title: miR-22 promotes HBV-related hepatocellular carcinoma development in males.
abstract: OBJECTIVE
  Previous reports have shown that IL-1α-MyD88-IL-6 signaling is essential in promoting hepatocellular carcinoma (HCC) development in a diethylnitrosamine (DEN)-induced mouse model. We aimed to determine whether interleukin (IL)-1α regulates HCC development in humans.
  
  
  METHODS
  HBV-associated HCC tissue, corresponding adjacent tissue, and normal tissue samples were obtained from 80 male and 36 female patients. IL-1α, ERα, IL-6, and MyD88 were quantified by using real-time PCR and Western blot. Stem-loop PCR was used to quantify miR-22 expression. Luciferase reporter assays were used to study transcriptional regulation.
  
  
  RESULTS
  IL-1α was highly expressed in male tumor adjacent tissue compared with normal tissue (P = 0.025); however, this was not the case for female subjects. A linear relationship was observed between increased IL-1α and decreased ERα expression in male tumor adjacent tissue (r = -0.616, P = 0.004). Our results also indicated that estrogen (E2) was suppressed upon IL-1α secretion in ERα-overexpressed HCC cells. We detected high expression of miR-22 in male tumor adjacent tissue compared with controls (P = 0.027); furthermore, we showed that miR-22 downregulates ERα transcription by targeting the 3'-untranslated region. In the DEN-induced model, IL-1α was highly expressed in sprouting tumors and gradually decreased in conjunction with HCC development.
  
  
  CONCLUSIONS
  Overexpression of miR-22 in male tumor adjacent tissue was associated with downregulated ERα expression, potentially by attenuating the protective effect of estrogen and causing increased IL-1α expression. These results may explain the high incidence of HBV-associated HCC in the male population.
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, PR China.
authors.forename: Runqiu
authors.initials: R
authors.lastname: Jiang
authors.forename: Lei
authors.initials: L
authors.lastname: Deng
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Xia
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.forename: Beicheng
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000472:pathogenicity*; D006801:Humans; D053582:Interleukin-1alpha / Q000032:analysis / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000096:biosynthesis; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000032:analysis / Q000096:biosynthesis; D012727:Sex Characteristics; D015398:Signal Transduction
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D053582:Interleukin-1alpha; D015850:Interleukin-6; C548375:MIRN22 microRNA, human; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human