title: An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.
abstract: Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hatziapostolou
authors.forename: Christos
authors.initials: C
authors.lastname: Polytarchou
authors.forename: Eleni
authors.initials: E
authors.lastname: Aggelidou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Drakaki
authors.forename: George A
authors.initials: GA
authors.lastname: Poultsides
authors.forename: Savina A
authors.initials: SA
authors.lastname: Jaeger
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Ogata
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Kevin
authors.initials: K
authors.lastname: Struhl
authors.forename: Margarita
authors.initials: M
authors.lastname: Hadzopoulou-Cladaras
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C508603:IL6R protein, human; C509207:MIRN124 microRNA, human; C543845:MIRN24 microRNA, human; C569688:MIRN629 microRNA, human; D035683:MicroRNAs; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor