Heat Shock Protein 70I Promotes Carcinogen-induced Liver Tumorigenesis by Regulating Hepatic Metabolism and Insulin Sensitivity

Hdl Handle:
http://hdl.handle.net/10675.2/317262
Title:
Heat Shock Protein 70I Promotes Carcinogen-induced Liver Tumorigenesis by Regulating Hepatic Metabolism and Insulin Sensitivity
Authors:
Cho, Wonkyoung
Abstract:
Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in the world. The treatment options for HCC, however are very limited. In mice, the carcinogen diethylnitrosamine (DEN) induces HCC, which has been proven to be comparable to human HCC in many key aspects. DEN-induced HCC leads to initial hepatocyte death followed by compensatory proliferation and inflammatory response. The cycles of hepatocyte death and compensatory proliferation eventually lead to genomic mutations and HCC development. The inducible heat shock protein-HSP70 (HSP70i) is overexpressed in a number of malignancies, including liver cancer. Tumor cells have metabolic changes which producing intermediates for cell growth and division. We hypothesize that HSP70i plays a role in HCC development through its control of glucose metabolism. To determine the impact of HSP70i in HCC, we treated a cohort of wild-type and hsp70i-deficient mice using the carcinogen DEN. Tumor development in the liver was examined after 8 months. Results show that the deletion of hsp70i leads to a significant delay in HCC development. DEN-treated hsp70i-/- mice exhibit reduced levels of alanine aminotransferase (ALT) and asparate aminotransferase (AST) in the serum compared to wild-type (WT) mice, suggesting reduced liver damage in hsp70i-/- mice. Furthermore, to investigate the mechanisms underlying HSP70i inhibition of tumorigenesis, we performed TUNEL assays to detect hepatocyte death, and Ki67 immunostaining to detect hepatocyte proliferation. As expected, hsp70i-/- mice exhibit a lower level of cell death and lower levels of cellular proliferations compared to wild-type mice. In addition, hsp70i-/- mice exhibit increased glucose consumption as evident by an increase in key enzymes involved in both glycolysis and TCA cycle. Low net glucose production induces lower lipid accumulation. Finally, treatment of DEN-treated wild-type mice with 2-phenylethynesulfonamid (PES), which is an HSP70i specific inhibitor, also delays HCC development. Overall, the alterations in the metabolic pathways in hsp70i null mice appear to contribute to delayed HCC development. Therefore, we conclude that HSP70i can be a powerful therapeutic target for HCC.
Affiliation:
Biochemistry and Molecular Biology
Issue Date:
Dec-2011
URI:
http://hdl.handle.net/10675.2/317262
Additional Links:
http://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/920880695?accountid=12365
Type:
Dissertation
Language:
en_US
Appears in Collections:
Theses and Dissertations; Department of Biochemistry and Molecular Biology Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorCho, Wonkyoungen
dc.date.accessioned2014-05-21T19:16:30Z-
dc.date.available2014-05-21T19:16:30Z-
dc.date.issued2011-12-
dc.identifier.urihttp://hdl.handle.net/10675.2/317262-
dc.description.abstractHepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers in the world. The treatment options for HCC, however are very limited. In mice, the carcinogen diethylnitrosamine (DEN) induces HCC, which has been proven to be comparable to human HCC in many key aspects. DEN-induced HCC leads to initial hepatocyte death followed by compensatory proliferation and inflammatory response. The cycles of hepatocyte death and compensatory proliferation eventually lead to genomic mutations and HCC development. The inducible heat shock protein-HSP70 (HSP70i) is overexpressed in a number of malignancies, including liver cancer. Tumor cells have metabolic changes which producing intermediates for cell growth and division. We hypothesize that HSP70i plays a role in HCC development through its control of glucose metabolism. To determine the impact of HSP70i in HCC, we treated a cohort of wild-type and hsp70i-deficient mice using the carcinogen DEN. Tumor development in the liver was examined after 8 months. Results show that the deletion of hsp70i leads to a significant delay in HCC development. DEN-treated hsp70i-/- mice exhibit reduced levels of alanine aminotransferase (ALT) and asparate aminotransferase (AST) in the serum compared to wild-type (WT) mice, suggesting reduced liver damage in hsp70i-/- mice. Furthermore, to investigate the mechanisms underlying HSP70i inhibition of tumorigenesis, we performed TUNEL assays to detect hepatocyte death, and Ki67 immunostaining to detect hepatocyte proliferation. As expected, hsp70i-/- mice exhibit a lower level of cell death and lower levels of cellular proliferations compared to wild-type mice. In addition, hsp70i-/- mice exhibit increased glucose consumption as evident by an increase in key enzymes involved in both glycolysis and TCA cycle. Low net glucose production induces lower lipid accumulation. Finally, treatment of DEN-treated wild-type mice with 2-phenylethynesulfonamid (PES), which is an HSP70i specific inhibitor, also delays HCC development. Overall, the alterations in the metabolic pathways in hsp70i null mice appear to contribute to delayed HCC development. Therefore, we conclude that HSP70i can be a powerful therapeutic target for HCC.en
dc.language.isoen_USen
dc.relation.urlhttp://ezproxy.gru.edu/login?url=http://search.proquest.com/docview/920880695?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en
dc.subjectHepatocellular carcinomaen
dc.subjectHSP70 inducible formen
dc.subject2-phenylethynesulfonamiden
dc.subjectTUNELen
dc.subjectKi67en
dc.subjectAlanine Aminotransferaseen
dc.subjectAsparate Amino-transferaseen
dc.subjectMetabolismen
dc.titleHeat Shock Protein 70I Promotes Carcinogen-induced Liver Tumorigenesis by Regulating Hepatic Metabolism and Insulin Sensitivityen
dc.typeDissertationen
dc.contributor.departmentBiochemistry and Molecular Biologyen
dc.description.advisorMivechi, Nahiden
dc.description.committeeMoskophidis, Dimitrios; Horuzsko, Anatolij; Chadli, Ahmed; Schoenlein, Patricia.en
dc.description.degreeDoctor of Philosophy (Ph.D.)en
All Items in Scholarly Commons are protected by copyright, with all rights reserved, unless otherwise indicated.