title: Perturbation of MicroRNA-370/Lin-28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma.
abstract: MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer-associated genomic region. However, the role of miR-370 in malignances remains controversial. Here, we report that miR-370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated that miR-370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR-370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA-binding protein, LIN28A, was identified as a direct functional target of miR-370, which, in turn, blocked the biogenesis of miR-370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR-370 on migration and invasion of HCC cells by post-transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF-κB) pathway. Interleukin-6 (IL-6), a well-known NF-κB downstream inflammatory molecule, reduced miR-370 but increased LIN28A levels in HCC. Furthermore, miR-370 levels were inversely correlated with LIN28A and IL-6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL-6 expression in human HCC samples. Interestingly, reduction of miR-370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients.
  
  
  CONCLUSIONS
  These data demonstrate the involvement of a novel regulatory circuit consisting of miR-370, LIN28A, RelA/p65 and IL-6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Yi
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Li
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Cong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Bei-Fang
authors.initials: BF
authors.lastname: Ning
authors.forename: Chuan
authors.initials: C
authors.lastname: Yin
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Huang
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Jiang
authors.forename: Yue-Xiang
authors.initials: YX
authors.lastname: Chen
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Xia
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D016601:RNA-Binding Proteins; D051996:Transcription Factor RelA / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; C516326:LIN28B protein, human; C526503:MIRN370 microRNA, human; C000600513:MIRN370 microRNA, rat; D035683:MicroRNAs; D016328:NF-kappa B; C498143:RELA protein, human; D016601:RNA-Binding Proteins; D051996:Transcription Factor RelA