Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin.
Metastasis occurrence in the course of hepatocellular carcinoma (HCC) severely affects prognosis and survival. We have shown that HCC invasive cells express alpha3beta1-integrin whereas noninvasive cells do not. Here we show that transforming growth factor (TGF)-beta1 stimulates alpha3-integrin expression at a transcriptional level in noninvasive HCC cells, causing transformation into a motile and invasive phenotype. Such activities are inhibited by neutralizing anti-alpha3- but not anti-alpha6-integrin monoclonal antibodies. HCC invasive cells secrete abundant levels of active TGF-beta1 in comparison with noninvasive cells, but in the latter, addition of active matrix metalloproteinases-2 increases the concentration of active TGF-beta1. In this way, the cells express alpha3-integrin at a transcriptional level and acquire motility on Ln-5. By contrast, an anti-TGF-beta1-neutralizing antibody reduces alpha3-integrin expression and the invasive ability of HCC invading cells. In HCC patients, TGF-beta1 serum concentrations and alpha3-integrin expression are strongly correlated. The integrin, absent in normal and peritumoral liver parenchyma, is abundantly expressed in HCC primary and metastatic tissue. In particular, patients with metastasis show higher levels of TGF-beta1 serum concentrations and stronger expression of TGF-beta1 and alpha3-integrin in HCC tissues. In conclusion, TGF-beta1 may play an important role in HCC invasiveness by stimulating alpha3-integrin expression, and could therefore be an important target for new therapies.
Giannelli
Gianluigi
G
Department of Internal Medicine, Immunology, and Infectious Diseases, University of Bari Medical School, Bari, Italy. g.giannelli@intmed.uniba.it
Fransvea
Emilia
E
Marinosci
Felice
F
Bergamini
Carlo
C
Colucci
Silvia
S
Schiraldi
Oronzo
O
Antonaci
Salvatore
S
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D001672:Biocompatible Materials; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D006801:Humans; D039422:Integrin alpha3; D039201:Integrin alpha3beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007797:Laminin; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D011509:Proteoglycans; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D000097794:Kalinin
D000906:Antibodies; D015703:Antigens, CD; D001672:Biocompatible Materials; D015815:Cell Adhesion Molecules; D003094:Collagen; D004338:Drug Combinations; D039422:Integrin alpha3; D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D020778:Matrix Metalloproteinase 2; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000097794:Kalinin; C508960:TGFB1 protein, human; C059485:matrigel