Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins

Carlo Bergamini, Concetta Sgarra, Paolo Trerotoli, Luigi Lupo, Amalia Azzariti, Salvatore Antonaci, Gianluigi Giannelli

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1801-1809
Number of pages9
JournalHepatology
Volume46
Issue number6
DOIs
Publication statusPublished - Dec 2007

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Integrins
Hepatocellular Carcinoma
Growth
Cell Proliferation
Epidermal Growth Factor
Cell Line
kalinin
Collagen
Phosphorylation
Extracellular Matrix Proteins
Fibronectins
Fluorescent Antibody Technique
Transfection
Real-Time Polymerase Chain Reaction
Intercellular Signaling Peptides and Proteins
Cell Count
Staining and Labeling

ASJC Scopus subject areas

  • Hepatology

Cite this

Bergamini, C., Sgarra, C., Trerotoli, P., Lupo, L., Azzariti, A., Antonaci, S., & Giannelli, G. (2007). Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins. Hepatology, 46(6), 1801-1809. https://doi.org/10.1002/hep.21936

Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins. / Bergamini, Carlo; Sgarra, Concetta; Trerotoli, Paolo; Lupo, Luigi; Azzariti, Amalia; Antonaci, Salvatore; Giannelli, Gianluigi.

In: Hepatology, Vol. 46, No. 6, 12.2007, p. 1801-1809.

Research output: Contribution to journalArticle

Bergamini, C, Sgarra, C, Trerotoli, P, Lupo, L, Azzariti, A, Antonaci, S & Giannelli, G 2007, 'Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins', Hepatology, vol. 46, no. 6, pp. 1801-1809. https://doi.org/10.1002/hep.21936
Bergamini C, Sgarra C, Trerotoli P, Lupo L, Azzariti A, Antonaci S et al. Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins. Hepatology. 2007 Dec;46(6):1801-1809. https://doi.org/10.1002/hep.21936
Bergamini, Carlo ; Sgarra, Concetta ; Trerotoli, Paolo ; Lupo, Luigi ; Azzariti, Amalia ; Antonaci, Salvatore ; Giannelli, Gianluigi. / Laminin-5 stimulates hepatocellular carcinoma growth through a different function of α6β4 and α3β1 integrins. In: Hepatology. 2007 ; Vol. 46, No. 6. pp. 1801-1809.
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AU - Lupo, Luigi

AU - Azzariti, Amalia

AU - Antonaci, Salvatore

AU - Giannelli, Gianluigi

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N2 - 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.

AB - 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.

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