miR‑296‑3p targets APEX1 to suppress cell migration and invasion of non‑small‑cell lung cancer

Wang,Lifeng; Chen,Ruilin; Zhang,Yongqing

doi:10.3892/ol.2019.10572

miR‑296‑3p targets APEX1 to suppress cell migration and invasion of non‑small‑cell lung cancer

Authors:
- Lifeng Wang
- Ruilin Chen
- Yongqing Zhang
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Affiliations: Department of Respiration, Xi'an High‑tech Hospital, Xi'an, Shaanxi 710075, P.R. China, Department of Respiration, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
Published online on: July 5, 2019 https://doi.org/10.3892/ol.2019.10572
Pages: 2612-2618

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Abstract

Non‑small‑cell lung cancer (NSCLC) is the most common cause of cancer‑associated mortality worldwide. MicroRNAs (miRs) are a class of small non‑coding RNAs that are commonly dysregulated in human cancer. The aim of the current study was to evaluate the effect of miR‑296‑3p on the cell migration and invasion of NSCLC. Pairs of tumor tissues and para‑cancerous tissues (n=50) were collected from patients with NSCLC, and the expression of miR‑296‑3p was analyzed by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Additionally, tumor cell viability, migration and invasion were examined in vitro using Cell Counting Kit‑8, wound healing and Matrigel assays, respectively. Furthermore, potential targets of miR‑296‑3p were screened for using TargetScan and validated using a dual‑luciferase reporter assay. The expression levels of phosphoinositide‑3‑kinase (PI3K), AKT serine/threonine kinase (AKT), mammalian target of rapamycin (mTOR), matrix metallopeptidase 2 (MMP2) and SRY‑box 4 (SOX4) were detected by RT‑qPCR and western blot analysis. The data indicated that miR‑296‑3p was downregulated in tumor tissues compared with adjacent normal tissues. Overexpression of miR‑296‑3p inhibited NSCLC cell viability, migration and invasion in vitro. Furthermore, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) was identified as a direct target of miR‑296‑3p. APEX1 expression was upregulated in tumor tissues compared with para‑cancerous tissues, and the mRNA and protein expression levels of APEX1 were decreased following transfection of NSCLC cells with miR‑296‑3p mimics compared with control cells. Additional investigations revealed that miR‑296‑3p was involved in regulating the PI3K/AKT/mTOR signaling pathway, and miR‑296‑3p mimics decreased the mRNA and protein expression levels of MMP2 and SOX4. In summary, the findings demonstrated that miR‑296‑3p may function as a tumor suppressor, and inhibits the migration and invasion of NSCLC cells by targeting APEX1. miR‑296‑3p is therefore a potential therapeutic molecular modulator of NSCLC.

