DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1.

Binhui Xie,Guosheng Tan,Shiqiu Xiong,Weihao Lin,Heping Li,Junming Ye,Bing Zhang,Xiaonong Wang

doi:10.1186/s13046-015-0218-6

Abstract

BackgroundSeveral studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression. However, the role of DDR2 in hepatocellular carcinoma (HCC) progression and its downstream signaling pathways remain unclear.MethodsDDR2 expression was assessed in several cell lines and 112 pairs of HCC and matched adjacent noncancerous liver tissues. Clinical significance of DDR2 in HCC was analyzed. Phosphorylated DDR2 (p-DDR2) expression was detected by immunoblotting to evaluate its correlation with DDR2. The effect of DDR2 on HCC cell migration and invasion were examined. Cycloheximide chase experiments were performed to detect the half-life of SNAIL1. Moreover, DDR2 expression was detected by immunohistochemistry to evaluate its correlation with SNAIL1. The regulatory effect of DDR2 on ERK signaling, SNAIL1, EMT, MT1-MMP and MMP2 was confirmed by immunoblotting. The effect of type I collagen on DDR2/ERK2/SNAIL1 signaling was assessed.ResultsDDR2 was more highly expressed in HCC than in non-HCC tissues. DDR2 overexpression was correlated with clinicopathological features of poor prognosis. Clinical analysis revealed that DDR2 is an independent prognostic marker for predicting overall survival and disease free survival of HCC patients. Overexpression of DDR2 is associated with p-DDR2 amplification. In vitro studies showed that DDR2 facilitates HCC cell invasion, migration and EMT via activating ERK2 and stabilizing SNAIL1. DDR2 can up-regulate MT1-MMP and MMP2 expression through ERK2/SNAIL1 signaling in HCC. Additionally, collagen I can induce DDR2/ERK2/SNAIL1 signaling activation in HCC cells.ConclusionsOur findings suggest that DDR2 plays an important role in promoting HCC cell invasion and migration, and may serve as a novel therapeutic target in HCC.

Highlights

Several studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression
We found that DDR2 was more highly expressed in hepatocellular carcinoma (HCC) tissues than that in non-tumor tissues, and DDR2 overexpression was correlated with poor clinicopathological features and outcome of HCC patients
Our study identified that DDR2 is a novel regulator of epithelial–mesenchymal transition (EMT) through stabilizing SNAIL1, indicating its potential therapeutic value for reducing HCC invasion and metastasis

Summary

Introduction

Several studies have found that DDR2 is up-regulated in many tumor types and facilitates tumor progression. The role of DDR2 in hepatocellular carcinoma (HCC) progression and its downstream signaling pathways remain unclear. Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide and is the second leading cause of cancer-related death in China [1,2,3]. The incidence of HCC is increasing in many parts of the world including the United States, partly due to the rise in hepatitis C virus infection [4,5,6]. It was found that the abnormal expression of DDR2 implicated in cancer progression and a poor prognosis [17, 18]. The role of DDR2 in HCC and the molecular mechanisms by which DDR2 exerts its biological function are still unclear

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Conclusion