This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parent, R. Articles by Beretta, L. Search for Related Content PubMed PubMed Citation Articles by Parent, R. Articles by Beretta, L.

Mammalian Target of Rapamycin Activation Impairs Hepatocytic Differentiation and Targets Genes Moderating Lipid Homeostasis and Hepatocellular Growth

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Laura Beretta, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Phone: 206-667-7080; Fax: 206-667-2537; E-mail: lberetta{at}fhcrc.org.

The mammalian target of rapamycin (mTOR) pathway, a major regulator of translation, is frequently activated in hepatocellular carcinomas. We investigated the effects of mTOR activation in the human HepaRG cells, which possess potent hepatocytic differentiation capability. Differentiation of HepaRG cells into functional and polarized hepatocyte-like cells correlated with a decrease in mTOR and Akt activities. Stable cell lines expressing an activated mutant of mTOR were generated. Sustained activation of mTOR impaired the hepatocytic differentiation capability of these cells as shown by impaired formation of bile canaliculi, absence of polarity, and reduced secretion of 1-antitrypsin. An inhibitor of mTOR, rapamycin, was able to revert this phenotype. Furthermore, increased mTOR activity in HepaRG cells resulted in their resistance to the antiproliferative effects of transforming growth factor-ß1. Profiling of polysome-bound transcripts indicated that activated mTOR specifically targeted genes posttranscriptionally regulated on hepatocytic differentiation. Three major biological networks targeted by activated mTOR were identified: (a) cell death associated with tumor necrosis factor superfamily members, IFNs and caspases; (b) lipid homeostasis associated with the transcription factors PPAR, PPAR, and retinoid X receptor ß; and (c) liver development associated with CCAAT/enhancer binding protein and hepatic mitogens. In conclusion, increased mTOR activity conferred a preneoplastic phenotype to the HepaRG cells by altering the translation of genes vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. [Cancer Res 2007;67(9):4337–45]

This article has been cited by other articles:

				H. G. Woo, E. S. Park, J.-S. Lee, Y.-H. Lee, T. Ishikawa, Y. J. Kim, and S. S. Thorgeirsson Identification of Potential Driver Genes in Human Liver Carcinoma by Genomewide Screening Cancer Res., May 1, 2009; 69(9): 4059 - 4066. [Abstract] [Full Text] [PDF]

				J. S. Weiss, H. S. Kruth, H. Kuivaniemi, G. Tromp, P. S. White, R. S. Winters, W. Lisch, W. Henn, E. Denninger, M. Krause, et al. Mutations in the UBIAD1 Gene on Chromosome Short Arm 1, Region 36, Cause Schnyder Crystalline Corneal Dystrophy Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 5007 - 5012. [Abstract] [Full Text] [PDF]