Hypermethylation of normal mucosa of esophagus‑specific 1 is associated with an unfavorable prognosis in patients with non‑small cell lung cancer

Kim,Dong  Sun; Lee,Won  Kee; Park,Jae  Yong

doi:10.3892/ol.2018.8915

Hypermethylation of normal mucosa of esophagus‑specific 1 is associated with an unfavorable prognosis in patients with non‑small cell lung cancer

Authors:
- Dong Sun Kim
- Won Kee Lee
- Jae Yong Park
View Affiliations

Affiliations: Department of Anatomy, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea, Department of Preventive Medicine, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 702‑422, Republic of Korea
Published online on: June 6, 2018 https://doi.org/10.3892/ol.2018.8915
Pages: 2409-2415
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lung cancer is the leading cause of cancer‑associated mortality due to high incidence and poor survival rates, irrespective of global variations in its biology and treatment. Changes in DNA methylation are frequent in cancer and constitute an important mechanism in tumorigenesis. Normal mucosa of esophagus‑specific 1 (NMES1) is expressed in epithelial tissue and is believed to be a tumor suppressor gene. The present study investigated the methylation status of the NMES1 promoter in 178 cases of primary non‑small cell lung cancer (NSCLC) by pyrosequencing and evaluated the prognostic value of this methylation. NMES1 methylation‑positive tumors above the background threshold for non‑malignant tissue were found in 15 cases (8.4%) and were detected exclusively in malignant tissues. In addition, univariate and multivariate analyses showed that methylation‑positive patients experienced worse overall survival rate (OSR) compared with methylation‑negative patients (adjusted hazard ratio, 2.62; 95% confidence interval, 1.20‑5.69; P=0.02). Notably, within the methylation‑positive group, patients with strong methylation tended to experience worse OSR compared with those with weak methylation (adjusted hazard ratio, 2.45 vs. 3.05; Ptrend=0.02). These findings suggest that NMES1 may serve an important role in lung cancer pathogenesis, and its methylation could be considered a prognostic marker for NSCLC. Further studies with large numbers of samples are required to confirm this conclusion.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	McIntyre A and Ganti AK: Lung cancer-A global perspective. J Surg Oncol. 115:550–554. 2017. View Article : Google Scholar : PubMed/NCBI
3	I H and Cho JY: Lung cancer biomarkers. Adv Clin Chem. 72:107–170. 2015. View Article : Google Scholar : PubMed/NCBI
4	Vargas AJ and Harris CC: Biomarker development in the precision medicine era: Lung cancer as a case study. Nat Rev Cancer. 16:525–537. 2016. View Article : Google Scholar : PubMed/NCBI
5	Baylin SB and Jones PA: A decade of exploring the cancer epigenome-biological and translational implications. Nat Rev Cancer. 11:726–734. 2011. View Article : Google Scholar : PubMed/NCBI
6	Liloglou T, Bediaga NG, Brown BR, Field JK and Davies MP: Epigenetic biomarkers in lung cancer. Cancer Lett. 342:200–212. 2014. View Article : Google Scholar : PubMed/NCBI
7	Walter K, Holcomb T, Januario T, Yauch RL, Du P, Bourgon R, Seshagiri S, Amler LC, Hampton GM and S Shames D: Discovery and development of DNA methylation-based biomarkers for lung cancer. Epigenomics. 6:59–72. 2014. View Article : Google Scholar : PubMed/NCBI
8	Zhou J, Wang H, Lu A, Hu G, Luo A, Ding F, Zhang J, Wang X, Wu M and Liu Z: A novel gene, NMES1, downregulated in human esophageal squamous cell carcinoma. Int J Cancer. 101:311–316. 2002. View Article : Google Scholar : PubMed/NCBI
9	Arai M, Imazeki F, Sakai Y, Mikata R, Tada M, Seki N, Shimada H, Ochiai T and Yokosuka O: Analysis of the methylation status of genes up-regulated by the demethylating agent, 5-aza-2′-deoxycytidine, in esophageal squamous cell carcinoma. Oncol Rep. 20:405–412. 2008.PubMed/NCBI
10	Sova P, Feng Q, Geiss G, Wood T, Strauss R, Rudolf V, Lieber A and Kiviat N: Discovery of novel methylation biomarkers in cervical carcinoma by global demethylation and microarray analysis. Cancer Epidemiol Biomarkers Prev. 15:114–123. 2006. View Article : Google Scholar : PubMed/NCBI
