title: Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Saleh
authors.initials: S
authors.lastname: Rachidi
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Bill X
authors.initials: BX
authors.lastname: Wu
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jones
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Drake
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Besim
authors.initials: B
authors.lastname: Ogretmen
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson Veteran's Affairs Medical Center, Charleston, SC, United States.
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Cowart
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, United States.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.affiliation: Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, United States.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States. Electronic address: zihai@musc.edu.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004052:Diethylnitrosamine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D018832:Molecular Chaperones / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000477:Alkylating Agents; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin; D004052:Diethylnitrosamine
keywords: Liver cancer; Molecular chaperone; gp96; grp94