9610 Background: Hedgehog (Hh) pathway activation promotes foregut tumors, such as pancreatic cancer. Whether Hh activity modulates hepatocellular carcinoma (HCC) pathogenesis is unknown. Although mature hepatocytes do not express the pathway, liver development requires Hh signaling. Blocking Hh prevents hepatogenesis and promotes pancreatic differentiation, suggesting a common precursor for liver and pancreas. The Hh pathway is activated when Sonic (Shh) or Indian (Ihh) ligands bind to the receptor, Patched (Ptc). When unoccupied by ligand, Ptc is a tumor suppressor because it binds Smoothened (Smo), an oncogenic protein, preventing Smo from activating Gli1. When ligand binds to Ptc, Smo is released and activates Gli1, which induces the transcription of its target gene, Ptc. Thus, Ptc mRNA levels increase with Hh activity. Aim: Determine if mRNAs of tumor suppressor (Ptc) or oncogenic (Shh, Ihh, Smo, Gli1) Hh pathway components are altered in human HCC. Methods: Total RNA was extracted from HCC and non-cancerous livers of 12 adults with HCC and various chronic liver diseases (alcoholic 8%, viral 50%, cryptogenic cirrhosis 25%). Two-step real-time PCR was done to compare expression of Shh, Ihh, Ptc, Smo, and Gli1 in HCC and non-tumor tissue from each patient. *p<0.05. Results: HCC ranged from 1–11 cm (mean 4±3 cm). The oncogenic factor, Smo, averaged >2-fold increase in the HCCs compared to non-tumorous liver. Regression analysis demonstrated that Smo mRNA levels correlated with HCC size*. In 8/12 (67%) HCCs, expression of the tumor suppressor, Ptc, was also significantly different than that of non-cancerous liver: 6 HCC had a 3× decrease, while 2 had an 11× increase in Ptc mRNA. Tumors with decreased Ptc were larger than HCC with normal expression (5±4 v. 3±1 cm)*. Serum levels of α-fetoprotein were barely elevated in any patient (mean 6.4±4.3 ng/mL) and did not correlate with HCC size or expression of Hh signaling components. Conclusion: Human HCCs have altered expression of Hh pathway components that regulate development of the liver from endodermal precursors. Although this pathway has been implicated in carcinogenesis of other endodermally-derived tissues, this is the first evidence for altered Hh pathway activity in hepatocarcinogenesis. No significant financial relationships to disclose.