Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma

Thiago De Almeida Pereira, Rafal P. Witek, Wing Kin Syn, Steve S. Choi, Shelton Bradrick, Gamze F. Karaca, Kolade M. Agboola, Youngmi Jung, Alessia Omenetti, Cynthia A. Moylan, Liu Yang, Martin E. Fernandez-Zapico, Ravi Jhaveri, Vijay H. Shah, Fausto E. Pereira, Anna M. Diehl

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.

Original languageEnglish (US)
Pages (from-to)1690-1703
Number of pages14
JournalLaboratory Investigation
Volume90
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

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Hepatitis, Viral, Human
Hepatocellular Carcinoma
Fibrosis
Liver
Hepacivirus
Chronic Hepatitis
Hepatitis B virus
Neoplastic Stem Cells
Ligands
Hepatocytes
Myofibroblasts
Chronic Hepatitis B
Virus Diseases
Liver Neoplasms
Infection
Liver Cirrhosis
Disease Progression
Cultured Cells
Immunohistochemistry

Keywords

  • fibrosis
  • Hedgehog pathway
  • hepatitis B
  • hepatitis C
  • liver progenitors
  • morphogens

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Pereira, T. D. A., Witek, R. P., Syn, W. K., Choi, S. S., Bradrick, S., Karaca, G. F., ... Diehl, A. M. (2010). Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Laboratory Investigation, 90(12), 1690-1703. https://doi.org/10.1038/labinvest.2010.147

Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. / Pereira, Thiago De Almeida; Witek, Rafal P.; Syn, Wing Kin; Choi, Steve S.; Bradrick, Shelton; Karaca, Gamze F.; Agboola, Kolade M.; Jung, Youngmi; Omenetti, Alessia; Moylan, Cynthia A.; Yang, Liu; Fernandez-Zapico, Martin E.; Jhaveri, Ravi; Shah, Vijay H.; Pereira, Fausto E.; Diehl, Anna M.

In: Laboratory Investigation, Vol. 90, No. 12, 12.2010, p. 1690-1703.

Research output: Contribution to journalArticle

Pereira, TDA, Witek, RP, Syn, WK, Choi, SS, Bradrick, S, Karaca, GF, Agboola, KM, Jung, Y, Omenetti, A, Moylan, CA, Yang, L, Fernandez-Zapico, ME, Jhaveri, R, Shah, VH, Pereira, FE & Diehl, AM 2010, 'Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma', Laboratory Investigation, vol. 90, no. 12, pp. 1690-1703. https://doi.org/10.1038/labinvest.2010.147
Pereira, Thiago De Almeida ; Witek, Rafal P. ; Syn, Wing Kin ; Choi, Steve S. ; Bradrick, Shelton ; Karaca, Gamze F. ; Agboola, Kolade M. ; Jung, Youngmi ; Omenetti, Alessia ; Moylan, Cynthia A. ; Yang, Liu ; Fernandez-Zapico, Martin E. ; Jhaveri, Ravi ; Shah, Vijay H. ; Pereira, Fausto E. ; Diehl, Anna M. / Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. In: Laboratory Investigation. 2010 ; Vol. 90, No. 12. pp. 1690-1703.
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