Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis
Open Access
- 28 August 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 59 (3), 947-957
- https://doi.org/10.1002/hep.26711
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. Conclusion: GRP94 is a novel regulator of cell adhesion, liver homeostasis, and tumorigenesis. (Hepatology 2014;59:947–957)This publication has 34 references indexed in Scilit:
- β1 integrin deletion enhances progression of prostate cancer in the TRAMP mouse modelScientific Reports, 2012
- Gene Deletions and Amplifications in Human Hepatocellular Carcinomas: Correlation with Hepatocyte Growth RegulationThe American Journal of Pathology, 2012
- GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulumBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2012
- Role of Integrins in Regulating Proteases to Mediate Extracellular Matrix RemodelingCancer Microenvironment, 2012
- Kupffer Cells Influence Parenchymal Invasion and Phenotypic Orientation, but Not the Proliferation, of Liver Progenitor Cells in a Murine Model of Liver InjuryThe American Journal of Pathology, 2011
- Expansion of Hepatic Tumor Progenitor Cells in Pten-Null Mice Requires Liver Injury and Is Reversed by Loss of AKT2Gastroenterology, 2010
- GRP94 in ER quality control and stress responsesSeminars in Cell & Developmental Biology, 2010
- Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liverGut, 2010
- Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epitheliumProceedings of the National Academy of Sciences of the United States of America, 2008
- ER chaperones in mammalian development and human diseasesFEBS Letters, 2007