Research Papers:

Epigenetic silencing of TMEM176A promotes esophageal squamous cell cancer development

Ying Wang, You Zhang, James G. Herman, Enqiang Linghu and Mingzhou Guo _

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Oncotarget. 2017; 8:70035-70048. https://doi.org/10.18632/oncotarget.19550

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Ying Wang1,2,*, You Zhang1,*, James G. Herman3, Enqiang Linghu1 and Mingzhou Guo1

1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing 100853, China

2Department of Gastroenterology, The Affiliated Fu Xing Hospital of Capital Medical University, Beijing 100038, China

3The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA

*These authors have contributed equally to this work

Correspondence to:

Mingzhou Guo, email: [email protected]

Enqiang Linghu, email: [email protected]

Keywords: TMEM176A, esophageal squamous cell cancer, DNA methylation, epigenetics, tumor suppressor

Received: February 04, 2017     Accepted: June 27, 2017     Published: July 25, 2017


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.

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