Integrated stable isotope labeling by amino acids in cell culture (SILAC) and isobaric tags for relative and absolute quantitation (iTRAQ) quantitative proteomic analysis identifies galectin-1 as a potential biomarker for predicting sorafenib resistance in liver cancer
Journal
Molecular and Cellular Proteomics
Journal Volume
14
Journal Issue
6
Pages
1527-1545
Date Issued
2015
Author(s)
Abstract
Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7R) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7R tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7R cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1μ signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy. ? 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
SDGs
Other Subjects
biological marker; galectin 1; hypoxia inducible factor 1alpha; mammalian target of rapamycin; protein kinase B; sorafenib; amino acid; antineoplastic agent; carbanilamide derivative; galectin 1; nicotinamide; sorafenib; tumor marker; advanced cancer; animal experiment; animal model; Article; cancer control; cancer prognosis; cancer resistance; cancer survival; cell adhesion; cell migration; cell proliferation; computer model; controlled study; diagnostic test accuracy study; drug efficacy; gene silencing; human; human cell; IC50; in vitro study; in vivo study; isobaric tag for relative and absolute quantitation; liver cancer; liver cancer cell line; lung metastasis; lung nodule; metastasis; mouse; nonhuman; overall survival; priority journal; progression free survival; protein expression; proteomics; quantitative analysis; signal transduction; stable isotope labeling with amino acid in cell culture; treatment response; tumor invasion; tumor xenograft; analogs and derivatives; animal; Bagg albino mouse; blood; cell motion; clinical trial; drug resistance; epithelial mesenchymal transition; genetics; isotope labeling; liver cell carcinoma; liver tumor; metabolism; physiology; procedures; protein protein interaction; proteomics; treatment outcome; tumor cell line; Amino Acids; Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Galectin 1; Gene Knockdown Techniques; Humans; Isotope Labeling; Liver Neoplasms; Mice, Inbred BALB C; Niacinamide; Phenylurea Compounds; Protein Interaction Maps; Proteomics; Treatment Outcome
Publisher
American Society for Biochemistry and Molecular Biology Inc.
Type
journal article