ADAM12 in human liver cancers: TGF-β-regulated expression in stellate cells is associated with matrix remodeling

“A disintegrin and metalloproteinases” (ADAMs) form a family of cell–surface glycoproteins with potential protease and cell–adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT–PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs). Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12. This expression was associated with the transition from quiescent to activated state of rat HSCs and markedly increased in human livers with cirrhosis. ADAM12 but not ADAM9 expression was up–regulated by transforming growth factor β (TGF–β) in human activated HSCs. The PI3K inhibitor LY294002 and the mitogen–activated protein kinase kinase (MEK) inhibitor UO126 prevented ADAM12 induction by TGF–β, suggesting the involvement of PI3K and MEK activities. In vivo , the steady–state of both ADAM9 and ADAM12 mRNA levels was nearly undetectable in both normal livers and benign tumors and increased in hepatocellular carcinomas (up to 3– and 6–fold, respectively) and liver metastases from colonic carcinomas (up to 40– and 60–fold, respectively). The up–regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12 expression is associated with tumor aggressiveness and progression.