UNLABELLED: 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.
UNLABELLED: 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.
Authors: Franziska van Zijl; Gudrun Zulehner; Michaela Petz; Doris Schneller; Christoph Kornauth; Mara Hau; Georg Machat; Markus Grubinger; Heidemarie Huber; Wolfgang Mikulits Journal: Future Oncol Date: 2009-10 Impact factor: 3.404
Authors: Francesco Dituri; Antonio Mazzocca; Joan Fernando; Fernando Juan Peidrò; Patrizia Papappicco; Isabel Fabregat; Flavia De Santis; Angelo Paradiso; Carlo Sabbà; Gianluigi Giannelli Journal: PLoS One Date: 2013-06-27 Impact factor: 3.240
Authors: Keane K Y Lai; Sufen Shang; Neha Lohia; Garrett C Booth; Derek J Masse; Nelson Fausto; Jean S Campbell; Laura Beretta Journal: PLoS Genet Date: 2011-06-23 Impact factor: 5.917