Identification of candidate genes and miRNAs for sensitizing resistant colorectal cancer cells to oxaliplatin and irinotecan.

Drug resistance to irinotecan and oxaliplatin, two widely used chemotherapeutic, has become a common problem in cancerous patients. Despite numerous valuable studies, distinct molecular mechanisms involved in the acquisition of resistance to these anti-cancer drugs have remained a challenge. In this study, we studied the possible resistance mechanisms to irinotecan and oxaliplatin in three CRC cell lines (HCT116, HT29, and LoVo) via integration of microarray data with gene regulatory networks. After determination of hub genes, corresponding miRNAs were predicted using several databases and used in construction and subsequent analysis of miRNA-gene networks. Following to preparation of chemo-resistance CRC cells, a standard real-time PCR was conducted for validation of in silico findings. Topological and functional enrichment analyses of the resulted networks introduced several previously reported drug-resistance genes as well as novel biomarkers as hub genes which seem to be crucial in resistance of colon cancer cells to irinotecan and oxaliplatin. Furthermore, results of the functional annotation revealed the essential role of different signaling pathways like metabolic pathways in drug resistance of CRC cell lines to these drugs. A part of in silico findings was also validated in vitro using oxaliplatin-resistant cell lines. While FOXC1 and NFIC were upregulated in cell lines which were resistant to oxaliplatin, silencing FOXC1 decreased the resistance of SW480 cell line to oxaliplatin. In conclusion, our comparative in silico and in vitro study introduces several novel genes and miRNAs as the resistance-mediators which can be used for sensitizing resistant CRC cells to oxaliplatin and irinotecan.