Profiling of the Tetraspanin CD151 Web and Conspiracy of CD151/Integrin β1 Complex in the Progression of Hepatocellular Carcinoma

Ranjan Prasad Devbhandari,Jian Zhou,Ai-Wu Ke,Xiao-Ying Wang,Xiao-Yong Huang,Ying-Hong Shi,Fei-Zhen Wu,Yang Xu,Zhen-Bin Ding,Zhi Dai,Guo-Ming Shi,Jia Fan,John Luk

doi:10.1371/journal.pone.0024901

Abstract

Tetraspanin CD151 has been implicated in metastasis through forming complexes with different molecular partners. In this study, we mapped tetraspanin web proteins centered on CD151, in order to explore the role of CD151 complexes in the progression of hepatocellular carcinoma (HCC). Immunoprecipitation was used to isolate tetraspanin complexes from HCCLM3 cells using a CD151 antibody, and associated proteins were identified by mass spectrometry. The interaction of CD151 and its molecular partners, and their roles in invasiveness and metastasis of HCC cells were assayed through disruption of the CD151 network. Finally, the clinical implication of CD151 complexes in HCC patients was also examined. In this study, we identified 58 proteins, characterized the tetraspanin CD151 web, and chose integrin β1 as a main partner to further investigate. When the CD151/integrin β1 complex in HCC cells was disrupted, migration, invasiveness, secretion of matrix metalloproteinase 9, and metastasis were markedly influenced. However, both CD151 and integrin β1 expression were untouched. HCC patients with high expression of CD151/integrin β1 complex had the poorest prognosis of the whole cohort of patients. Together, our data show that CD151 acts as an important player in the progression of HCC in an integrin β1-dependent manner.

Highlights

The dismal prognosis of hepatocellular carcinoma (HCC) is mostly attributed to high metastasis
Integrin b1 has been widely studied in the biology of solid tumors, as its expression positively correlates with poor prognosis in a several malignancies, including breast cancer [6] and HCC [7]
[19], and epithelial-mesenchymal transition (EMT) [8]. We showed that it was associated with the progression and metastasis of HCC by forming complexes with c-Met or integrin a6

Summary

Introduction

The dismal prognosis of hepatocellular carcinoma (HCC) is mostly attributed to high metastasis. This disease has attracted the considerable attention of investigators from the bench to the clinic [1,2]. Metastasis is a multi-step cascade involving migration of tumor cells from the original site, evasion of host defense systems, subsequent location to distant organs, and growth of secondary tumors [3,4]. Throughout the cascade, from its original location to distant sites, there is constant interplay between metastasizing tumor cells and the changing microenvironment, leading to the breakdown of normal cell adhesion which facilitates cell migration [5]. Proteins were resolved by SDS-PAGE (Fig. 1A), and CD151-containing complexes were identified by mass spectrometry

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Methods

Results