ERp29 controls invasion and metastasis of gastric carcinoma by inhibition of epithelial-mesenchymal transition via PI3K/Aktsignaling pathway

Jianxin Ye,Jinsheng Huang,Xu Lin,Jinzhou Wang,Qiang Huang,Yun Li,Xinjian Lin,Jie Xu,Wenjing Zhong

doi:10.1186/s12885-017-3613-x

Abstract

BackgroundGastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. Recently, the endoplasmic reticulum (ER) protein 29 (ERp29) has been shown to inversely associate with primary tumor development and function as a tumor suppressor in breast cancer. However, the role of ERp29 in GC patients’ prognosis and its function in GC progression is unknown.MethodsClinical importance of ERp29 in the prognosis of GC patients was assessed by examining its expression in 148 GC tumor samples and correlation with clinicopathological characteristics and survival of the patients. The function and underlying mechanisms of ERp29 in GC growth, invasion and metastasis were explored both in vitro and in vivo.ResultsDownregulation of ERp29 was commonly found in GC tissues and highly correlated with more aggressive phenotypes and poorer prognosis. Functional assays demonstrated that knockdown of ERp29 increased GC cell migration and invasion and promoted metastasis. Conversely, ectopic overexpression of ERp29 produced opposite effects. Mechanistic studies revealed that loss of ERp29 induced an epithelial-to-mesenchymal transition (EMT) in the GC cells through activation of PI3K/Akt pathway signaling.ConclusionThese findings suggest that downregulation of ERp29 is probably one of the key molecular mechanisms responsible for the development and progression of GC.

Highlights

Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death
Endoplasmic reticulum protein 29 (ERp29) downregulation in GC is correlated with poor prognosis To discern the prognostic relevance of ERp29 expression, IHC was performed in a cohort of archived tumor samples from 148 gastric cancer patients
Given the observation that ERp29 expression was downregulated in GC, Kaplan–Meier analysis was employed to evaluate the relationship of ERp29 protein expression as assessed by IHC with patient outcome

Summary

Introduction

Gastric cancer (GC) accounts for the fourth most occurring malignancy and the third major cause of cancer death. Identifying novel molecular signaling pathways participating in gastric tumorigenesis and progression is pivotal for rational design of targeted therapies to improve advanced GC outcome. While recent decades have witnessed therapeutic advances, the clinical outcome of gastric cancer (GC) is still disappointing in view of the facts that a majority of GC patients has advanced to late stage at diagnosis and that current chemotherapy only offers limited survival advantage. Advanced stage at initial diagnosis of GC is commonly seen in a large percentage of GC patients presenting unresectable disease or distant metastases. It is one of the most challenging clinical tasks to effectively manage and treat advanced GC patients. There is certainly a need to identify novel biomolecules for possible GC early diagnosis, prognosis prediction and potential targets for development of novel therapeutic agents that target such pivotal molecular

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