Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma

Chia Hung Liu, Tzu Chi Chen, Gar Yang Chau, Yi Hua Jan, Chun Houh Chen, Chun Nan Hsu, Kuan Ting Lin, Yue Li Juang, Pei Jung Lu, Hui Chuan Cheng, Ming Huang Chen, Chia Fen Chang, Yu Shan Ting, Cheng Yan Kao, Michael Hsiao, Chi Ying F. Huang

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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, CRKLFLT1, 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.

Original languageEnglish
Pages (from-to)1335-1349
Number of pages15
JournalMolecular and Cellular Proteomics
Volume12
Issue number5
DOIs
Publication statusPublished - 2013 May

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

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