期刊
JOURNAL OF HEPATOLOGY
卷 62, 期 4, 页码 879-888出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2014.11.010
关键词
grp94; Molecular chaperone; Liver cancer; gp96
资金
- NIH [AI070603, AI077283, CA97132]
- VA Merit Award [2I0BX000200-04]
- Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]
- Lipidomics Core in the SC Lipidomics and Pathobiology COBRE, Department of Biochemistry and Molecular Biology, MUSC [P20 RR017677]
- NATIONAL CANCER INSTITUTE [P30CA138313, P30CA008748, R01CA172546, P01CA097132, P01CA186866] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL117233] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI090501, R01AI077283, R01AI070603] Funding Source: NIH RePORTER
Background & Aims: gp96, or grp94, is an endoplasmic reticulum (ER)-localized heat shock protein 90 paralog that acts as a protein chaperone and plays an important role for example in ER homeostasis, ER stress, Wnt and integrin signaling, and calcium homeostasis, which are vital processes in oncogenesis. However, the cancer-intrinsic function of gp96 remains controversial. Methods: We studied the roles of gp96 in liver biology in mice via an Albumin promoter-driven Cre recombinase-mediated disruption of gp96 gene, hsp90b1. The impact of gp96 status on hepatic carcinogenesis in response to diethyl-nitrosoamine (DENA) was probed. The roles of gp96 on human hepatocellular carcinoma cells (HCC) were also examined pharmacologically with a targeted gp96 inhibitor. Results: We demonstrated that gp96 maintains liver development and hepatocyte function in vivo, and its loss genetically promotes adaptive accumulation of long chain ceramides, accompanied by steatotic regeneration of residual gp96+ hepatocytes. The need for compensatory expansion of gp96+ cells in the gp96- background predisposes mice to develop carcinogen-induced hepatic hyperplasia and cancer from gp96+ but not gp96- hepatocytes. We also found that genetic and pharmacological inhibition of gp96 in human HCCs perturbed multiple growth signals, and attenuated proliferation and expansion. Conclusions: gp96 is a pro-oncogenic chaperone and an attractive therapeutic target for HCC. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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