title: Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma.
abstract: Deciphering the network of signaling pathways in cancer via protein-protein interactions (PPIs) at the cellular level is a promising approach but remains incomplete. We used an in situ proximity ligation assay to identify and quantify 67 endogenous PPIs among 21 interlinked pathways in two hepatocellular carcinoma (HCC) cells, Huh7 (minimally migratory cells) and Mahlavu (highly migratory cells). We then applied a differential network biology analysis and determined that the novel interaction, CRKL-FLT1, has a high centrality ranking, and the expression of this interaction is strongly correlated with the migratory ability of HCC and other cancer cell lines. Knockdown of CRKL and FLT1 in HCC cells leads to a decrease in cell migration via ERK signaling and the epithelial-mesenchymal transition process. Our immunohistochemical analysis shows high expression levels of the CRKL and CRKL-FLT1 pair that strongly correlate with reduced disease-free and overall survival in HCC patient samples, and a multivariate analysis further established CRKL and the CRKL-FLT1 as novel prognosis markers. This study demonstrated that functional exploration of a disease network with interlinked pathways via PPIs can be used to discover novel biomarkers.
authors: Graduate Institute of Biomedical Electronic and Bioinformatics, National Taiwan University, Taipei 106, Taiwan.
authors: Chia-Hung
authors: CH
authors: Liu
authors: Tzu-Chi
authors: TC
authors: Chen
authors: Gar-Yang
authors: GY
authors: Chau
authors: Yi-Hua
authors: YH
authors: Jan
authors: Chun-Houh
authors: CH
authors: Chen
authors: Chun-Nan
authors: CN
authors: Hsu
authors: Kuan-Ting
authors: KT
authors: Lin
authors: Yue-Li
authors: YL
authors: Juang
authors: Pei-Jung
authors: PJ
authors: Lu
authors: Hui-Chuan
authors: HC
authors: Cheng
authors: Ming-Huang
authors: MH
authors: Chen
authors: Chia-Fen
authors: CF
authors: Chang
authors: Yu-Shan
authors: YS
authors: Ting
authors: Cheng-Yan
authors: CY
authors: Kao
authors: Michael
authors: M
authors: Hsiao
authors: Chi-Ying F
authors: CY
authors: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D018572:Disease-Free Survival; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D060066:Protein Interaction Maps; D012189:Retrospective Studies; D015398:Signal Transduction; D046888:Tissue Array Analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C082869:CRKL protein; D009687:Nuclear Proteins; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
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