Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression.

Y Tanaka,Y Asaoka,H Ijichi,K Tateishi,K Yamamoto,N Kokudo,T Nakatsuka,Y Kudo,T Ishizawa,K Miyabayashi,M Fukayama,R Tateishi,K Hasegawa,K Koike,R Takahashi,J Shibahara

doi:10.1038/oncsis.2016.76

Abstract

Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/β-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/β-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.

Highlights

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide
Sharpin overexpression led to increased expression of Versican, an aggregating chondroitin sulfate proteoglycan that plays biological roles in tumor progression and invasion,17,18 leading to HCC cell invasion
These results indicate that Sharpin expression frequently increases in human HCC and this increased Sharpin expression might be involved in the pathogenesis of a subset of HCC cases

Summary

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide. Sharpin (Shank-associated RH domain interacting protein), known as SIPL1 (Shank-interacting protein-like 1), was first identified as a protein that directly interacts with the ankyrin repeats of Shank family proteins in the postsynaptic density.4 Another important role of Sharpin was later recognized as one of the components of an E3 ubiquitin–protein ligase complex, the linear ubiquitin chain assembly complex (LUBAC). Growth, and invasion, suggesting tumor-associated roles during cancer biogenesis. These functions are dependent on NF-κB signaling functions such as the induction of matrix metalloproteinases (MMP-2 and MMP-9) and upregulation of survivin, a member of the inhibitor of apoptosis family.. Sharpin overexpression led to increased expression of Versican, an aggregating chondroitin sulfate proteoglycan that plays biological roles in tumor progression and invasion, leading to HCC cell invasion. Our findings indicate the importance of a novel Sharpin/Versican axis in HCC invasion

Background liver

25 Ctrl FL 1-351 1-221

DISCUSSION

MATERIALS AND METHODS

37 IP: FG IB