Carcinogenesis Advance Access published online on December 8, 2005
Carcinogenesis, doi:10.1093/carcin/bgi292
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1 Department of Surgery and Division of Surgical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Division of Gastroenterology and Duke Liver Center, Duke University Medical Center, Durham, NC
* To whom correspondence should be addressed. Hedgehog pathway activation promotes tumors in several endodermally-derived tissues, but its role in the pathogenesis of hepatocellular carcinoma (HCC) is unknown. Although normal hepatocytes lack Hedgehog signaling, activation of the Hedgehog pathway in endodermal progenitors is required for liver development. Thus, we hypothesized that hepatocarcinogenesis may involve regulation of Hedgehog signaling. This pathway is activated when Hedgehog ligand binds to its receptor, Patched (PTC). In an unoccupied state, PTC normally functions as a tumor suppressor that inhibits Smoothened (SMO), a proto-oncoprotein, from activating downstream components and transcription of target genes. Here we show that in HCCs, overexpression of the Smo proto-oncogene, as well as an increase in the stoichiometric ratio of Smo to Ptc mRNA levels, correlated with tumor size, a prognostic indicator in HCC biology. In one tumor we identified a novel Smo mutation in an evolutionarily-conserved residue. We also demonstrated that HCC cell lines (HepG2 and Hep3B) expressed Hedgehog pathway components and activated Hedgehog transcriptional targets. In Hep3B cells, cyclopamine, an inhibitor of wild-type SMO, had no effect, but KAAD-cyclopamine, a blocker of oncogenic SMO, inhibited Hedgehog signaling activity by 50%, decreased expression of the hepatocarcinogenic oncogene, c-myc, by 8-fold, and inhibited the growth rate of Hep3B cells by 94%. These data support our hypothesis that Hedgehog signaling is dysregulated in human hepatocarcinogenesis. We demonstrate that overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis and suggests that Smo is a prognostic factor in HCC tumorigenesis.
Received September 21, 2005
Revised October 26, 2005
Accepted November 22, 2005
CANCER BIOLOGY
Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis
Jason K. Sicklick 1,
Yin-Xiong Li 2,
Aruna Jayaraman 3,
Rajesh Kannangai 4,
Yi Qi 5,
Perumal Vivekanandan 4,
John W. Ludlow 6,
Kouros Owzar 7,
Wei Chen 5,
Michael S. Torbenson 4,
and
Anna Mae Diehl 5 *
2 Department of Cell Biology, Duke University Medical Center, Durham, NC; Department of Pediatrics, Duke University Medical Center, Durham, NC; Division of Gastroenterology and Duke Liver Center, Duke University Medical Center, Durham, NC
3 Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD
4 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
5 Division of Gastroenterology and Duke Liver Center, Duke University Medical Center, Durham, NC
6 Vesta Therapeutics, Inc., Durham, NC
7 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC
Anna Mae Diehl, E-mail: diehl004{at}mc.duke.edu
Abstract 
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