11	Spisák S, Kalmár A, Galamb O, Wichmann B, Sipos F, Péterfia B, Csabai I, Kovalszky I, Semsey S, Tulassay Z and Molnár B: Genome-wide screening of genes regulated by DNA methylation in colon cancer development. PLoS One. 7:e462152012. View Article : Google Scholar : PubMed/NCBI
12	Riggs PK, Angel JM, Abel EL and Digiovanni J: Differential gene expression in epidermis of mice sensitive and resistant to phorbol ester skin tumor promotion. Mol Carcinog. 44:122–136. 2005. View Article : Google Scholar : PubMed/NCBI
13	Detterbeck FC, Boffa DJ and Tanoue LT: The new lung cancer staging system. Chest. 136:260–271. 2009. View Article : Google Scholar : PubMed/NCBI
14	Shaw RJ, Hall GL, Lowe D, Bowers NL, Liloglou T, Field JK, Woolgar JA and Risk JM: CpG island methylation phenotype (CIMP) in oral cancer: Associated with a marked inflammatory response and less aggressive tumour biology. Oral Oncol. 43:878–886. 2007. View Article : Google Scholar : PubMed/NCBI
15	Lee SM, Lee WK, Kim DS and Park JY: Quantitative promoter hypermethylation analysis of RASSF1A in lung cancer: Comparison with methylation-specific PCR technique and clinical significance. Mol Med Rep. 5:239–244. 2012.PubMed/NCBI
16	Deaton AM and Bird A: CpG islands and the regulation of transcription. Genes Dev. 25:1010–1022. 2011. View Article : Google Scholar : PubMed/NCBI
17	Selamat SA, Chung BS, Girard L, Zhang W, Zhang Y, Campan M, Siegmund KD, Koss MN, Hagen JA, Lam WL, et al: Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res. 22:1197–1211. 2012. View Article : Google Scholar : PubMed/NCBI
18	Bert SA, Robinson MD, Strbenac D, Statham AL, Song JZ, Hulf T, Sutherland RL, Coolen MW, Stirzaker C and Clark SJ: Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell. 23:9–22. 2013. View Article : Google Scholar : PubMed/NCBI
19	Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, et al: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 41:178–186. 2009. View Article : Google Scholar : PubMed/NCBI
20	Kim DS, Lee SM, Yoon GS, Choi JE and Park JY: Infrequent hypermethylation of the PTEN gene in Korean non-small cell lung cancers. Cancer Sci. 101:568–572. 2010. View Article : Google Scholar : PubMed/NCBI
21	Lessi F, Beggs A, de Palo M, Anti M, Macarone Palmieri R, Francesconi S, Gomes V, Bevilacqua G, Tomlinson I and Segditsas S: Down-regulation of serum/glucocorticoid regulated kinase 1 in colorectal tumours is largely independent of promoter hypermethylation. PLoS One. 5:e138402010. View Article : Google Scholar : PubMed/NCBI
22	Braga LC, Silva LM, Ramos AP, Piedade JB, Vidigal PV, Traiman P and da Silva Filho AL: Single CpG island methylation is not sufficient to maintain the silenced expression of CASPASE-8 apoptosis-related gene among women with epithelial ovarian cancer. Biomed Pharmacother. 68:87–91. 2014. View Article : Google Scholar : PubMed/NCBI
23	Floyd BJ, Wilkerson EM, Veling MT, Minogue CE, Xia C, Beebe ET, Wrobel RL, Cho H, Kremer LS, Alston CL, et al: Mitochondrial protein interaction mapping identifies regulators of respiratory chain function. Mol Cell. 63:621–632. 2016. View Article : Google Scholar : PubMed/NCBI
24	Garcia-Heredia JM and Carnero A: Decoding Warburg's hypothesis: Tumor-related mutations in the mitochondrial respiratory chain. Oncotarget. 6:41582–41599. 2015. View Article : Google Scholar : PubMed/NCBI
25	Maunakea AK, Chepelev I, Cui K and Zhao K: Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 23:1256–1269. 2013. View Article : Google Scholar : PubMed/NCBI
26	Hitchins MP, Rapkins RW, Kwok CT, Srivastava S, Wong JJ, Khachigian LM, Polly P, Goldblatt J and Ward RL: Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell. 20:200–213. 2011. View Article : Google Scholar : PubMed/NCBI
27	Forn M, Muñoz M, Tauriello DV, Merlos-Suárez A, Rodilla V, Bigas A, Batlle E, Jordà M and Peinado MA: Long range epigenetic silencing is a trans-species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells. Mol Oncol. 7:1129–1141. 2013. View Article : Google Scholar : PubMed/NCBI