title: Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis.
abstract: Liver cancer is one of the most common solid tumors, with poor prognosis and high mortality. Mutation or deletion of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is strongly correlated with human liver cancer. Glucose-regulated protein 94 (GRP94) is a major endoplasmic reticulum (ER) chaperone protein, but its in vivo function is still emerging. To study the role of GRP94 in maintaining liver homeostasis and tumor development, we created two liver-specific knockout mouse models with the deletion of Grp94 alone, or in combination with Pten, using the albumin-cre system. We demonstrated that while deletion of GRP94 in the liver led to hyperproliferation of liver progenitor cells, deletion of both GRP94 and PTEN accelerated development of liver tumors, including both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), suggestive of progenitor cell origin. Furthermore, at the premalignant stage we observed disturbance of cell adhesion proteins and minor liver injury. When GRP94 was deleted in PTEN-null livers, ERK was selectively activated.
  
  
  CONCLUSIONS
  GRP94 is a novel regulator of cell adhesion, liver homeostasis, and tumorigenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California, Keck School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA.
authors.forename: Wan-Ting
authors.initials: WT
authors.lastname: Chen
authors.forename: Chun-Chih
authors.initials: CC
authors.lastname: Tseng
authors.forename: Kyle
authors.initials: K
authors.lastname: Pfaffenbach
authors.forename: Gary
authors.initials: G
authors.lastname: Kanel
authors.forename: Biquan
authors.initials: B
authors.lastname: Luo
authors.forename: Bangyan L
authors.initials: BL
authors.lastname: Stiles
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D007365:Intercellular Junctions / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; C053387:endoplasmin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
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