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Supplementary Table 2 from Identification of Galanin and Its Receptor GalR1 as Novel Determinants of Resistance to Chemotherapy and Potential Biomarkers in Colorectal Cancer
journal contribution
posted on 2023-03-31, 18:08 authored by Leanne Stevenson, Wendy L. Allen, Richard Turkington, Puthen V. Jithesh, Irina Proutski, Gail Stewart, Heinz-Josef Lenz, Sandra Van Schaeybroeck, Daniel B. Longley, Patrick G. JohnstonPDF file - 80K, Pathway analysis
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ARTICLE ABSTRACT
Purpose: A major factor limiting the effective clinical management of colorectal cancer (CRC) is resistance to chemotherapy. Therefore, the identification of novel, therapeutically targetable mediators of resistance is vital.Experimental design: We used a CRC disease-focused microarray platform to transcriptionally profile chemotherapy-responsive and nonresponsive pretreatment metastatic CRC liver biopsies and in vitro samples, both sensitive and resistant to clinically relevant chemotherapeutic drugs (5-FU and oxaliplatin). Pathway and gene set enrichment analyses identified candidate genes within key pathways mediating drug resistance. Functional RNAi screening identified regulators of drug resistance.Results: Mitogen-activated protein kinase signaling, focal adhesion, cell cycle, insulin signaling, and apoptosis were identified as key pathways involved in mediating drug resistance. The G-protein–coupled receptor galanin receptor 1 (GalR1) was identified as a novel regulator of drug resistance. Notably, silencing either GalR1 or its ligand galanin induced apoptosis in drug-sensitive and resistant cell lines and synergistically enhanced the effects of chemotherapy. Mechanistically, GalR1/galanin silencing resulted in downregulation of the endogenous caspase-8 inhibitor FLIPL, resulting in induction of caspase-8–dependent apoptosis. Galanin mRNA was found to be overexpressed in colorectal tumors, and importantly, high galanin expression correlated with poor disease-free survival of patients with early-stage CRC.Conclusion: This study shows the power of systems biology approaches to identify key pathways and genes that are functionally involved in mediating chemotherapy resistance. Moreover, we have identified a novel role for the GalR1/galanin receptor–ligand axis in chemoresistance, providing evidence to support its further evaluation as a potential therapeutic target and biomarker in CRC. Clin Cancer Res; 18(19); 5412–26. ©2012 AACR.Usage metrics
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Keywords
Cell Death And SenescenceCaspasesSurvival factorsChemotherapyCombination chemotherapyComputational MethodsGene expression profilingDrug Discovery TechnologiesScreening strategies (assays and chemical libraries)Drug ResistanceReversal of drug resistanceDrug TargetsCell surface receptor drug targetsGastrointestinal CancersColorectal cancerTumor Staging
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