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Identification of New Regulators of Pancreatic Cancer Cell Sensitivity to Oxaliplatin and Cisplatin
Authors:Vera Skripova  Ramilia Vlasenkova  Yan Zhou  Igor Astsaturov  Ramziya Kiyamova
Institution:1.“Biomarker” Research Laboratory, Institute of Fundamental Biology and Medicine, Kazan Federal University, 420008 Kazan, Russia; (V.S.); (R.V.);2.Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.Z.); (I.A.)
Abstract:The chemoresistance of tumor cells is one of the most urgent challenges in modern oncology and in pancreatic cancer, in which this problem is the most prominent. Therefore, the identification of new chemosensitizing co-targets may be a path toward increasing chemotherapy efficacy. In this work, we performed high-performance in vitro knockout CRISPR/Cas9 screening to find potential regulators of the sensitivity of pancreatic cancer. For this purpose, MIA PaCa-2 cells transduced with two sgRNA libraries (“cell cycle/nuclear proteins genes” and “genome-wide”) were screened by oxaliplatin and cisplatin. In total, 173 candidate genes were identified as potential regulators of pancreatic cancer cell sensitivity to oxaliplatin and/or cisplatin; among these, 25 genes have previously been reported, while 148 genes were identified for the first time as potential platinum drug sensitivity regulators. We found seven candidate genes involved in pancreatic cancer cell sensitivity to both cisplatin and oxaliplatin. Gene ontology enrichment analysis reveals the enrichment of single-stranded DNA binding, damaged DNA binding pathways, and four associated with NADH dehydrogenase activity. Further investigation and validation of the obtained results by in vitro, in vivo, and bioinformatics approaches, as well as literature analysis, will help to identify novel pancreatic cancer platinum sensitivity regulators.
Keywords:pancreatic cancer  chemotherapy resistance  oxaliplatin  cisplatin  CRISPR/Cas9 screening  biomarkers
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