Hepatoma-derived growth factor/nucleolin axis as a novel oncogenic pathway in liver carcinogenesis.
Hepatoma-derived growth factor (HDGF) overexpression is involved in liver fibrosis and carcinogenesis. However, the receptor(s) and signaling for HDGF remain unclear. By using affinity chromatography and proteomic techniques, nucleolin (NCL) was identified and validated as a HDGF-interacting membrane protein in hepatoma cells. Exogenous HDGF elicited the membrane NCL accumulation within 0.5 hour by protein stabilization and transcriptional NCL upregulation within 24 hours. Blockade of surface NCL by antibodies neutralization potently suppressed HDGF uptake and HDGF-stimulated phosphatidylinositol 3-kinase (PI3K)/Akt signaling in hepatoma cells. By using rescectd hepatocellular carcinoma (HCC) tissues, immunohistochemical analysis revealed NCL overexpression was correlated with tumour grades, vascular invasion, serum alpha-fetoprotein levels and the poor survival in HCC patients. Multivariate analysis showed NCL was an independent prognostic factor for survival outcome of HCC patients after surgery. To delineate the role of NCL in liver carcinogenesis, ectopic NCL overexpression promoted the oncogenic behaviours and induced PI3K/Akt activation in hepatoma cells. Conversely, NCL knockdown by RNA interference attenuated the oncogenic behaviours and PI3K/Akt signaling, which could be partially rescued by exogenous HDGF supply. In summary, this study provides the first evidence that surface NCL transmits the oncogenic signaling of HDGF and facilitates a novel diagnostic and therapeutic target for HCC.
Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
San-Cher
SC
Chen
Division of Hepato-Gastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Tsung-Hui
TH
Hu
Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Chao-Cheng
CC
Huang
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Mei-Lang
ML
Kung
Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Tian-Huei
TH
Chu
Division of Hepato-Gastroenterology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Li-Na
LN
Yi
Graduate Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Shih-Tsung
ST
Huang
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
Hoi-Hung
HH
Chan
Department of Pediatric Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Jiin-Haur
JH
Chuang
Department of Biological Science & Technology, I-Shou University, Kaohsiung 840, Taiwan.
Li-Feng
LF
Liu
Graduate Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.|Institute of Cellular and Organismic Biology and Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
Han-Chung
HC
Wu
Center for Stem Cell Research and Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Deng-Chyang
DC
Wu
Division of Colorectal Surgery, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
Min-Chi
MC
Chang
Center for Neuroscience, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.|Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.|Graduate Program in Marine Biotechnology, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
Ming-Hong
MH
Tai
D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D040901:Proteomics / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000097796:Nucleolin
D036341:Intercellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C051610:hepatoma-derived growth factor
hepatocellular carcinoma; hepatoma-derived growth factor; nucleolin; tumour progression