title: GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN.
abstract: Glucose-regulated protein 78 (GRP78), a molecular chaperone widely elevated in human cancers, is critical for endoplasmic reticulum (ER) protein folding, stress signaling and PI3K/AKT activation. Genetic knockout models of GRP78 revealed that GRP78 maintains homeostasis of metabolic organs, including liver, pancreas and adipose tissues. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the most common liver cancers. There is a lack of effective therapeutics for HCC and CC, highlighting the need to further understand liver tumorigenic mechanisms. PTEN (phosphatase and tenson homolog deleted on chromosome 10), a tumor suppressor that antagonizes the PI3K/AKT pathway, is inactivated in a wide range of tumors, including 40-50% of human liver cancers. To elucidate the role of GRP78 in liver cancer, we created a mouse model with biallelic liver-specific deletion of Pten and Grp78 mediated by Albumin-Cre-recombinase (cP(f/f)78(f/f)). Interestingly, in contrast to PTEN, deletion of GRP78 was progressive but incomplete. At 3 months, cP(f/f)78(f/f) livers showed hepatomegaly, activation of lipogenic genes, exacerbated steatosis and liver injury, implying that GRP78 protects the liver against PTEN-null-mediated pathogenesis. Furthermore, in response to liver injury, we observed increased proliferation and expansion of bile duct and liver progenitor cells in cP(f/f)78(f/f) livers. Strikingly, bile duct cells in cP(f/f)78(f/f) livers maintained wild-type (WT) GRP78 level, whereas adjacent areas showed GRP78 reduction. Analysis of signaling pathways revealed selective JNK activation, β-catenin downregulation, along with PDGFRα upregulation, which was unique to cP(f/f)78(f/f) livers at 6 months. Development of both HCC and CC was accelerated and was evident in cP(f/f)78(f/f) livers at 8-9 months, coinciding with intense GRP78 expression in the cancer lesions, and GRP78 expression in adjacent normal areas reverted back to the WT level. In contrast, c78(f/f) livers showed no malignancy even at 14 months. These studies reveal that GRP78 is a novel regulator for PTEN-loss-mediated liver injury and cancer progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: W-T
authors.initials: WT
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Biology, Eastern Oregon University, La Grande, OR, USA.
authors.forename: K
authors.initials: K
authors.lastname: Pfaffenbach
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Kanel
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Stiles
authors.affiliation: Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Lee
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics; D018450:Disease Progression; D000091342:Endoplasmic Reticulum Chaperone BiP; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics*; D017353:Gene Deletion; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse