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The Diagnostic Significance of PDGF, EphA7, CCR5, and CCL5 Levels in Colorectal Cancer
Open AccessArticle

In Vitro and In Silico Mechanistic Insights into miR-21-5p-Mediated Topoisomerase Drug Resistance in Human Colorectal Cancer Cells

by Jung-Chien Chen 1,2,3,†, Yao-Yu Hsieh 1,4,5,†, Hsiang-Ling Lo 1,6, Albert Li 1,6,7, Chia-Jung Chou 1,6,8 and Pei-Ming Yang 1,6,8,9,*
1
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 111, Taiwan
2
Department of Surgery, Min-Sheng General Hospital, Taoyuan 168, Taiwan
3
Central Clinic and Hospital, Taipei 106, Taiwan
4
Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
5
Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 111, Taiwan
6
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 111, Taiwan
7
School of Medicine, Taipei Medical University, Taipei 111, Taiwan
8
TMU Research Center of Cancer Translational Medicine, Taipei 111, Taiwan
9
Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 111, Taiwan
*
Author to whom correspondence should be addressed.
These authors contribute equally to this work.
Biomolecules 2019, 9(9), 467; https://doi.org/10.3390/biom9090467
Received: 2 August 2019 / Revised: 6 September 2019 / Accepted: 7 September 2019 / Published: 9 September 2019
(This article belongs to the Section Biochemistry)
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. View Full-Text
Keywords: autophagy; colorectal cancer; Connectivity Map; drug resistance; microRNA autophagy; colorectal cancer; Connectivity Map; drug resistance; microRNA
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Chen, J.-C.; Hsieh, Y.-Y.; Lo, H.-L.; Li, A.; Chou, C.-J.; Yang, P.-M. In Vitro and In Silico Mechanistic Insights into miR-21-5p-Mediated Topoisomerase Drug Resistance in Human Colorectal Cancer Cells. Biomolecules 2019, 9, 467.

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