In Vitro and In Silico Mechanistic Insights into miR-21-5p-Mediated Topoisomerase Drug Resistance in Human Colorectal Cancer Cells
2019
Jung-Chien Chen | Yao-Yu Hsieh | Hsiang-Ling Lo | Albert Li | Chia-Jung Chou | Pei-Ming Yang
Although chemotherapy for treating colorectal cancer has had some success, drug resistance and metastasis remain the major causes of death for colorectal cancer patients. MicroRNA-21-5p (hereafter denoted as miR-21) is one of the most abundant miRNAs in human colorectal cancer. A Kaplan−Meier survival analysis found a negative prognostic correlation of miR-21 and metastasis-free survival in colorectal cancer patients (The Cancer Genome Atlas Colon Adenocarcinoma/TCGA-COAD cohort). To explore the role of miR-21 overexpression in drug resistance, a stable miR-21-overexpressing clone in a human DLD-1 colorectal cancer cell line was established. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay found that miR-21 overexpression induced drug resistance to topoisomerase inhibitors (SN-38, doxorubicin, and etoposide/VP-16). Mechanistically, we showed that miR-21 overexpression reduced VP-16-induced apoptosis and concomitantly enhanced pro-survival autophagic flux without the alteration of topoisomerase expression and activity. Bioinformatics analyses suggested that miR-21 overexpression induced genetic reprogramming that mimicked the gene signature of topoisomerase inhibitors and downregulated genes related to the proteasome pathway. Taken together, our results provide a novel insight into the role of miR-21 in the development of drug resistance in colorectal cancer.
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