Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma.
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2010-12
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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.
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Pereira, Tde A, RP Witek, WK Syn, SS Choi, S Bradrick, GF Karaca, KM Agboola, Y Jung, et al. (2010). Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest, 90(12). pp. 1690–1703. 10.1038/labinvest.2010.147 Retrieved from https://hdl.handle.net/10161/11085.
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Scholars@Duke
Steven Sok Choi
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Cynthia Ann Moylan
My research interests focus on the study of chronic liver disease and primary liver cancer, particularly from metabolic dysfunction associated steatotic liver disease (MASLD), formerly called nonalcoholic fatty liver disease (NAFLD). As part of the MASLD Research Team at Duke, we are investigating the role of environmental contaminants, epigenetics, and genetics on the development of advanced fibrosis and liver cancer from MASLD and other chronic liver diseases. We are also interested in understanding risks for progressive liver disease including developmental programming and in utero exposures and have been investigating these risks through studies of the Newborn Epigenetics Study (NEST). The long term goal of our research is to develop non-invasive biomarkers to identify those patients at increased risk for cirrhosis and end stage liver disease in order to risk stratify patients as well as to develop better preventative and therapeutic strategies.
Anna Mae Diehl
Our lab has a long standing interest in liver injury and repair. To learn more about the mechanisms that regulate this process, we study cultured cells, animal models of acute and chronic liver damage and samples from patients with various types of liver disease. Our group also conducts clinical trials in patients with chronic liver disease. We are particularly interested in fatty liver diseases, such as alcoholic fatty liver disease and nonalcoholic fatty liver disease (NAFLD).
Research by our group has advanced understanding in two main areas: 1) immune system regulation of liver injury and regeneration and 2)the role of fetal morphogens, such as the hedgehog pathway, in regulating fibrotic responses to liver damage. Our basic research programs have been enjoyed continuous NIH support since 1989. We welcome students, post-doctoral fellows and visiting scientists who have interests in this research area to contact us about training opportunities and potential collaborations.
Since 2001 we have also been an active participant in the NIDDK-funded Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), a national consortium comprised of 8 university medical centers selected to generate a national registry for patients with NAFLD and to conduct multicenter treatment trials for this disorder. We are actively recruiting patients for this program, as well as a number of other industry-supported NAFLD studies.
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