Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice
Open Access
- 20 August 2010
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 52 (6), 2096-2108
- https://doi.org/10.1002/hep.23919
Abstract
Prohibitin 1 (PHB1) is a highly conserved, ubiquitously expressed protein that participates in diverse processes including mitochondrial chaperone, growth and apoptosis. The role of PHB1 in vivo is unclear and whether it is a tumor suppressor is controversial. Mice lacking methionine adenosyltransferase 1A (MAT1A) have reduced PHB1 expression, impaired mitochondrial function, and spontaneously develop hepatocellular carcinoma (HCC). To see if reduced PHB1 expression contributes to the Mat1a knockout (KO) phenotype, we generated liver-specific Phb1 KO mice. Expression was determined at the messenger RNA and protein levels. PHB1 expression in cells was varied by small interfering RNA or overexpression. At 3 weeks, KO mice exhibit biochemical and histologic liver injury. Immunohistochemistry revealed apoptosis, proliferation, oxidative stress, fibrosis, bile duct epithelial metaplasia, hepatocyte dysplasia, and increased staining for stem cell and preneoplastic markers. Mitochondria are swollen and many have no discernible cristae. Differential gene expression revealed that genes associated with proliferation, malignant transformation, and liver fibrosis are highly up-regulated. From 20 weeks on, KO mice have multiple liver nodules and from 35 to 46 weeks, 38% have multifocal HCC. PHB1 protein levels were higher in normal human hepatocytes compared to human HCC cell lines Huh-7 and HepG2. Knockdown of PHB1 in murine nontransformed AML12 cells (normal mouse hepatocyte cell line) raised cyclin D1 expression, increased E2F transcription factor binding to cyclin D1 promoter, and proliferation. The opposite occurred with PHB1 overexpression. Knockdown or overexpression of PHB1 in Huh-7 cells did not affect proliferation significantly or sensitize cells to sorafenib-induced apoptosis. Conclusion: Hepatocyte-specific PHB1 deficiency results in marked liver injury, oxidative stress, and fibrosis with development of HCC by 8 months. These results support PHB1 as a tumor suppressor in hepatocytes. (HEPATOLOGY 2010.)This publication has 29 references indexed in Scilit:
- Rescue of paclitaxel sensitivity by repression of Prohibitin1 in drug-resistant cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2010
- Changes in the expression of methionine adenosyltransferase genes and S-adenosylmethionine homeostasis during hepatic stellate cell activationHepatology, 2009
- Prohibitin Is a Novel Regulator of Antioxidant Response That Attenuates Colonic Inflammation in MiceGastroenterology, 2009
- Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core proteinHepatology, 2009
- Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondriaGenes & Development, 2008
- A Repressive Role for Prohibitin in Estrogen SignalingMolecular Endocrinology, 2008
- Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficient miceHepatology, 2007
- Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repressionOncogene, 2002
- Prohibitins act as a membrane-bound chaperone for the stabilization of mitochondrial proteinsThe EMBO Journal, 2000
- Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liverBiochemical and Biophysical Research Communications, 1989