Premium
Laminin‐5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins
Author(s) -
Bergamini Carlo,
Sgarra Concetta,
Trerotoli Paolo,
Lupo Luigi,
Azzariti Amalia,
Antonaci Salvatore,
Giannelli Gianluigi
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21936
Subject(s) - integrin , laminin , cell growth , cancer research , fibronectin , extracellular matrix , epidermal growth factor , microbiology and biotechnology , cell cycle , biology , cell culture , cell , chemistry , biochemistry , genetics
Hepatocellular carcinoma (HCC) growth severely affects prognosis. Ki‐67, a known marker of cell proliferation, is a negative prognostic factor in HCC. Growth factors such as the epidermal growth factor (EGF) induce HCC cell proliferation but do not explain the great heterogeneity of HCC growth. Laminin‐5 (Ln‐5) is an extracellular matrix protein (ECM) present in the tissue microenvironment of HCC. The two main receptors for Ln‐5, integrins α3β1 and α6β4, are expressed on the cell surface of HCC cells. The aim of this study is to investigate an alternative mechanism of HCC growth whereby Ln‐5 promotes HCC cell proliferation through α3β1 and α6β4. HCC tissues containing Ln‐5 display a larger diameter and higher number of positive cells for Ki‐67, a well known proliferative index, as determined by double immunofluorescence staining and real‐time PCR on microdissected tissues. In vitro , Ln‐5, but not collagen I, collagen IV or fibronectin, induces proliferation as much as EGF does, via Erk phosphorylation as a consequence of β4 integrin phosphorylation. However, the two HCC cell lines do not proliferate in presence of Ln‐5 despite β4 integrin and Erk1/2 activation. After transfection with α3 integrin, in the presence of Ln‐5 one of these HCC cell lines acquires a proliferative activity whereas one of the proliferative HCC cell lines, knocked‐down for α3 integrin, loses its proliferative activity. Conclusions: Our study suggests a new mechanism of HCC growth whereby Ln‐5 stimulates proliferation via a different function of α6β4 and α3β1. (H EPATOLOGY 2007.)