title: Expression profile of microRNA-200 family in hepatocellular carcinoma with bile duct tumor thrombus.
abstract: OBJECTIVE
  The aim of this study was to assess the role of the miR-200 family in the pathogenesis of hepatocellular carcinoma with bile duct tumor thrombus (HCC-BDTT).
  
  
  BACKGROUND
  Hepatocellular carcinoma with bile duct tumor thrombus is a challenging condition because of its rarity and dismal prognosis. Epithelial-to-mesenchymal transition (EMT) is considered a critical step in the progression and metastasis of HCC and is regulated by the microRNA-200 (miR-200) family.
  
  
  METHODS
  Thirty patients with HCC-BDTT were enrolled and 1240 patients with conventional HCC (cHCC) served as clinicopathologic controls. Sixty age- and sex-matched cHCC patients were selected to compare the miR-200 family expression profile and immunohistochemical characteristics. Gain- and loss-of-function studies of the miR-200 family were conducted using the hepatoma cell lines.
  
  
  RESULTS
  Although the mean size of HCC-BDTT was smaller than that of cHCC, the former had a higher incidence of vascular invasion and a poorer long-term survival. The expressions of miR-200c and miR-141 were downregulated in HCC-BDTT (4.5- and 4.8-fold decrease, respectively). Downregulation of both miR-200c and miR-141 independently predicted disease-free survival. The HCC-BDTT, but not cHCC, exhibited overexpression of ZEB1, Twist, transforming growth factor-β receptor type II, and vimentin, and aberrant E-cadherin expression, indicating EMT. The HCC-BDTT demonstrated increased expression in IL-6 and stemness factor Bmi1, but reduced level of metastasis-suppressive protein, insulin-like growth factor-binding protein 4. The invasive ability of the highly aggressive Mahlavu cell was attenuated by pre-miR-200c+141, whereas the invasive ability of the less aggressive Huh7 cell was enhanced by anti-miR-200c+141.
  
  
  CONCLUSIONS
  Simultaneous silencing of miR-200c and miR-141 was likely to be responsible for the development of HCC-BDTT via ZEB1-directed EMT activation and Sec23a-mediated secretome.
authors.affiliation: Departments of *Surgery; and †Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Yu
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Jan
authors.forename: Miin-Fu
authors.initials: MF
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006498:Hepatectomy; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs