  24. Rare squamous cell carcinoma of the kidney with concurrent xanthogranulomatous pyelonephritis: A case report and review of the literature
  25. An infertile female delivered a baby after removal of primary renal carcinoid tumor
  26. Research Articles
  27. Hypertension, BMI, and cardiovascular and cerebrovascular diseases
  28. Case Report
  29. Coexistence of bilateral macular edema and pale optic disc in the patient with Cohen syndrome
  30. Research Articles
  31. Correlation between kinematic sagittal parameters of the cervical lordosis or head posture and disc degeneration in patients with posterior neck pain
  32. Review Articles
  33. Hepatoid adenocarcinoma of the lung: An analysis of the Surveillance, Epidemiology, and End Results (SEER) database
  34. Research Articles
  35. Thermography in the diagnosis of carpal tunnel syndrome
  36. Pemetrexed-based first-line chemotherapy had particularly prominent objective response rate for advanced NSCLC: A network meta-analysis
  37. Comparison of single and double autologous stem cell transplantation in multiple myeloma patients
  38. The influence of smoking in minimally invasive spinal fusion surgery
  39. Impact of body mass index on left atrial dimension in HOCM patients
  40. Expression and clinical significance of CMTM1 in hepatocellular carcinoma
  41. miR-142-5p promotes cervical cancer progression by targeting LMX1A through Wnt/β-catenin pathway
  42. Comparison of multiple flatfoot indicators in 5–8-year-old children
  43. Early MRI imaging and follow-up study in cerebral amyloid angiopathy
  44. Intestinal fatty acid-binding protein as a biomarker for the diagnosis of strangulated intestinal obstruction: A meta-analysis
  45. miR-128-3p inhibits apoptosis and inflammation in LPS-induced sepsis by targeting TGFBR2
  46. Dynamic perfusion CT – A promising tool to diagnose pancreatic ductal adenocarcinoma
  47. Biomechanical evaluation of self-cinching stitch techniques in rotator cuff repair: The single-loop and double-loop knot stitches
  48. Review Articles
  49. The ambiguous role of mannose-binding lectin (MBL) in human immunity
  50. Case Report
  51. Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report
  52. Fertility problems in males carrying an inversion of chromosome 10
  53. Acute myeloid leukemia with leukemic pleural effusion and high levels of pleural adenosine deaminase: A case report and review of literature
  54. Metastatic renal Ewing’s sarcoma in adult woman: Case report and review of the literature
  55. Burkitt-like lymphoma with 11q aberration in a patient with AIDS and a patient without AIDS: Two cases reports and literature review
  56. Skull hemophilia pseudotumor: A case report
  57. Judicious use of low-dosage corticosteroids for non-severe COVID-19: A case report
  58. Adult-onset citrullinaemia type II with liver cirrhosis: A rare cause of hyperammonaemia
  59. Clinicopathologic features of Good’s syndrome: Two cases and literature review
  60. Fatal immune-related hepatitis with intrahepatic cholestasis and pneumonia associated with camrelizumab: A case report and literature review
  61. Research Articles
  62. Effects of hydroxyethyl starch and gelatin on the risk of acute kidney injury following orthotopic liver transplantation: A multicenter retrospective comparative clinical study
  63. Significance of nucleic acid positive anal swab in COVID-19 patients
  64. circAPLP2 promotes colorectal cancer progression by upregulating HELLS by targeting miR-335-5p
  65. Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients
  66. Risk factors of left atrial appendage thrombus in patients with non-valvular atrial fibrillation
  67. Clinical features of hypertensive patients with COVID-19 compared with a normotensive group: Single-center experience in China
