Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway

Xia,Yang; He,Zhicheng; Liu,Bin; Wang,Pengli; Chen,Yijiang

doi:10.3892/mmr.2015.3897

Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway

Authors:
- Yang Xia
- Zhicheng He
- Bin Liu
- Pengli Wang
- Yijiang Chen
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Affiliations: Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China
Published online on: June 8, 2015 https://doi.org/10.3892/mmr.2015.3897
Pages: 4530-4537

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Abstract

Maternally expressed gene 3 (Meg3) has been shown to promote tumor progression. However, the role of Meg3 in the development of a chemoresistant phenotype of human lung cancer has remains. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression of Meg3. Flow cytometric analysis and MTT assay were also used to investigate the cell cycle and apoptosis. The present study detected that the expression levels of Meg3 were significantly lower in cisplatin‑resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. Furthermore, upregulation of Meg3 was able to re‑sensitize the A549/DDP cells to cisplatin in vitro. Whereas downregulation of Meg3, by RNA interference, decreased the sensitivity of A549 cells to cisplatin. The results of the present study also demonstrated that the Meg3‑mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, β‑catenin and survivin, which is a target gene of the WNT/β‑catenin signaling pathway. In conclusion, these results suggested that Meg3 may have a crucial role in the development of cisplatin resistance in non-small cell lung cancer.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Sánchez de Cos J, Sojo González MA, Montero MV, et al: Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 63:140–145. 2009. View Article : Google Scholar
3	Chen CL, Ip SM, Cheng D, Wong LC and Ngan HY: Loss of imprinting of the IGF-II and H19 genes in epithelial ovarian cancer. Clin Cancer Res. 6:474–479. 2000.PubMed/NCBI
4	Yang F, Zhang L, Huo XS, et al: Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 54:1679–1689. 2011. View Article : Google Scholar : PubMed/NCBI
5	Lai MC, Yang Z, Zhou L, et al: Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 29:1810–1816. 2012. View Article : Google Scholar
6	Tsang WP and Kwok TT: Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene. 26:4877–4881. 2007. View Article : Google Scholar : PubMed/NCBI
7	Fan Y, Shen B, Tan M, et al: Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J. 281:1750–1758. 2014. View Article : Google Scholar : PubMed/NCBI
8	Jiang M, Huang O, Xie Z, et al: A novel long non-coding RNA-ARA: Adriamycin resistance-associated. Biochem Pharmacol. 87:254–283. 2014. View Article : Google Scholar
9	Gejman R, Batista DL, Zhong Y, et al: Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 93:4119–4125. 2008. View Article : Google Scholar : PubMed/NCBI
10	Sun M, Xia R, Jin F, et al: Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol. 35:1065–1073. 2014. View Article : Google Scholar
11	Ying L, Huang Y, Chen H, et al: Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Mol Biosyst. 9:407–411. 2013. View Article : Google Scholar : PubMed/NCBI
12	Wang P, Ren Z and Sun P: Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. J Cell Biochem. 113:1868–1874. 2012. View Article : Google Scholar : PubMed/NCBI
13	Qin R, Chen Z, Ding Y, Hao J, Hu J and Guo F: Long non-coding RNA MEG3 inhibits the proliferation of cervical carcinoma cells through the induction of cell cycle arrest and apoptosis. Neoplasma. 60:486–492. 2013. View Article : Google Scholar : PubMed/NCBI
14	Zhao X, Xu Z, Wang Z, et al: RNA silencing of integrin-linked kinase increases the sensitivity of the A549 lung cancer cell line to cisplatin and promotes its apoptosis. Mol Med Rep. 12:960–966. 2015.PubMed/NCBI
15	Stewart DJ: Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. 106:djt3562014. View Article : Google Scholar
16	Ward JH: NCCN Guidelines and the International Community. J Natl Compr Canc Netw. 9:133–134. 2011.PubMed/NCBI
17	Zhou Y, Zhong Y, Wang Y, et al: Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 282:24731–24742. 2007. View Article : Google Scholar : PubMed/NCBI
18	Miao W, Liu X, Wang H, et al: p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis. Mol Med Rep. 11:4165–4173. 2015.PubMed/NCBI
19	Sadot E, Geiger B, Oren M and Ben-Ze'ev A: Down-regulation of beta-catenin by activated p53. Mol Cell Biol. 21:6768–6781. 2001. View Article : Google Scholar : PubMed/NCBI
20	Wu MY, Xie X, Xu ZK, et al: PP2A inhibitors suppress migration and growth of PANC-1 pancreatic cancer cells through inhibition on the Wnt/beta-catenin pathway by phosphorylation and degradation of β-catenin. Oncol Rep. 32:513–522. 2014.PubMed/NCBI
21	Gao Y, Liu Z, Zhang X, et al: Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells. Cancer Lett. 336:231–239. 2013. View Article : Google Scholar : PubMed/NCBI
22	Ren S, Liu Y, Xu W, et al: Long noncoding RNA MALAT-1 is a new potential therapeutic target for castration resistant prostate cancer. J Urol. 190:2278–2287. 2013. View Article : Google Scholar : PubMed/NCBI
23	Schmidt LH, Spieker T, Koschmieder S, et al: The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 6:1984–1992. 2011. View Article : Google Scholar : PubMed/NCBI
24	Xi YN, Xin XY and Ye HM: Effects of HMGA2 on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Asian Pac J Trop Med. 7:289–292. 2014. View Article : Google Scholar : PubMed/NCBI
25	Prensner JR, Iyer MK, Sahu A, et al: The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 45:1392–1398. 2013. View Article : Google Scholar : PubMed/NCBI
26	Yang F, Huo XS, Yuan SX, et al: Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell. 49:1083–1096. 2013. View Article : Google Scholar : PubMed/NCBI
27	Chang A: Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 71:3–10. 2011. View Article : Google Scholar
28	Strathdee G: Epigenetic markers and response to chemotherapy in cancer. Dis Markers. 23:43–49. 2007. View Article : Google Scholar : PubMed/NCBI
29	Liu Z, Sun M, Lu K, et al: The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21 (WAF1/CIP1) expression. PloS One. 8:e772932013. View Article : Google Scholar
30	Braconi C, Kogure T, Valeri N, et al: microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 30:4750–4756. 2011. View Article : Google Scholar : PubMed/NCBI
31	Butz H and Patocs A: Pituitary tumorigenesis: role of regulation of Wee1 kinase by microRNAs. Tumors of the Central Nervous System. Hayat M: 10. Springer; Dordrecht: pp. 141–150. 2013
32	McCubrey JA, Steelman LS, Abrams SL, et al: Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 46:249–279. 2006. View Article : Google Scholar : PubMed/NCBI
33	Bouwman P and Jonkers J: The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer. 12:587–598. 2012. View Article : Google Scholar : PubMed/NCBI
34	Cui J, Jiang W, Wang S, Wang L and Xie K: Role of Wnt/β-catenin signaling in drug resistance of pancreatic cancer. Curr Pharm Des. 18:2464–2471. 2012. View Article : Google Scholar
35	Yang D, Welm A and Bishop JM: Cell division and cell survival in the absence of survivin. Proc Natl Acad Sci USA. 101:15100–15105. 2004. View Article : Google Scholar : PubMed/NCBI