Keratin 19 as a key molecule in progression of human hepatocellular carcinomas through invasion and angiogenesis

BMC Cancer

Research Article

Keiji Shimada¹  Noboru Konishi¹  Tomomi Fujii¹  Yoshiyuki Nakajima²  Masato Takano³  Chiho Obayashi³  Maiko Takeda³  Kohei Morita³  Akitaka Nonomura⁴ 

[1] Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, 634-8521, Kashihara, Nara, Japan;Department of Surgery, Nara Medical University School of Medicine, 840 Shijo-cho, 634-8521, Kashihara, Nara, Japan;Departments of Diagnostic Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, 634-8521, Kashihara, Nara, Japan;Hokuriku CPL, 15-36 Ninomiya-cho, 920-0067, Kanazawa, Ishikawa, Japan;

关键词: Keratin 19;    Hepatocellular carcinoma;    Senescence;    Apoptosis;    Angiogenesis;   

DOI  :  10.1186/s12885-016-2949-y

 received in 2015-08-31, accepted in 2016-11-13,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundKeratin (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.MethodsK19 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.ResultsAnalysis 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.ConclusionK19 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.

【 授权许可】

CC BY   
© The Author(s). 2016