YAP1 enhances cell proliferation, migration, and invasion of gastric cancer in vitro and in vivo.

Dan Sun,Huan Wang,Xiaoting Li,Shanshan Jiang,Ying Wang,Yan Xin,Yingjian He,Wenhui Li

doi:10.18632/oncotarget.13188

Abstract

Yes-associated protein 1 (YAP1) plays an important role in the development of carcinomas such as breast, colorectal, and gastric (GC) cancers, but the role of YAP1 in GC has not been investigated comprehensively. The present study strongly suggests that YAP1 and P62 were significantly up-regulated in GC specimens, compared with normal gastric mucosa. In addition, the YAP1high P62high expression was independently associated with poor prognosis in GC (hazard ratio: 1.334, 95% confidence interval: 1.045–1.704, P = 0.021). Stable YAP1 silencing inhibited the proliferation, migration, and invasion of BGC-823 GC cells in vitro and inhibited the growth of xenograft tumor and hematogenous metastasis of BGC-823 GC cells in vivo. The mechanism was associated with inhibited extracellular signal-regulated kinases (ERK)1/2 phosphorylation, elevated E-cadherin protein expression and decreased vimentin protein expression, down-regulated β-catenin protein expression and elevated α-catenin protein expression, and down-regulated long non-coding RNA (lncRNA) expressions including HOX transcript antisense RNA (HOTAIR), H19, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), human large tumor suppressor-2 (LATS2)-AS1-001, and LATS2. YAP1 over-expression promoted the proliferation, migration, and invasion of human immortalized normal gastric mucosa GES-1 cells in vitro by reversing the above signal molecules. Subcutaneous inoculation of GES-1 cells and YAP1-over-expressing GES-1 cells into nude mice did not generate tumors. We successfully established the xenograft tumor models using MKN-45 GC cells, but immunochemistry showed that there was no YAP1 expression in MKN-45 cells. These results suggest that YAP1 is not a direct factor affecting tumor formation, but could accelerate tumor growth and metastasis. Collectively, this study highlights an important role for YAP1 as a promoter of GC growth and metastasis, and suggests that YAP1 could possibly be a potential treatment target for GC.

Highlights

Gastric cancer is a leading cause of cancer-related death in China and most gastric cancer patients are already diagnosed with late stage disease [1]
Compared with normal gastric mucosa, Yes-associated protein 1 (YAP1) expression was significantly up-regulated in moderately differentiated gastric adenocarcinoma, poorly differentiated adenocarcinoma, and signet ring cell cancer (Figure 1A–1D)
YAP1 is an effector of the Hippo pathway, which promoted cell proliferation and tumor growth in mammals [17, 18], but the influence of YAP1 in GC has not been comprehensively investigated

Summary

Introduction

Gastric cancer is a leading cause of cancer-related death in China and most gastric cancer patients are already diagnosed with late stage disease [1]. The Hippo-YAP signaling pathway regulates cell proliferation and apoptosis [3]. Within this pathway, the Yes-associated protein 1 (YAP1) is a negative regulator of the Hippo-YAP pathway [4]. The WW domain of YAP1 directly interacts with the transcription factor polyomavirus enhancer binding protein 2α (PEBP2α) through the PPXY motif [4]. YAP1 acts as a transcription co-activator of the Hippo-YAP signaling pathway together with PEBP2α [5]. YAP1 www.impactjournals.com/oncotarget can co-activate other PPXY-motif-containing transcription factors such as receptor tyrosine-protein kinase erbB4 (ERBB4) and p73 [6]. YAP1 interacts with the transcription factors TEA domain transcription factors (TEAD) and plays an essential role in mediating TEAD-dependent gene expression, which are involved in cell proliferation and survival [7]

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Results

Conclusion