Abstract 3088: Mammalian sterile-20 like kinase 1(Mst1) upregulates cyclin D1 to promote hepatocellular carcinoma cell growth

Abstract

Abstract Although hepatocellular carcinoma (HCC) is highly related to the chronic infection of hepatitis B or C viruses, the progression of the malignancies is caused by the increased proliferation of the HCC cells. The proliferation of tumor cells is usually resulted from dysregulations in cell cycle progression or apoptosis induction. Current evidence indicates that the cytoplasmic serine/threonine kinase Mammalian Sterile-20 like kinase 1 (Mst1) suppresses HCC development by inactivating the oncoprotein YAP65 in normal livers. Furthermore, upon DNA damage, the caspase cleavage of the full-length cytoplasmic Mst1 proteins is activated, which then leads to Mst1 nuclear translocation and apoptosis induction via transcriptional activation of the Forkhead tumor suppressor Foxo3a. Using an HCC cell line model, the Hep3B cells, we found that transient transfection of Mst1 did not induce apoptosis, but rather enhanced the cellular proliferation by 74% within 2 days after transfection. The growth-promoting activity of Mst1 in the HCC cells was confirmed as Hep3B cell growth was significantly reduced by transient expression of the Mst1 kinase dead mutant (26% reduction) or Mst1 specific shRNAs (62% reduction). The Mst1-induced cell proliferation was further evidenced by the presence of Ki67 nuclear staining in the transfected Hep3B cells while the cells expressing the kinase dead mutant of Mst1 did not have Ki67 nuclear staining. Moreover, Western blot analyses showed that phosphorylation of YAP65 was not dependent upon Mst1 overexpression, suggesting that the hippo pathway was not involved in the Mst1 induced cell proliferation. Interestingly, Western blotting showed that such a growth-promoting activity of Mst1 in Hep3B cells was associated with a sustained upregulation of Cyclin D1 expression, an important marker for proliferation, after Mst1 overexpression. Our findings suggest that an alteration of Mst1 function exists in HCC cells, which drives aberrant HCC proliferation via Cycin D1 upregulation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3088.