. 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  (TGF-) in human activated HSCs. The PI3K inhibitor LY294002 and the mitogen-activated protein kinase kinase (MEK) inhibitor UO126 prevented ADAM12 induction by TGF-, 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. I ncreased expression and activities of matrix metalloproteinase (MMP) has been shown widely in malignant phenotypes facilitating the breakdown of extracellular matrix component and cell evasion, but also unmasking bioactive cryptic fragments and releasing active growth factors which, in turn, favor tumor growth. 1 The ADAMs (a disintegrin and metalloproteinase-containing proteins) are a family of multidomain glycoproteins highly homologous to the class III snake venom metalloprotease-disintegrins. 2 The common extracellular part of the proteins includes a regulatory prodomain and metalloprotease, disintegrin-like and cystein-rich domains. Further, ADAMs are characterized by an epidermal growth factor (EGF)-like domain, a transmembrane domain, and a cytoplasmic tail. More than 30 members have been identified in the ADAM family with a broad tissue distribution and have been involved in specific cellular processes including sperm-egg interaction, 3 myocyte fusion, 4 neurogenesis, 5 and adipogenesis. 6 Recently, ADAM12 gene therapy was shown to rescue the pathology of mdx-gene deficient dystrophic mice.
Staphylococcus aureus pathogenesis is directed by regulatory proteins and RNAs. We report the case of an RNA attenuating virulence and host uptake, possibly to sustain commensalism. A S. aureus sRNA, SprC (srn_3610), reduced virulence and bacterial loads in a mouse infection model. S. aureus deleted for sprC became more virulent and increased bacterial dissemination in colonized animals. Conversely, inducing SprC expression lowered virulence and the bacterial load. Without sprC, S. aureus phagocytosis by monocytes and macrophages was higher, whereas bacteria were internalized at lower yields when SprC expression was stimulated. Without sprC, higher internalization led to a greater number of extracellular bacteria, facilitating colonization. SprC expression decreased after phagocytosis, concurring with the facilitated growth of bacteria lacking the sRNA in the presence of an oxidant. The major staphylococcal autolysin facilitates S. aureus uptake by human phagocytes. ATL proved to be negatively regulated by SprC. The SprC domains involved in pairing with atl mRNA were analyzed. The addition of ATL reduced phagocytosis of bacteria lacking sprC with no effects on wild-type bacterial uptake, implying that SprC influences phagocytosis, at least in part, by controlling ATL. Since the control of SprC on ATL was modest, other factors must contribute to atl regulation.
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