  68. Surgical myocardial revascularization outcomes in Kawasaki disease: systematic review and meta-analysis
  69. Decreased chromobox homologue 7 expression is associated with epithelial–mesenchymal transition and poor prognosis in cervical cancer
  70. FGF16 regulated by miR-520b enhances the cell proliferation of lung cancer
  71. Platelet-rich fibrin: Basics of biological actions and protocol modifications
  72. Accurate diagnosis of prostate cancer using logistic regression
  73. miR-377 inhibition enhances the survival of trophoblast cells via upregulation of FNDC5 in gestational diabetes mellitus
  74. Prognostic significance of TRIM28 expression in patients with breast carcinoma
  75. Integrative bioinformatics analysis of KPNA2 in six major human cancers
  76. Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p
  77. A four-lncRNA signature for predicting prognosis of recurrence patients with gastric cancer
  78. Knockdown of circ_0003204 alleviates oxidative low-density lipoprotein-induced human umbilical vein endothelial cells injury: Circulating RNAs could explain atherosclerosis disease progression
  79. Propofol postpones colorectal cancer development through circ_0026344/miR-645/Akt/mTOR signal pathway
  80. Knockdown of lncRNA TapSAKI alleviates LPS-induced injury in HK-2 cells through the miR-205/IRF3 pathway
  81. COVID-19 severity in relation to sociodemographics and vitamin D use
  82. Clinical analysis of 11 cases of nocardiosis
  83. Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems
  84. Four long noncoding RNAs act as biomarkers in lung adenocarcinoma
  85. Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens
  86. Relation between IL-8 level and obstructive sleep apnea syndrome
  87. circAGFG1 sponges miR-28-5p to promote non-small-cell lung cancer progression through modulating HIF-1α level
  88. Nomogram prediction model for renal anaemia in IgA nephropathy patients
  89. Effect of antibiotic use on the efficacy of nivolumab in the treatment of advanced/metastatic non-small cell lung cancer: A meta-analysis
  90. NDRG2 inhibition facilitates angiogenesis of hepatocellular carcinoma
  91. A nomogram for predicting metabolic steatohepatitis: The combination of NAMPT, RALGDS, GADD45B, FOSL2, RTP3, and RASD1
  92. Clinical and prognostic features of MMP-2 and VEGF in AEG patients
  93. The value of miR-510 in the prognosis and development of colon cancer
  94. Functional implications of PABPC1 in the development of ovarian cancer
  95. Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy
  96. Sublingual immunotherapy increases Treg/Th17 ratio in allergic rhinitis
  97. Prediction of improvement after anterior cruciate ligament reconstruction
  98. Effluent Osteopontin levels reflect the peritoneal solute transport rate
  99. circ_0038467 promotes PM2.5-induced bronchial epithelial cell dysfunction
  100. Significance of miR-141 and miR-340 in cervical squamous cell carcinoma
  101. Association between hair cortisol concentration and metabolic syndrome
  102. Microvessel density as a prognostic indicator of prostate cancer: A systematic review and meta-analysis
  103. Characteristics of BCR–ABL gene variants in patients of chronic myeloid leukemia
  104. Knee alterations in rheumatoid arthritis: Comparison of US and MRI
  105. Long non-coding RNA TUG1 aggravates cerebral ischemia and reperfusion injury by sponging miR-493-3p/miR-410-3p
  106. lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p
  107. Development and validation of a nomogram for predicting severity in patients with hemorrhagic fever with renal syndrome: A retrospective study
  108. Analysis of COVID-19 outbreak origin in China in 2019 using differentiation method for unusual epidemiological events
  109. Laparoscopic versus open major liver resection for hepatocellular carcinoma: A case-matched analysis of short- and long-term outcomes
  110. Travelers’ vaccines and their adverse events in Nara, Japan
  111. Association between Tfh and PGA in children with Henoch–Schönlein purpura
  112. Can exchange transfusion be replaced by double-LED phototherapy?
  113. circ_0005962 functions as an oncogene to aggravate NSCLC progression
  114. Circular RNA VANGL1 knockdown suppressed viability, promoted apoptosis, and increased doxorubicin sensitivity through targeting miR-145-5p to regulate SOX4 in bladder cancer cells
  115. Serum intact fibroblast growth factor 23 in healthy paediatric population
  116. Algorithm of rational approach to reconstruction in Fournier’s disease
  117. A meta-analysis of exosome in the treatment of spinal cord injury
  118. Src-1 and SP2 promote the proliferation and epithelial–mesenchymal transition of nasopharyngeal carcinoma
  119. Dexmedetomidine may decrease the bupivacaine toxicity to heart
  120. Hypoxia stimulates the migration and invasion of osteosarcoma via up-regulating the NUSAP1 expression
  121. Long noncoding RNA XIST knockdown relieves the injury of microglia cells after spinal cord injury by sponging miR-219-5p
  122. External fixation via the anterior inferior iliac spine for proximal femoral fractures in young patients
  123. miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12
  124. HAGLR promotes neuron differentiation through the miR-130a-3p-MeCP2 axis
  125. Phosphoglycerate mutase 2 is elevated in serum of patients with heart failure and correlates with the disease severity and patient’s prognosis
  126. Cell population data in identifying active tuberculosis and community-acquired pneumonia
  127. Prognostic value of microRNA-4521 in non-small cell lung cancer and its regulatory effect on tumor progression
  128. Mean platelet volume and red blood cell distribution width is associated with prognosis in premature neonates with sepsis
  129. 3D-printed porous scaffold promotes osteogenic differentiation of hADMSCs
  130. Association of gene polymorphisms with women urinary incontinence
  131. Influence of COVID-19 pandemic on stress levels of urologic patients
  132. miR-496 inhibits proliferation via LYN and AKT pathway in gastric cancer
  133. miR-519d downregulates LEP expression to inhibit preeclampsia development
  134. Comparison of single- and triple-port VATS for lung cancer: A meta-analysis
  135. Fluorescent light energy modulates healing in skin grafted mouse model
  136. Silencing CDK6-AS1 inhibits LPS-induced inflammatory damage in HK-2 cells
  137. Predictive effect of DCE-MRI and DWI in brain metastases from NSCLC
  138. Severe postoperative hyperbilirubinemia in congenital heart disease
  139. Baicalin improves podocyte injury in rats with diabetic nephropathy by inhibiting PI3K/Akt/mTOR signaling pathway
  140. Clinical factors predicting ureteral stent failure in patients with external ureteral compression
  141. Novel H2S donor proglumide-ADT-OH protects HUVECs from ox-LDL-induced injury through NF-κB and JAK/SATA pathway
  142. Triple-Endobutton and clavicular hook: A propensity score matching analysis
  143. Long noncoding RNA MIAT inhibits the progression of diabetic nephropathy and the activation of NF-κB pathway in high glucose-treated renal tubular epithelial cells by the miR-182-5p/GPRC5A axis
  144. Serum exosomal miR-122-5p, GAS, and PGR in the non-invasive diagnosis of CAG
  145. miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1
  146. Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p
  147. The diagnostic and prognostic value of miR-92a in gastric cancer: A systematic review and meta-analysis
  148. Prognostic value of α2δ1 in hypopharyngeal carcinoma: A retrospective study
  149. No significant benefit of moderate-dose vitamin C on severe COVID-19 cases
  150. circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p
  151. Downregulation of RAB7 and Caveolin-1 increases MMP-2 activity in renal tubular epithelial cells under hypoxic conditions
  152. Educational program for orthopedic surgeons’ influences for osteoporosis
  153. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma
  154. GJA1 promotes hepatocellular carcinoma progression by mediating TGF-β-induced activation and the epithelial–mesenchymal transition of hepatic stellate cells
  155. lncRNA-ZFAS1 promotes the progression of endometrial carcinoma by targeting miR-34b to regulate VEGFA expression
  156. Anticoagulation is the answer in treating noncritical COVID-19 patients
  157. Effect of late-onset hemorrhagic cystitis on PFS after haplo-PBSCT
  158. Comparison of Dako HercepTest and Ventana PATHWAY anti-HER2 (4B5) tests and their correlation with silver in situ hybridization in lung adenocarcinoma
  159. VSTM1 regulates monocyte/macrophage function via the NF-κB signaling pathway
  160. Comparison of vaginal birth outcomes in midwifery-led versus physician-led setting: A propensity score-matched analysis
  161. Treatment of osteoporosis with teriparatide: The Slovenian experience
  162. New targets of morphine postconditioning protection of the myocardium in ischemia/reperfusion injury: Involvement of HSP90/Akt and C5a/NF-κB
  163. Superenhancer–transcription factor regulatory network in malignant tumors
