Aberrant microRNA-137 promoter methylation is associated with lymph node metastasis and poor clinical outcomes in non-small cell lung cancer

Min,Lingfeng; Wang,Fang; Hu,Suwei; Chen,Yong; Yang,Junjun; Liang,Sudong; Xu,Xingxiang

doi:10.3892/ol.2018.8273

Aberrant microRNA-137 promoter methylation is associated with lymph node metastasis and poor clinical outcomes in non-small cell lung cancer

Authors:
- Lingfeng Min
- Fang Wang
- Suwei Hu
- Yong Chen
- Junjun Yang
- Sudong Liang
- Xingxiang Xu
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Affiliations: Department of Respiratory Medicine, Subei People's Hospital, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China, Medical Genetic Center, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225002, P.R. China, Department of Medical Oncology, Subei People's Hospital, Clinical Medical College of Yangzhou University, Yangzhou, Jiangsu 225001, P.R. China, Department of Urology, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
Published online on: March 15, 2018 https://doi.org/10.3892/ol.2018.8273
Pages: 7744-7750
Copyright: © Min et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MicroRNA-137 (miR-137) functions as a tumor suppressor and is silenced by aberrant promoter methylation. Previous studies have demonstrated that miR‑137 is downregulated in lung cancer. The purpose of the present study was to investigate miR‑137 promoter methylation and to assess its prognostic value in non‑small cell lung cancer (NSCLC). The expression of miR‑137 was analyzed inhuman lung cancer A549 and H1299 cells and normal bronchial epithelial BEAS‑2B cells, 10 paired formalin‑fixed paraffin‑embedded lung cancer and normal tissue samples, and 56 archived paraffin-embedded lung cancer tissues. Quantitative methylation‑specific polymerase chain reaction analysis was used to assess the miR-137 methylation status. The associations between miR‑137 promoter methylation and the clinicopathological features and prognosis of patients with NSCLC (n=56) were analyzed using analysis of variance. miR‑137 was markedly downregulated in lung cancer cells and lung cancer tissue specimens compared with expression in BEAS‑2B cells and matched adjacent normal lung tissues. A significant negative correlation between miR‑137 expression and miR‑137 promoter methylation was observed in human lung cancer tissues (r=‑0.343; P=0.01). Smoking, lymph node metastasis and advanced clinical stage were associated with significantly lower expression of miR‑137 in variance analysis. High levels of miR‑137 promoter methylation were associated with a significantly poorer disease‑free survival rate (P=0.034), but were not associated with overall survival, in Kaplan‑Meier analysis and univariate analysis. In conclusion, the results of the present study indicated that miR‑137 is downregulated and that its promoter is aberrantly methylated in lung cancer, and that high levels of miR‑137 promoter methylation may have prognostic value for poor disease-free survival.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM and Peters S: ESMO Guidelines Working Group: Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 25 Suppl 3:iii27–iii39. 2014. View Article : Google Scholar : PubMed/NCBI
3	Field JK, Oudkerk M, Pedersen JH and Duffy SW: Prospects for population screening and diagnosis of lung cancer. Lancet. 382:732–741. 2013. View Article : Google Scholar : PubMed/NCBI
4	Minna JD, Roth JA and Gazdar AF: Focus on lung cancer. Cancer Cell. 1:49–52. 2002. View Article : Google Scholar : PubMed/NCBI
5	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
7	Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
8	Garzon R, Calin GA and Croce CM: MicroRNAs in cancer. Annu Rev Med. 60:167–179. 2009. View Article : Google Scholar : PubMed/NCBI
9	Han L, Witmer PD, Casey E, Valle D and Sukumar S: DNA methylation regulates MicroRNA expression. Cancer Biol Ther. 6:1284–1288. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kozaki K, Imoto I, Mogi S, Omura K and Inazawa J: Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in oral cancer. Cancer Res. 68:2094–2105. 2008. View Article : Google Scholar : PubMed/NCBI
11	Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, et al: miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 6(14)2008.PubMed/NCBI
