Sonic Hedgehog Signaling Pathway in Hepatocellular Carcinoma and Its Association With Tumor Recurrence Following Liver Transplantation: A Pilot Study

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Introduction: Sonic hedgehog (Shh) signaling pathway is involved in the pathogenesis of several tumor types, but its role in hepatocellular carcinoma (HCC) has not been defined. Biological markers to predict tumor behavior and select HCC patients for liver transplantation (LT) are needed. We assessed the expression of Shh biomarkers in HCC tumors and surrounding non-tumorous tissues and correlated their expression with HCC recurrence following LT. Methods: Patients who underwent LT for HCC at our institution between 2002 and 2006 were reviewed. Tissue samples were retrieved from the explanted tumorous livers. Routine immunohistochemistry techniques were used to detect 3 specific Shh biomarkers: Shh, patched-1 (PTCH), and glioma associated oncogene-1 (GLI1). Computerized quantitative analysis was then utilized to evaluate the differential expression of these biomarkers in both HCC and surrounding non-tumorous tissue. Analysis of variance was used to assess the differential tissue expression of the biomarkers between patients with and without HCC recurrence. Time-to-event analysis was performed to assess the association of the biomarkers expression with hazard of HCC recurrence following LT. Results: A total of 21 patients were included. Mean age was 57±8 years and 56% were male. Sixty-two percent had hepatitis C virus infection, 14% had hepatitis B virus infection, 43% had alcoholic cirrhosis, and 91% were within Milan criteria at time of LT. Average follow-up time after LT was 36±15 months, during which 19% of patients had HCC recurrence and 29% died. Shh, PTCH, and GLI1 were detected in the liver tissues of all patients. There was no evidence to suggest differential expression between HCC and the surrounding non-tumorous tissue. Association of Shh, PTCH, or GLI1 with HCC recurrence following LT could not be demonstrated given the small sample size (Figure 1).Figure 1Conclusion: In a proof-of-concept study, we demonstrated expression of 3 Shh biomarkers within HCC and surrounding cirrhotic tissue. The study was not powered to detect an association between these biomarkers and HCC recurrence following LT. Further larger studies are required to assess the utility of these biomarkers in HCC.