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Proapoptotic Function of Integrin β₃ in Human Hepatocellular Carcinoma Cells

Authors' Affiliations: ¹ State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai, P.R. China; ² Division of Molecular Radiobiology, School of Health Sciences and Purdue Cancer Center, Purdue University, West Lafayette, Indiana; and ³ Program of Cell Death and Apoptosis, The Burnham Institute for Medical Research, La Jolla, California

Requests for reprints: Long Yu, State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China. Phone: 86-21-65643713; Fax: 86-21-65643250; E-mail: longyu{at}fudan.edu.cn.

Purpose: This study evaluates the proapoptotic function of integrin β₃ in human hepatocellular carcinoma (HCC).

Experimental Design: The expression of integrin β₃ in 67 HCC specimens paired with corresponding neighboring nontumorous tissue was studied by quantitative real-time PCR and Western blot. The proapoptotic function of integrin β₃ in SMMC-7721 human hepatoma cells overexpressing ITGB3 (gene coding integrin β₃) was determined through colony formation, serum starvation, and anoikis assay.

Results: Compared with neighboring pathologically normal liver tissue, 60% of the HCC specimens showed a significant down-regulated level of integrin β₃ expression. Transient expression of integrin β₃ in SMMC-7721 resulted in an enhanced level of apoptosis and suppression of colony formation. Cell growth inhibition on serum/ligand deprivation and incidences of anoikis were remarkably increased in SMMC-7721 with stable expression of integrin β₃ in comparison with vector control transfectants. In addition, expression of fibrinogen and vitronectin, two native ligands for integrin _vβ₃ in liver, was inhibited, which was correlated with the decreased integrin β₃ expression. Replenishing these ligands to the starved SMMC-7721 stable transfectants effectively restored the proapoptotic function of integrin β₃.

Conclusions: Down-regulation of integrin β₃ and its ligands in liver is related to the aggressive growth of HCC. Thus, reconstitution of integrin β₃ in HCC may be a potential therapeutic approach to inhibit aggressive growth of liver cancer.