{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:55:09Z","timestamp":1791309309384,"version":"4.3.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2038,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,2]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>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 1\u03b1 (<\/jats:bold>\n                                 <jats:bold>\n                                    HNF1A\n                                 <\/jats:bold>\n                                 <jats:bold>) transcription factor have been frequently identified and in rare cases of hepatocellular carcinomas developed in noncirrhotic liver. Because<\/jats:bold>\n                                 <jats:bold>\n                                    HNF1A\n                                 <\/jats:bold>\n                                 <jats:bold>meets the genetic criteria of a tumor suppressor gene, we aimed to elucidate the tumorigenic mechanisms related to HNF1\u03b1 inactivation in hepatocytes. We searched for signaling pathways aberrantly activated in human<\/jats:bold>\n                                 <jats:bold>\n                                    HNF1A\n                                 <\/jats:bold>\n                                 <jats:bold>-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 HNF1\u03b1 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 HNF1\u03b1 recapitulated most of these identified transcriptional deregulations, demonstrating that they were related to HNF1\u03b1 inhibition.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>H-HCA showed a combination of alterations related to HNF1\u03b1 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. (Hepatology 2009.)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.23362","type":"journal-article","created":{"date-parts":[[2009,10,5]],"date-time":"2009-10-05T22:38:29Z","timestamp":1254782309000},"page":"557-566","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":74,"title":["Loss of Hepatocyte Nuclear Factor 1\u03b1 Function in Human Hepatocellular Adenomas Leads to Aberrant Activation of Signaling Pathways Involved in Tumorigenesis"],"prefix":"10.1097","volume":"51","author":[{"given":"Laura","family":"Pelletier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Rebouissou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estelle","family":"Rathahao-Paris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Perdu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulette","family":"Bioulac-Sage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Imbeaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Zucman-Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-26-20241201","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1056\/NEJM197602262940904","article-title":"Livercell 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