Sonic hedgehog signaling in hepatocellular carcinoma: A pilot study

Abstract

Hedgehog signaling is involved in the pathogenesis of several tumor types; however, its role in hepatocellular carcinoma (HCC) has not been fully elucidated. Biomarkers that reflect tumor aggressiveness are of potential value in selecting HCC patients for liver transplantation (LT). The aim of the present study was to assess the tissue expression of sonic hedgehog (Shh) biomarkers in HCC and surrounding non-tumorous liver tissue, and to correlate this expression with HCC recurrence following LT. Patients who underwent LT for HCC at the Cleveland Clinic (Cleveland, OH, USA) between 2002 and 2006 were randomly selected for analysis. Tissue samples were retrieved from the explanted tumorous livers. Routine immunohistochemistry was used to detect three specific Shh pathway biomarkers: The ligand Shh, the receptor patched-1 (Ptch) and the transcription factor glioma-associated oncogene homolog 1 (Gli1). Computerized quantitative analysis was used to evaluate the expression levels of these markers in HCC and surrounding non-tumorous liver tissue. Analysis of variance was used to compare the differential tissue expression between patients with and those without HCC recurrence. A time-to-event analysis was performed to assess the association of hedgehog biomarker expression with the risk of HCC recurrence following LT. A total of 53 tissue specimens from 21 patients were analyzed. The mean patient age was 57±8 years and 86% of the patients were male. A total of 62% patients had hepatitis C virus infection, 14% had hepatitis B virus infection, 43% had alcoholic cirrhosis and 91% fulfilled the Milan criteria at the time of LT. The average follow-up time after LT was 36±15 months, during which 19% of the patients developed HCC recurrence and 29% died. Shh, Ptch and Gli1 were detected in the HCC tissues of all the patients. Ptch was overexpressed in HCC compared with the surrounding non-tumorous tissue. The statistical power of this study was unable to associate Shh pathway markers with HCC recurrence following LT. In a proof-of-concept study, we demonstrated tissue expression of three Shh biomarkers within HCC tumors, and also identified differences in Ptch expression between tumor and surrounding non-tumorous tissue. Further larger studies are required to assess the utility of these biomarkers in HCC.