Co-Expression of XIAP and Cyclin D1 Complex Correlates with a Poor Prognosis in Patients with Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. Despite improved diagnosis and treatment, the prognosis for HCC patients remains poor. The goal of this study was to identify key regulatory proteins and signaling pathways important for cell apoptosis and proliferation as biomarkers for prognostication and targeted therapy. Protein Pathway Array was applied to screen 38 signaling proteins and phosphoproteins in 12 paired HCC tumors and surrounding benign tissues and found that 20 of them, including MAP, CDK4, CDK6, and Cyclin D1, were overexpressed in HCC tissues. Immunostaining results of MAP, CDK4, and Cyclin D1 in an additional 59 HCC tissues showed that the expression of MAP correlated with the expression of CDK4/Cyclin D1, and that the increased expression of these proteins correlated with poor overall survival in these patients. Further studies using the HCC Huh7 cell line transfected with MAP siRNA or expression vector demonstrated that MAP regulated the expression of CDK4, CDK6, and Cyclin D1 via NF-eB and PTEN pathways. Finally, inhibition of MAP using embelin, a XIAP-specific small molecule, leads to an increased apoptosis and decreased cell proliferation via arrest at G1 phase. Taken together, XIAP is a central modulator regulating cell apoptosis and cell cycle progression. Therefore, MAP together with cell cycle regulatory proteins can be used as prognostic markers and therapeutic targets. (Am J Pathol 2012, 180: 1798-1807; DOI: 10.1016/j.ajpath.2012.01.016)