Abstract
The function of human transmembrane protein 176A (TMEM176A) in cancer remains unclear. To understand the function and mechanism of TMEM176A in human esophageal cancer development, 13 esophageal cancer cell lines and 267 cases of primary esophageal squamous cell cancer (ESCC) samples were analyzed by methylation specific PCR (MSP), flow cytometry, immunohistochemistry and transfection assays. TMEM176A was highly expressed in BIC1 cells and loss of TMEM176A expression was found in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2 and COLO680N cells. Complete methylation was detected in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2 and COLO680N cells, while unmethylation was detected in BIC1 cells. Restoration of TMEM176A expression was induced by 5-aza-2’-deoxycytidine treatment in methylated cell lines. TMEM176A was methylated in 66.7% (178/267) of primary esophageal cancer samples, and promoter region methylation was significantly associated with tumor differentiation (p<0.001) and loss off/reduced expression of TMEM176A (p<0.05). Methylation of TMEM176A was significantly associated with poor 5-year overall survival (p < 0.05). Cox proportional hazards model analysis suggest that TMEM176A methylation is an independent prognostic factor for poor 5-years OS. TMEM176A inhibited cell invasion and migration, and induced apoptosis in esophageal cancer cells. TMEM176A suppressed esophageal cancer cell growth both in vitro and in vivo. In conclusion, TMEM176A is frequently methylated in human ESCC and the expression of TMEM176A is regulated by promoter region methylation. TMEM176A methylation may serve as a diagnostic and prognostic marker in ESCC. TMEM176A is a potential tumor suppressor in human ESCC.
Highlights
Esophageal cancer (EC) is one of the most common malignancies
Complete methylation was found in TE1, TE3, TE13, KYSE140, KYSE180, KYSE410, KYSE450, KYSE520, Segl, KYSE150, YES2, and COLO680N cells, while unmethylation was detected in BIC1 cells (Figure 1B)
These results demonstrated that loss of TMEM176A expression is related to promoter hypermethylation in esophageal cancer cells
Summary
Esophageal cancer (EC) is one of the most common malignancies. The overall 5-year survival ranges from 15% to 25% [1]. Esophageal squamous cell cancer (ESCC) is the major tissue type of EC and accounts for 90% of cases worldwide [2]. The so-called “Asian Esophageal Cancer Belt” encompasses areas including Turkey, Iran, Kazakhstan and northern and central China, with an estimated incidence of more than 100 cases/100,000 people per year [3,4,5]. Alcohol and nitrates are regarded as major risk factors of esophageal cancer www.impactjournals.com/oncotarget [6]. Environmental factors may play important roles in esophageal carcinogenesis [7,8,9]. The role of environmental chemicals as determinants of DNA methylation has gained considerable attention [10,11,12,13]. Epigenetics may play more important roles than genetics in esophageal cancer. CHFR, a DNA damage repair gene, is frequently methylated but rarely mutated in human ESCC [14, 15]
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