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1	Gridelli C, Rossi A, Carbone DP, Guarize J, Karachaliou N, Mok T, Petrella F, Spaggiari L and Rosell R: Non-small-cell lung cancer. Nat Rev Dis Primers. 1:150092015. View Article : Google Scholar : PubMed/NCBI
2	Rosell R, Bivona TG and Karachaliou N: Genetics and biomarkers in personalisation of lung cancer treatment. Lancet. 382:720–731. 2013. View Article : Google Scholar : PubMed/NCBI
3	Skjefstad K, Johannessen C, Grindstad T, Kilvaer T, Paulsen EE, Pedersen M, Donnem T, Andersen S, Bremnes R, Richardsen E, et al: A gender specific improved survival related to stromal miR-143 and miR-145 expression in non-small cell lung cancer. Sci Rep. 8:85492018. View Article : Google Scholar : PubMed/NCBI
4	Custodio A, Méndez M and Provencio M: Targeted therapies for advanced non-small-cell lung cancer: Current status and future implications. Cancer Treat Rev. 38:36–53. 2012. View Article : Google Scholar : PubMed/NCBI
5	Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R and Rajewsky N: Widespread changes in protein synthesis induced by microRNAs. Nature. 455:58–63. 2008. View Article : Google Scholar : PubMed/NCBI
6	Doench JG and Sharp PA: Specificity of microRNA target selection in translational repression. Genes Dev. 18:504–511. 2004. View Article : Google Scholar : PubMed/NCBI
7	Farazi TA, Spitzer JI, Morozov P and Tuschl T: miRNAs in human cancer. J Pathol. 223:102–115. 2011. View Article : Google Scholar : PubMed/NCBI
8	Lv L and Wang X: MicroRNA-296 targets specificity protein 1 to suppress cell proliferation and invasion in cervical cancer. Oncol Res. 26:775–783. 2018. View Article : Google Scholar : PubMed/NCBI
9	Li H, Li J, Shi B and Chen F: MicroRNA-296 targets AKT2 in pancreatic cancer and functions as a potential tumor suppressor. Mol Med Rep. 16:466–472. 2017. View Article : Google Scholar : PubMed/NCBI
10	He Z, Yu L, Luo S, Li M, Li J, Li Q, Sun Y and Wang C: miR-296 inhibits the metastasis and epithelial-mesenchymal transition of colorectal cancer by targeting S100A4. BMC Cancer. 17:1402017. View Article : Google Scholar : PubMed/NCBI
11	Li H, Ouyang XP, Jiang T, Zheng XL, He PP and Zhao GJ: MicroRNA-296: A promising target in the pathogenesis of atherosclerosis? Mol Med. 24:122018. View Article : Google Scholar : PubMed/NCBI
12	Xu C, Li S, Chen T, Hu H, Ding C, Xu Z, Chen J, Liu Z, Lei Z, Zhang HT, et al: MiR-296-5p suppresses cell viability by directly targeting PLK1 in non-small cell lung cancer. Oncol Rep. 35:497–503. 2016. View Article : Google Scholar : PubMed/NCBI
13	Luo W, Lin Y, Meng S, Guo Y, Zhang J and Zhang W: miRNA-296-3p modulates chemosensitivity of lung cancer cells by targeting CX3CR1. Am J Transl Res. 8:1848–1856. 2016.PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Liu X, Chen Q, Yan J, Wang Y, Zhu C, Chen C, Zhao X, Xu M, Sun Q, Deng R, et al: MiRNA-296-3p-ICAM-1 axis promotes metastasis of prostate cancer by possible enhancing survival of natural killer cell-resistant circulating tumour cells. Cell Death Dis. 4:e9282013. View Article : Google Scholar : PubMed/NCBI
16	Wang X, Hu Y, Cui J, Zhou Y and Chen L: Coordinated targeting of MMP-2/MMP-9 by miR-296-3p/FOXCUT exerts tumor-suppressing effects in choroidal malignant melanoma. Mol Cell Biochem. 445:25–33. 2018. View Article : Google Scholar : PubMed/NCBI
17	Ba Y, Liao H, Liu T, Zeng X, Xiao F, Luo L, Guo H and Guo L: MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-à-go-go (EAG1). Eur J Cancer. 49:710–724. 2013. View Article : Google Scholar : PubMed/NCBI
18	Li H, Liu G, Xia L, Zhou Q, Xiong J, Xian J, Du M, Zhang L, Liao L, Su X, et al: A polymorphism in the DNA repair domain of APEX1 is associated with the radiation-induced pneumonitis risk among lung cancer patients after radiotherapy. Br J Radiol. 87:201400932014. View Article : Google Scholar : PubMed/NCBI
19	Kelley MR, Cheng L, Foster R, Tritt R, Jiang J, Broshears J and Koch M: Elevated and altered expression of the multifunctional DNA base excision repair and redox enzyme Ape1/ref-1 in prostate cancer. Clin Cancer Res. 7:824–830. 2001.PubMed/NCBI
20	Wang D, Luo M and Kelley MR: Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition. Mol Cancer Ther. 3:679–686. 2004.PubMed/NCBI
21	Yang S, Irani K, Heffron SE, Jurnak F and Meyskens FL Jr: Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor. Mol Cancer Ther. 4:1923–1935. 2005. View Article : Google Scholar : PubMed/NCBI
22	Woo J, Park H, Sung SH, Moon BI, Suh H and Lim W: Prognostic value of human apurinic/apyrimidinic endonuclease 1 (APE1) expression in breast cancer. PLoS One. 9:e995282014. View Article : Google Scholar : PubMed/NCBI
23	Kim MH, Kim HB, Yoon SP, Lim SC, Cha MJ, Jeon YJ, Park SG, Chang IY and You HJ: Colon cancer progression is driven by APEX1-mediated upregulation of Jagged. J Clin Invest:. (pii): 655212013.PubMed/NCBI
24	Yang J, Yang D, Cogdell D, Du X, Li H, Pang Y, Sun Y, Hu L, Sun B, Trent J, et al: APEX1 gene amplification and its protein overexpression in osteosarcoma: Correlation with recurrence, metastasis, and survival. Technol Cancer Res Treat. 9:161–169. 2010. View Article : Google Scholar : PubMed/NCBI
25	Puglisi F, Aprile G, Minisini AM, Barbone F, Cataldi P, Tell G, Kelley MR, Damante G, Beltrami CA and Di Loreto C: Prognostic significance of Ape1/ref-1 subcellular localization in non-small cell lung carcinomas. Anticancer Res. 21:4041–4049. 2001.PubMed/NCBI
26	Osaki M, Oshimura M and Ito H: PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 9:667–676. 2004. View Article : Google Scholar : PubMed/NCBI
27	Engelman JA: Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
28	Lv X, Li CY, Han P and Xu XY: MicroRNA-520a-3p inhibits cell growth and metastasis of non-small cell lung cancer through PI3K/AKT/mTOR signaling pathway. Eur Rev Med Pharmacol Sci. 22:2321–2327. 2018.PubMed/NCBI
29	Tsurutani J, Fukuoka J, Tsurutani H, Shih JH, Hewitt SM, Travis WD, Jen J and Dennis PA: Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. J Clin Oncol. 24:306–314. 2006. View Article : Google Scholar : PubMed/NCBI
30	Testa JR and Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 98:10983–10985. 2001. View Article : Google Scholar : PubMed/NCBI
31	Bruhn MA, Pearson RB, Hannan RD and Sheppard KE: AKT-independent PI3-K signaling in cancer-emerging role for SGK3. Cancer Manag Res. 5:281–292. 2013.PubMed/NCBI
32	Wang XX, Cheng Q, Zhang SN, Qian HY, Wu JX, Tian H, Pei DS and Zheng JN: PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell. Tumour Biol. 34:2721–2729. 2013. View Article : Google Scholar : PubMed/NCBI
33	Du Q, Liu J, Zhang X, Zhang X, Zhu H, Wei M and Wang S: Propofol inhibits proliferation, migration, and invasion but promotes apoptosis by regulation of Sox4 in endometrial cancer cells. Braz J Med Bio Res. 51:e68032018.