TMEM16A overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-β signaling.

Fang Liu,Rong-Cheng Luo,Qing-Hua Cao,Xiao-Fang Lu,De-Jian Lu,Bin Luo,Xiao-Guang Wang

doi:10.18632/oncotarget.3412

Abstract

TMEM16A is a newly identified calcium activated chloride channel, and has been reported to be overexpressed by various solid malignant cancers to promote proliferation and invasion, yet little is known about its role in gastric cancer(GC). Therefore, we investigated the role of TMEM16A in GC and its clinical significance by a retrospective analysis of 367 GC patients, and in vitro study was performed for validation and underlying molecular mechanism.TMEM16A was significantly upregulated and amplified in GC tissues, and its overexpression was positively correlated with disease stage, negatively with patient survival and identified as an independent prognostic factor for patient outcome. A negative correlation between TMEM16A and E-cadherin was found in 367 GC specimens. TMEM16A silencing significantly decreased calcium activated chloride currents, impaired TGF-β secretion, reduced E-cadherin expression, and inhibited the migration and invasion without affecting proliferation of GC cells (AGS and BGC-823). Supplement of TGF-β reverted the effects of TMEM16A silencing on E-cadherin expression, cell migration and invasion.In conclusion, TMEM16A promotes invasion and metastasis in GC, and might be a novel prognostic biomarker and potential therapeutic target in the treatment of GC.

Highlights

Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancerrelated death worldwide [1], especially the incidence of GC is much higher in china than in any other country [2]
Transmembrane protein 16A (TMEM16A) has been found to be upregulated in many tumor types including gastrointestinal stromal tumor, breast cancer, prostate cancer, esophyageal cancer, and head and neck squamous cell cancer (HNSCC) [6,7,8,9], and overexpression of TMEM16A has been implicated in promoting tumor proliferation [10], migration and invasion [11]
We found that TMEM16A was markedly upregulated and amplified in GC tissues, and its overexpression significantly correlated with the clinicopathological characteristics and shorter survival of patients with GC, its expression was inverse relation with E-cadherin in 367 GC specimens, corresponding lymph node metastases and adjacent no-tumor tissues

Summary

Introduction

Gastric cancer (GC) is the fourth most common cancer and the second most common cause of cancerrelated death worldwide [1], especially the incidence of GC is much higher in china than in any other country [2]. The diagnosis, staging and treatment of GC have improved over past decades, the prognosis remains poor due to local invasion and distal metastasis [3]. The complex molecular mechanisms underlying invasion and metastasis are not well characterized [4]. The biological role and clinical significance of TMEM16A in GC remain largely elusive. TMEM16A is located within 11q13 chromosome amplicon, which is proved to be associated with carcinogenesis of GC [12, 13]. All of these information aroused our curiosity to investigate whether TMEM16A is relevant with tumorigenesis and progression of GC

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