Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis Journal Article
| Authors: | Rachidi, S.; Sun, S.; Wu, B. X.; Jones, E.; Drake, R. R.; Ogretmen, B.; Cowart, L. A.; Clarke, C. J.; Hannun, Y. A.; Chiosis, G.; Liu, B.; Li, Z. |
| Article Title: | Endoplasmic reticulum heat shock protein gp96 maintains liver homeostasis and promotes hepatocellular carcinogenesis |
| Abstract: | 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. © 2015 European Association for the Study of the Liver. |
| Keywords: | controlled study; unclassified drug; human cell; liver cell carcinoma; liver function; nonhuman; protein function; cell proliferation; mouse; cell death; cell survival; gene expression; cell growth; animal experiment; animal model; in vivo study; alanine aminotransferase blood level; scatter factor; alanine aminotransferase; bilirubin; albumin; tissue distribution; microarray analysis; fat content; carcinogenicity; liver cancer; down regulation; upregulation; cell regeneration; liver cell; liver regeneration; homeostasis; disease predisposition; cre recombinase; cell expansion; liver weight; fatty liver; ceramide; sphingomyelin phosphodiesterase; carcinogen; glycoprotein gp 96; gp96; sphingolipid; molecular chaperone; endoplasmic reticulum stress; liver carcinogenesis; human; male; female; priority journal; article; sphingolipid metabolism; alkaline ceramidase; ceramide synthase 1; diethylnitrosamine; sphingomyelin phosphodiesterase 5; hepg2 cell line |
| Journal Title: | Journal of Hepatology |
| Volume: | 62 |
| Issue: | 4 |
| ISSN: | 0168-8278 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2015-04-01 |
| Start Page: | 879 |
| End Page: | 888 |
| Language: | English |
| DOI: | 10.1016/j.jhep.2014.11.010 |
| PROVIDER: | scopus |
| PMCID: | PMC4369194 |
| PUBMED: | 25463537 |
| DOI/URL: | |
| Notes: | Export Date: 4 May 2015 -- Source: Scopus |
