Involvement of hepatopoietin Cn in the development of human hepatocellular carcinoma.
Hepatopoietin Cn (HPPCn) is a novel nuclear protein with the ability to promote liver regeneration. In the present study, we investigated the expression profile of HPPCn and its functional activity in human hepatocellular carcinoma (HCC) cell line and tissue samples. HPPCn expression was detected in HCC cell lines and 54 paired HCC carcinomas by immunochemical staining and Western blotting. The functional activity of HPPCn in cell lines was evaluated by MTT and colony formation assays and with nude mouse model. The correlation of HPPCn expression with clinicopathological characteristics of 54 HCC patients was also analyzed. Our results showed that HPPCn protein was prominently located within the nuclei of hepatocytes and the expression level was evidently increased in HepG2 and Bel7402 cell lines compared with L02 normal hepatocytes. HPPCn silencing by small interfering RNA greatly suppressed HepG2 cell proliferation and colony formation capacity and the inhibitory effect was also observed in a Balb/c-null mouse model. The silencing HPPCn expression effectively enhanced the apoptosis of HepG2 cells. In addition, HPPCn expression was detected in 48 of 54 (89%) human HCC tissues in sharp contrast with the corresponding non-tumor liver tissues. HPPCn protein was mainly accumulated in the tumor nucleus. The elevated expression of HPPCn protein in tumors was significantly associated with poor tumor cellular differentiation and present of vascular invasion. Patients with higher HPPCn expression in tumors had significantly shorter overall survival (OS) of both all of patients and the patients at the early stage. On multivariate Cox analysis, elevated expression of HPPCn in tumors was found to be an independent prognostic factor for OS. Therefore, these data suggest that HPPCn expression might be involved in the development of HCC and could be served as a promising biomarker.
Zhu
Bu-Dong
BD
Department of Breast Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, China. zhubd2008@gmail.com
Li
Xiao-Li
XL
Liu
Yong
Y
Chang
Jing
J
Liu
Yang
Y
Zhang
Dong-Dong
DD
Wang
Qiang
Q
Ren
Jun
J
Cui
Chun-Ping
CP
D000328:Adult; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D015999:Multivariate Analysis; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D012333:RNA, Messenger; C553972:hepatopoietin Cn, human; D017228:Hepatocyte Growth Factor