title: Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis.
abstract: Keratin (K) 19-positive hepatocellular carcinoma (HCC) is well known to have a higher malignant potential than K19-negative HCC: However, the molecular mechanisms involved in K19-mediated progression of HCC remain unclear. We attempted to clarify whether K19 directly affects cell survival and invasiveness in association with cellular senescence or epithelial-mesenchymal transition (EMT) in K19-positive HCC.
  
  
  
  K19 expression was analysed in 136 HCC surgical specimens. The relationship of K19 with clinicopathological factors and survival was analysed. Further, the effect of K19 on cell proliferation, invasion, and angiogenesis was examined by silencing K19 in the human HCC cell lines, HepG2, HuH-7, and PLC/PRF/5. Finally, we investigated HCC invasion, proliferation, and angiogenesis using K19-positive HCC specimens.
  
  
  
  Analysis of HCC surgical specimens revealed that K19-positive HCC exhibited higher invasiveness, metastatic potential, and poorer prognosis. In vitro experiments using the human HCC cell lines revealed that K19 silencing suppressed cell growth by inducting apoptosis or upregulating p16 and p27, resulting in cellular senescence. In addition, transfection with K19 siRNA upregulated E-cadherin gene expression, significantly inhibited the invasive capacity of the cells, downregulated angiogenesis-related molecules such as vasohibin-1 (VASH1) and fibroblast growth factor 1 (FGFR1), and upregulated vasohibin-2 (VASH2). K19-positive HCC specimens exhibited a high MIB-1 labelling index, decreased E-cadherin expression, and high microvessel density around cancer foci.
  
  
  
  K19 directly promotes cancer cell survival, invasion, and angiogenesis, resulting in HCC progression and poor clinical outcome. K19 may therefore be a novel drug target for the treatment of K19-positive HCC.
authors.affiliation: Departments of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. tkn@naramed-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Takano
authors.affiliation: Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Departments of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Morita
authors.affiliation: Departments of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Surgery, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Hokuriku CPL, 15-36 Ninomiya-cho, Kanazawa, Ishikawa, 920-0067, Japan.
authors.forename: Akitaka
authors.initials: A
authors.lastname: Nonomura
authors.affiliation: Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
authors.affiliation: Departments of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Obayashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053539:Keratin-19 / Q000235:genetics*; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D034622:RNA Interference
chemical_list: C000614131:CDKN2A protein, human; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000628304:KRT19 protein, human; D053539:Keratin-19; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Angiogenesis; Apoptosis; Hepatocellular carcinoma; Keratin 19; Senescence