  164. β-Cell function is associated with osteosarcopenia in middle-aged and older nonobese patients with type 2 diabetes: A cross-sectional study
  165. Clinical features of atypical tuberculosis mimicking bacterial pneumonia
  166. Proteoglycan-depleted regions of annular injury promote nerve ingrowth in a rabbit disc degeneration model
  167. Effect of electromagnetic field on abortion: A systematic review and meta-analysis
  168. miR-150-5p affects AS plaque with ASMC proliferation and migration by STAT1
  169. MALAT1 promotes malignant pleural mesothelioma by sponging miR-141-3p
  170. Effects of remifentanil and propofol on distant organ lung injury in an ischemia–reperfusion model
  171. miR-654-5p promotes gastric cancer progression via the GPRIN1/NF-κB pathway
  172. Identification of LIG1 and LIG3 as prognostic biomarkers in breast cancer
  173. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy
  174. Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
  175. circATP2A2 promotes osteosarcoma progression by upregulating MYH9
  176. Prognostic role of oxytocin receptor in colon adenocarcinoma
  177. Review Articles
  178. The function of non-coding RNAs in idiopathic pulmonary fibrosis
  179. Efficacy and safety of therapeutic plasma exchange in stiff person syndrome
  180. Role of cesarean section in the development of neonatal gut microbiota: A systematic review
  181. Small cell lung cancer transformation during antitumor therapies: A systematic review
  182. Research progress of gut microbiota and frailty syndrome
  183. Recommendations for outpatient activity in COVID-19 pandemic
  184. Rapid Communication
  185. Disparity in clinical characteristics between 2019 novel coronavirus pneumonia and leptospirosis
  186. Use of microspheres in embolization for unruptured renal angiomyolipomas
  187. COVID-19 cases with delayed absorption of lung lesion
  188. A triple combination of treatments on moderate COVID-19
  189. Social networks and eating disorders during the Covid-19 pandemic
  190. Letter
  191. COVID-19, WHO guidelines, pedagogy, and respite
  192. Inflammatory factors in alveolar lavage fluid from severe COVID-19 pneumonia: PCT and IL-6 in epithelial lining fluid
  193. COVID-19: Lessons from Norway tragedy must be considered in vaccine rollout planning in least developed/developing countries
  194. What is the role of plasma cell in the lamina propria of terminal ileum in Good’s syndrome patient?
  195. Case Report
  196. Rivaroxaban triggered multifocal intratumoral hemorrhage of the cabozantinib-treated diffuse brain metastases: A case report and review of literature
  197. CTU findings of duplex kidney in kidney: A rare duplicated renal malformation
  198. Synchronous primary malignancy of colon cancer and mantle cell lymphoma: A case report
  199. Sonazoid-enhanced ultrasonography and pathologic characters of CD68 positive cell in primary hepatic perivascular epithelioid cell tumors: A case report and literature review
  200. Persistent SARS-CoV-2-positive over 4 months in a COVID-19 patient with CHB
  201. Pulmonary parenchymal involvement caused by Tropheryma whipplei
  202. Mediastinal mixed germ cell tumor: A case report and literature review
  203. Ovarian female adnexal tumor of probable Wolffian origin – Case report
  204. Rare paratesticular aggressive angiomyxoma mimicking an epididymal tumor in an 82-year-old man: Case report
  205. Perimenopausal giant hydatidiform mole complicated with preeclampsia and hyperthyroidism: A case report and literature review
  206. Primary orbital ganglioneuroblastoma: A case report
  207. Primary aortic intimal sarcoma masquerading as intramural hematoma
  208. Sustained false-positive results for hepatitis A virus immunoglobulin M: A case report and literature review
  209. Peritoneal loose body presenting as a hepatic mass: A case report and review of the literature
  210. Chondroblastoma of mandibular condyle: Case report and literature review
  211. Trauma-induced complete pacemaker lead fracture 8 months prior to hospitalization: A case report
  212. Primary intradural extramedullary extraosseous Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (PIEES/PNET) of the thoracolumbar spine: A case report and literature review
  213. Computer-assisted preoperative planning of reduction of and osteosynthesis of scapular fracture: A case report
  214. High quality of 58-month life in lung cancer patient with brain metastases sequentially treated with gefitinib and osimertinib
  215. Rapid response of locally advanced oral squamous cell carcinoma to apatinib: A case report
  216. Retrieval of intrarenal coiled and ruptured guidewire by retrograde intrarenal surgery: A case report and literature review
  217. Usage of intermingled skin allografts and autografts in a senior patient with major burn injury
  218. Retraction
  219. Retraction on “Dihydromyricetin attenuates inflammation through TLR4/NF-kappa B pathway”
  220. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part I
  221. An artificial immune system with bootstrap sampling for the diagnosis of recurrent endometrial cancers
  222. Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning
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