Dysregulation of hedgehog pathway signaling in hepatocellular carcinoma

2676 Hepatocellular carcinoma (HCC) is major cancer worldwide whose incidence is rapidly increasing due to end-stage chronic hepatitis C virus (HCV) infection. There is no first line systemic treatment for advanced HCC. Knowledge of of the signaling pathways involved in the initiation/progression of HCC will provide a rationale for the design of new molecular targeting agents. In order to characterize the changes in gene expression during the development of HCV-associated HCC, we collected samples from 78 HCV-cirrhotic patients undergoing surgical resection or liver transplantation for HCC. Gene expression of 56 candidate tumor pathway mRNAs were analyzed by real-time RT-PCR in lesions representing progressive histologic stages (10 normal, 10 cirrhosis, 18 dysplastic lesions, 40 HCCs) of HCC. Among these, key components of the hedgehog (Hh) signaling pathway, a tumor promoting pathway not previously studied in HCC, were, significantly dysregulated. The Hh pathway is crucial for normal embryonic development; however, reactivation of Hh signaling in adults is associated with several sporadic tumors. We found that 24/40 (60%) of HCV-associated HCCs displayed two-fold or more upregulation of Indian Hedgehog (IHH, Hh ligand) expression compared to 1/28 (3.6%) of cirrhotic livers and dysplastic lesions (p