Laminin-5 stimulates hepatocellular carcinoma growth through a different function of alpha6beta4 and alpha3beta1 integrins.
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 alpha3beta1 and alpha6beta4, 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 alpha3beta1 and alpha6beta4. 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 beta4 integrin phosphorylation. However, the two HCC cell lines do not proliferate in presence of Ln-5 despite beta4 integrin and Erk1/2 activation. After transfection with alpha3 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 alpha3 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 alpha6beta4 and alpha3beta1.
Bergamini
Carlo
C
Department of Internal Medicine, Immunology, and Infectious Diseases, Section of Internal Medicine, University of Bari Medical School, Italy.
Sgarra
Concetta
C
Trerotoli
Paolo
P
Lupo
Luigi
L
Azzariti
Amalia
A
Antonaci
Salvatore
S
Giannelli
Gianluigi
G
D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D039201:Integrin alpha3beta1; D039161:Integrin alpha6beta4; D000097794:Kalinin