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miR-21-5p 介导的人结直肠癌细胞拓扑异构酶药物耐药的体外和计算机模拟机制研究

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

机构信息

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 111, Taiwan.

Department of Surgery, Min-Sheng General Hospital, Taoyuan 168, Taiwan.

出版信息

Biomolecules. 2019 Sep 9;9(9):467. doi: 10.3390/biom9090467.

DOI:10.3390/biom9090467
PMID:31505885
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6769444/
Abstract

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.

摘要

尽管化疗在治疗结直肠癌方面取得了一些成功，但耐药性和转移仍然是结直肠癌患者死亡的主要原因。微小 RNA-21-5p（以下简称 miR-21）是人类结直肠癌中最丰富的 miRNA 之一。一项 Kaplan-Meier 生存分析发现，miR-21 与结直肠癌患者的无转移生存呈负相关（癌症基因组图谱结肠腺癌/TCGA-COAD 队列）。为了探讨 miR-21 过表达在耐药性中的作用，在人 DLD-1 结直肠癌细胞系中建立了稳定的 miR-21 过表达克隆。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）细胞活力测定发现，miR-21 过表达诱导拓扑异构酶抑制剂（SN-38、阿霉素和依托泊苷/VP-16）耐药。从机制上讲，我们表明 miR-21 过表达降低了 VP-16 诱导的细胞凋亡，同时增强了存活的自噬通量，而不会改变拓扑异构酶的表达和活性。生物信息学分析表明，miR-21 过表达诱导了遗传重编程，模拟了拓扑异构酶抑制剂的基因特征，并下调了与蛋白酶体途径相关的基因。总之，我们的研究结果提供了一个新的视角，说明了 miR-21 在结直肠癌耐药性发展中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/8aad8dc75b4a/biomolecules-09-00467-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/3969d9be5c12/biomolecules-09-00467-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/22df530ed7a0/biomolecules-09-00467-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/c30e7b9fcf34/biomolecules-09-00467-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/267c031aec9a/biomolecules-09-00467-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/1e5d526f3dac/biomolecules-09-00467-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/8aad8dc75b4a/biomolecules-09-00467-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/3969d9be5c12/biomolecules-09-00467-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/22df530ed7a0/biomolecules-09-00467-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/c30e7b9fcf34/biomolecules-09-00467-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/267c031aec9a/biomolecules-09-00467-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/1e5d526f3dac/biomolecules-09-00467-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21a7/6769444/8aad8dc75b4a/biomolecules-09-00467-g006.jpg

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