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Loss of hepatocyte nuclear factor 1α function in human hepatocellular adenomas leads to aberrant activation of signaling pathways involved in tumorigenesis
Author(s) -
Pelletier Laura,
Rebouissou Sandra,
Paris Alain,
RathahaoParis Estelle,
Perdu Elisabeth,
BioulacSage Paulette,
Imbeaud Sandrine,
ZucmanRossi Jessica
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23362
Subject(s) - hepatocyte nuclear factors , biology , carcinogenesis , cancer research , transcription factor , pi3k/akt/mtor pathway , foxa1 , hepatocyte nuclear factor 4 , small interfering rna , signal transduction , gene silencing , cell cycle , microbiology and biotechnology , cell , nuclear receptor , cell culture , gene , transfection , genetics
Hepatocellular adenomas (HCAs) are benign liver tumors that usually develop in women who are taking oral contraceptives. Among these tumors, biallelic inactivating mutations of the hepatocyte nuclear factor 1α ( HNF1A ) transcription factor have been frequently identified and in rare cases of hepatocellular carcinomas developed in noncirrhotic liver. Because HNF1A meets the genetic criteria of a tumor suppressor gene, we aimed to elucidate the tumorigenic mechanisms related to HNF1α inactivation in hepatocytes. We searched for signaling pathways aberrantly activated in human HNF1A ‐mutated HCA (H‐HCA) using a genome‐wide transcriptome analysis comparing five H‐HCA with four normal livers. We validated the main pathways by quantitative reverse transcription polymerase chain reaction (RT‐PCR) and western blotting in a large series of samples. Then, we assessed the role of HNF1α in the observed deregulations in hepatocellular cell models (HepG2 and Hep3B) by silencing its endogenous expression using small interfering RNA. Along with the previously described induction of glycolysis and lipogenesis, H‐HCA also displayed overexpression of several genes encoding growth factor receptors, components of the translation machinery, cell cycle, and angiogenesis regulators, with, in particular, activation of the mammalian target of rapamycin (mTOR) pathway. Moreover, estradiol detoxification activities were shut down, suggesting a hypersensitivity of H‐HCA to estrogenic stimulation. In the cell model, inhibition of HNF1α recapitulated most of these identified transcriptional deregulations, demonstrating that they were related to HNF1α inhibition. Conclusion: H‐HCA showed a combination of alterations related to HNF1α inactivation that may cooperate to promote tumor development. Interestingly, mTOR appears as a potential new attractive therapeutic target for treatment of this group of HCAs. (H EPATOLOGY 2009.)