title: Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression.
abstract: Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4α expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-κB activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4α on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4α, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-κB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4α levels through down-regulating HNF4α-3'UTR activity.
  
  
  CONCLUSIONS
  Collectively, an HNF4α-NF-κB feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis. These findings broaden the knowledge of hepatic inflammation and cancer initiation/progression, and also provide novel prognostic biomarkers and therapeutic targets for HCC.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Bei-Fang
authors.initials: BF
authors.lastname: Ning
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.forename: Chuan
authors.initials: C
authors.lastname: Yin
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Xu
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Cong
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Xing
authors.initials: X
authors.lastname: Deng
authors.forename: Pei-Qin
authors.initials: PQ
authors.lastname: Wang
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Jiang
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality; D002478:Cells, Cultured; D002681:China / Q000453:epidemiology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D017208:Rats, Wistar; D051996:Transcription Factor RelA / Q000378:metabolism; D055815:Young Adult
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D035683:MicroRNAs; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA