Bioinformatics screening of therapeutic targets in chemoresistance human colon cancer HCT8 cell line

Zohreh  Jahanafrooz

doi:10.18502/bccr.v16i1.18755

Zohreh Jahanafrooz Department of Biology, Faculty of Sciences, University of Maragheh, Maragheh, Iran

DOI: https://doi.org/10.18502/bccr.v16i1.18755

Keywords: 5-Fluorouracil, Cisplatin, Colon adenocarcinoma, Drug resistance, HCT8 cell line

Abstract

Background: Chemoresistance is still one of the main challenges in treatment of cancers, including colon adenocarcinoma (COAD). COAD is a common cancer with a high mortality. The goal of this study was to identify and evaluate the differentially ex- pressed mRNAs (DEmRNAs) associated with both 5-fluorouracil (5-Fu) and cisplatin (DDP) resistance in human COAD cell line.

Methods: Common DEmRNAs, DEmiRNAs, and DElncRNAs were obtained from the gene expression profile GSE173606 between acquired two chemoresistance (5-Fu and DDP) and sensitive HCT8 cells. PPI network of overlapped DEmRNAs was obtained based on STRING database and Cytoscape and Gephi software. Degree algorithm in CytoHubba was used to determine hub genes. The hub genes were evaluated in TIM- ER2.0 and GEPIA databases. miRTarBase database was used to find DEmiRNAs which target the common DEmRNAs. Then DElncRNAs which have interaction with the se- lected DEmiRNAs were obtained from RNAInter database. LncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network visualized using Cytoscape software.

Results: A high number of common DEmRNAs (about 1780) in chemoresistance HCT8 cells were identified. TIMER2.0 database showed that the expression of high-ex- pressed hub genes, including EGFR, TGFB1, ESR1, ICAM1, PECAM1, CAV1, and CCL5 has significant positive correlations with tumor infiltration of cancer-associated fibroblasts in COAD. CeRNA networks included the low-expressed mRNAs (as targets of upregulated miR-675-3p, miR-6084, and miR-1182) whose expression is also down- regulated in COAD tissues based on GEPIA database. MDM2 (as a target of downregu- lated miR-4635 and miR-4306 in the ceRNA network) was an upregulated gene in both chemoresistance cells and COAD tumor tissues. RNAactDrug database confirmed the association of the high expression of four mRNAs of the ceRNA network (i.e., EFNB2, F2RL2, FLT1, and ADGRF1) with decreased drug sensitivity of DDP.

Conclusion: The results of this study can offer therapeutic targets. For example, in- hibition of CCL5, oncogenic miR-675-3p, and MDM2 might be a good choice for gene targeted therapy to overcome the multi-drug resistance in COAD. Moreover, it can pro- vide multiple mRNAs and miRNAs for predicting chemoresistance COAD.