12	Zhang B, Liu T, Wu T, Wang Z, Rao Z and Gao J: microRNA-137 functions as a tumor suppressor in human non-small cell lung cancer by targeting SLC22A18. Int J Biol Macromol. 74:111–118. 2015. View Article : Google Scholar : PubMed/NCBI
13	Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, Xiang C, Poisson L, deCarvalho AC, Slavin S, et al: MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1. Oncotarget. 4:665–676. 2013. View Article : Google Scholar : PubMed/NCBI
14	Chen L, Wang X, Wang H, Li Y, Yan W, Han L, Zhang K, Zhang J, Wang Y, Feng Y, et al: miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. Eur J Cancer. 48:3104–3111. 2012. View Article : Google Scholar : PubMed/NCBI
15	Chen Q, Chen X, Zhang M, Fan Q, Luo S and Cao X: miR-137 is frequently down-regulated in gastric cancer and is a negative regulator of Cdc42. Dig Dis Sci. 56:2009–2016. 2011. View Article : Google Scholar : PubMed/NCBI
16	Balaguer F, Link A, Lozano JJ, Cuatrecasas M, Nagasaka T, Boland CR and Goel A: Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis. Cancer Res. 70:6609–6618. 2010. View Article : Google Scholar : PubMed/NCBI
17	Steponaitiene R, Kupcinskas J, Langner C, Balaguer F, Venclauskas L, Pauzas H, Tamelis A, Skieceviciene J, Kupcinskas L, Malfertheiner P and Link A: Epigenetic silencing of miR-137 is a frequent event in gastric carcinogenesis. Mol Carcinog. 55:376–386. 2015. View Article : Google Scholar : PubMed/NCBI
18	Langevin SM, Stone RA, Bunker CH, Lyons-Weiler MA, LaFramboise WA, Kelly L, Seethala RR, Grandis JR, Sobol RW and Taioli E: MicroRNA-137 promoter methylation is associated with poorer overall survival in patients with squamous cell carcinoma of the head and neck. Cancer. 117:1454–1462. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kang N, Choi SY, Kim YK, Yoo IeR, Han DH, Lee DS, Kim YS, Hong SH, Kang JH, Lee KY, et al: Silencing of miR-137 by aberrant promoter hypermethylation in surgically resected lung cancer. Lung Cancer. 89:99–103. 2015. View Article : Google Scholar : PubMed/NCBI
20	Reddel RR, Ke Y, Gerwin BI, McMenamin MG, Lechner JF, Su RT, Brash DE, Park JB, Rhim JS and Harris CC: Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes. Cancer Res. 48:1904–1909. 1988.PubMed/NCBI
21	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
22	Shepherd FA, Crowley J, Van Houtte P, Postmus PE, Carney D, Chansky K, Shaikh Z and Goldstraw P; International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions, . The international association for the study of lung cancer lung cancer staging project: Proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2:1067–1077. 2007. View Article : Google Scholar : PubMed/NCBI
23	Dacic S, Kelly L, Shuai Y and Nikiforova MN: miRNA expression profiling of lung adenocarcinomas: Correlation with mutational status. Mod Pathol. 23:1577–1582. 2010. View Article : Google Scholar : PubMed/NCBI
24	Bemis LT, Chen R, Amato CM, Classen EH, Robinson SE, Coffey DG, Erickson PF, Shellman YG and Robinson WA: MicroRNA-137 targets microphthalmia-associated transcription factor in melanoma cell lines. Cancer Res. 68:1362–1368. 2008. View Article : Google Scholar : PubMed/NCBI
25	Deng Y, Deng H, Bi F, Liu J, Bemis LT, Norris D, Wang XJ and Zhang Q: MicroRNA-137 targets carboxyl-terminal binding protein 1 in melanoma cell lines. Int J Biol Sci. 7:133–137. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zhao Y, Li Y, Lou G, Zhao L, Xu Z, Zhang Y and He F: miR-137 targets estrogen-related receptor alpha and impairs the proliferative and migratory capacity of breast cancer cells. PLoS One. 7:e391022012. View Article : Google Scholar : PubMed/NCBI
27	Zhu X, Li Y, Shen H, Li H, Long L, Hui L and Xu W: miR-137 inhibits the proliferation of lung cancer cells by targeting Cdc42 and Cdk6. FEBS Lett. 587:73–81. 2013. View Article : Google Scholar : PubMed/NCBI
28	Bi Y, Han Y, Bi H, Gao F and Wang X: miR-137 impairs the proliferative and migratory capacity of human non-small cell lung cancer cells by targeting paxillin. Hum Cell. 27:95–102. 2014. View Article : Google Scholar : PubMed/NCBI
29	Li P, Ma L, Zhang Y, Ji F and Jin F: MicroRNA-137 down-regulates KIT and inhibits small cell lung cancer cell proliferation. Biomed Pharmacother. 68:7–12. 2014. View Article : Google Scholar : PubMed/NCBI