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Nei Endonuclease VIII-like 2 Gene rs8191670 Polymorphism affects the Sensitivity of Non-small Cell Lung Cancer to Cisplatin by binding with MiR-548a.

ABSTRACT: Background: Nei endonuclease VIII-like 2 (NEIL2) is a gene encoding DNA repair enzyme, which is involved in the base excision repair (BER) pathway in mammalian cells. Cisplatin is a common cytotoxic anti-tumor agent in clinic by destroying normal structure of DNA and inducing cell apoptosis. However, how NEIL2 affects the sensitivity of NSCLC to cisplatin is still unclear. Methods: The clinical data from 206 patients diagnosed pathologically were collected. The DNA sequencing of NEIL2 gene 3'UTR and the PFS curve of NSCLC patients receiving cisplatin-based chemotherapy were performed. Western blot analysis and immunohistochemistry were used to detect NEIL2 protein expression. Human NSCLC cell lines A549 and H1299 were cultured and evaluated for cell viability. RT-PCR was performed for quantitative detection of miR-548a. 3'UTR reporter plasmid was constructed and luciferase reporter assay was used to verify the target gene regulated by miR-548a. Results: In this study, we found that the Neil2 gene had the polymorphism (T/C) in rs8191670 and it is associated with the PFS of advanced NSCLC patients. MiR-548a targets NEIL2 3'UTR to suppress its expression. Upregulation of NEIL2 expression or downregulation of miR-548a could reduce the sensitivity of NSCLC cells to cisplatin. Conclusion: Our results demonstrated that NEIL2 gene rs8191670 polymorphism affects the PFS of advanced NSCLC patients, and the underlying molecular mechanisms may be that miR-548a can regulate NEIL2 expression by binding to its 3'UTR seed region containing rs8191670.

SUBMITTER: He W

PROVIDER: S-EPMC7330683 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Nei Endonuclease VIII-like 2 Gene rs8191670 Polymorphism affects the Sensitivity of Non-small Cell Lung Cancer to Cisplatin by binding with MiR-548a.

He Wei W Pang Lina L Gong Shuai S Wang Xin X Hou Lixia L

Journal of Cancer 20200606 16

<b>Background:</b> Nei endonuclease VIII-like 2 (NEIL2) is a gene encoding DNA repair enzyme, which is involved in the base excision repair (BER) pathway in mammalian cells. Cisplatin is a common cytotoxic anti-tumor agent in clinic by destroying normal structure of DNA and inducing cell apoptosis. However, how NEIL2 affects the sensitivity of NSCLC to cisplatin is still unclear. <b>Methods:</b> The clinical data from 206 patients diagnosed pathologically were collected. The DNA sequencing of <i ...[more]

PMID: 32626527

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Project description:BackgroundsAs previously reported, midazolam anesthesia exerts tumor-suppressing effects in non-small cell lung cancer (NSCLC), but the regulating effects of this drug on cisplatin-resistance in NSCLC have not been studied. Thus, we designed this study to investigate this issue and preliminarily delineate the potential molecular mechanisms.MethodsWe performed MTT assay and trypan blue staining assay to measure cell proliferation and viability. Cell apoptosis was examined by FCM. qRT-PCR and immunoblotting were performed to determine the expression levels of genes. The targeting sites between genes were predicted by bioinformatics analysis and were validated by dual-luciferase reporter gene system assay. Mice tumor-bearing models were established and the tumorigenesis was evaluated by measuring tumor weight and volume. Immunohistochemistry (IHC) was used to examine the pro-proliferative Ki67 protein expressions in mice tumor tissues.ResultsThe cisplatin-resistant NSCLC (CR-NSCLC) cells were treated with high-dose cisplatin (50 μg/ml) and low-dose midazolam (10 μg/ml), and the results showed that midazolam suppressed cell proliferation and viability, and promoted cell apoptosis in cisplatin-treated CR-NSCLC cells. In addition, midazolam enhanced cisplatin-sensitivity in CR-NSCLC cell via modulating the miR-194-5p/hook microtubule-tethering protein 3 (HOOK3) axis. Specifically, midazolam upregulated miR-194-5p, but downregulated HOOK3 in the CR-NSCLC cells, and further results validated that miR-194-5p bound to the 3' untranslated region (3'UTR) of HOOK3 mRNA for its inhibition. Also, midazolam downregulated HOOK3 in CR-NSCLC cells by upregulating miR-194-5p. Functional experiments validated that both miR-194-5p downregulation and HOOK3 upregulation abrogated the promoting effects of midazolam on cisplatin-sensitivity in CR-NSCLC cells.ConclusionsTaken together, this study found that midazolam anesthesia reduced cisplatin-resistance in CR-NSCLC cells by regulating the miR-194-5p/HOOK3 axis, implying that midazolam could be used as adjuvant drug for NSCLC treatment in clinical practices.

Project description:Cisplatin is effective as a single agent or in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). A concerning clinical challenge with cisplatin-based NSCLC chemotherapy is the intrinsic and acquired chemoresistance to cisplatin. The sterile ? motif domain-containing (SAMD9) gene has been reported as a potent tumor suppressor gene that inhibits tumorigenesis and progression of NSCLC. microRNAs (miRNA) have been revealed to play important roles in the regulation of cancer chemoresistance. To the best of our knowledge the present study explored the role of miRNA/SAMD9 signaling in regulating cisplatin chemoresistance in NSCLC for the first time. Out of the several candidate miRNAs predicted to bind the 3'-untranslated region (UTR) of the SAMD9 gene, miRNA-96 (miR-96) demonstrated significant target-sequence-specific inhibition of the SAMD9 3'-UTR luciferase reporter activity in NSCLC cells. In addition, while NSCLC tumor samples exhibited significantly higher expression levels of miR-96 compared with adjacent normal tissues, the expression levels of SAMD9 were significantly lower than those in adjacent normal tissues. miR-96 and SAMD9 were overexpressed and knocked down in the human NSCLC H358 and H23 cell lines and the half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. The present results identified that overexpression of miR-96 in NSCLC cells markedly decreased SAMD9 expression and cisplatin-induced apoptosis, and increased the cisplatin IC50, which could be eliminated by overexpression of SAMD9. By contrast, knocking down miR-96 in NSCLC cells using antagomir-96 significantly increased SAMD9 expression and the cisplatin-induced apoptosis and decreased cisplatin IC50, which could be completely reversed by a knockdown of SAMD9. In conclusion, the current study demonstrates that miR-96 targets and downregulates SAMD9 in NSCLC, which decreases cisplatin-induced apoptosis and induces cisplatin chemoresistance in NSCLC cells. The findings of the present study add novel insights into the function of miR-96 and SAMD9 in cancer, as well as into the molecular mechanisms underlying NSCLC chemoresistance.

Dataset Information

Nei Endonuclease VIII-like 2 Gene rs8191670 Polymorphism affects the Sensitivity of Non-small Cell Lung Cancer to Cisplatin by binding with MiR-548a.

Publications

Nei Endonuclease VIII-like 2 Gene rs8191670 Polymorphism affects the Sensitivity of Non-small Cell Lung Cancer to Cisplatin by binding with MiR-548a.

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