期刊
ONCOTARGET
卷 5, 期 11, 页码 3579-3589出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1961
关键词
platinum resistant ovarian cancer; decitabine; gene expression; chemosensitization; DNA methylation; pathway analysis
资金
- Integrative Cancer Biology Program (ICBP): Centers for Cancer Systems Biology (CCSB) summer research program
Combination therapy with decitabine, a DNMTi and carboplatin resensitized chemoresistant ovarian cancer (OC) to platinum inducing promising clinical activity. We investigated gene-expression profiles in tumor biopsies to identify decitabine-reactivated pathways associated with clinical response. Gene-expression profiling was performed using RNA from paired tumor biopsies before and 8 days after decitabine from 17 patients with platinum resistant OC. Bioinformatic analysis included unsupervised hierarchical-clustering, pathway and GSEA distinguishing profiles of responders (progression-free survival, PFS>6months) and non-responders (PFS<6months). Functional validation of selected results was performed in OC cells/tumors. Pre-treatment tumors from responders expressed genes associated with enhanced glycosphingolipid biosynthesis, translational misregulation, decreased ABC transporter expression, TGF-beta signaling, and numerous metabolic pathways. Analysis of post-treatment biopsies from responders revealed overexpression of genes associated with reduced Hedgehog pathway signaling, reduced DNA repair/ replication, and cancer-associated metabolism. GO and GSEA analyses revealed upregulation of genes associated with glycosaminoglycan binding, cell-matrix adhesion, and cell-substrate adhesion. Computational findings were substantiated by experimental validation of expression of key genes involved in two critical pathways affected by decitabine (TGF-beta and Hh). Gene-expression profiling identified specific pathways altered by decitabine and associated with platinum-resensitization and clinical benefit in OC. Our data could influence patient stratification for future studies using epigenetic therapies.
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