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Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes.
J Virol 2015; 89(22):11549-56JV

Abstract

We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621-13628, 2012, http://dx.doi.org/10.1128/JVI.02016-12). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected in vitro with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth.

IMPORTANCE

HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.

Authors+Show Affiliations

Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA.Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA.Department of Pathology, Saint Louis University, St. Louis, Missouri, USA.Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA rayr@slu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26355082

Citation

Kwon, Young-Chan, et al. "Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes." Journal of Virology, vol. 89, no. 22, 2015, pp. 11549-56.
Kwon YC, Bose SK, Steele R, et al. Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. J Virol. 2015;89(22):11549-56.
Kwon, Y. C., Bose, S. K., Steele, R., Meyer, K., Di Bisceglie, A. M., Ray, R. B., & Ray, R. (2015). Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. Journal of Virology, 89(22), pp. 11549-56. doi:10.1128/JVI.01946-15.
Kwon YC, et al. Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. J Virol. 2015;89(22):11549-56. PubMed PMID: 26355082.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. AU - Kwon,Young-Chan, AU - Bose,Sandip K, AU - Steele,Robert, AU - Meyer,Keith, AU - Di Bisceglie,Adrian M, AU - Ray,Ratna B, AU - Ray,Ranjit, Y1 - 2015/09/09/ PY - 2015/07/31/received PY - 2015/08/31/accepted PY - 2015/9/11/entrez PY - 2015/9/12/pubmed PY - 2016/1/30/medline SP - 11549 EP - 56 JF - Journal of virology JO - J. Virol. VL - 89 IS - 22 N2 - UNLABELLED: We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621-13628, 2012, http://dx.doi.org/10.1128/JVI.02016-12). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected in vitro with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth. IMPORTANCE: HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/26355082/Promotion_of_Cancer_Stem_Like_Cell_Properties_in_Hepatitis_C_Virus_Infected_Hepatocytes_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=26355082 DB - PRIME DP - Unbound Medicine ER -