miR-5000-3p confers oxaliplatin resistance by targeting ubiquitin-specific peptidase 49 in colorectal cancer.
miR-5000-3p confers oxaliplatin resistance by targeting ubiquitin-specific peptidase 49 in colorectal cancer.
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miR-5000-3p 通过靶向泛素特异性肽酶 49 赋予结直肠癌奥沙利铂耐药性
DOI：
10.1038/s41420-021-00494-0
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发表时间：
2021-06-01
影响因子：
7
通讯作者：
Xu XY
中科院分区：
文献类型：
--
作者：
Zhuang YY;Zhong W;Xia ZS;Lin SZ;Chan MC;Jiang K;Li WF;Xu XY
结直肠癌（CRC）是最常见的胃肠道恶性肿瘤。越来越多的关于奥沙利铂（OXA）耐药性在结直肠癌治疗中的报道表明，耐药性是临床应用中迫切需要解决的问题，特别是寻找有效的治疗靶点。近年来，有报道称microRNAs （miRNAs）在肿瘤进展和多药耐药中发挥着关键作用。本研究的主要目的是确定miR-5000-3p是否是一种对OXA耐药的癌基因，并进一步确认其在CRC中的潜在调节作用。从gene expression Omnibus （GEO）数据库下载结直肠癌细胞中oxa相关基因表达数据集。采用统计学软件R对oxa耐药(OR)-CRC细胞与CRC细胞差异表达基因（DEGs）进行显著性分析，结果显示泛素特异性肽酶49 （USP49）在OR-CRC细胞中表达上调。荧光素酶报告基因实验证实USP49是miR-5000-3p的下游靶基因。TCGA数据库结果显示，CRC患者miR-5000-3p表达上调，USP49表达下调。采用MTT法、伤口愈合、Transwell和流式细胞术检测miR-5000-3p的功能。此外，通过体外和体内实验证实，与正常细胞系相比，miR-5000-3p在CRC细胞或or -CRC细胞中的表达上调。分子机制分析显示，USP49与miR-5000-3p启动子结合，增加miR-5000-3p的表达，导致癌细胞对OXA敏感。综上所述，这些结果提示miR-5000-3p可能是参与结直肠癌耐药进展的新型生物标志物。此外，miR-5000-3p/USP49轴的耐药机制在临床试验中为结直肠癌提供了新的治疗策略。
Colorectal cancer (CRC) is the most common form of gastrointestinal malignancies. A growing number of reports focusing on oxaliplatin (OXA) resistance in CRC treatment have revealed that drug resistance is an urgent issue in clinical applications, especially for finding effective therapeutic targets. Recently, microRNAs (miRNAs) are reported to play a critical role in tumor progressions and multi-drug resistance. The main aim of this study is to establish whether miR-5000-3p is an oncogene that is resistant to OXA and further confirm its underlying regulatory role in CRC. The OXA-associated gene expression dataset in CRC cells was downloaded from Gene Expression Omnibus (GEO) database. Statistical software R was used for significance analysis of differentially expressed genes (DEGs) between OXA-resistant (OR)-CRC cells and CRC cells, and results indicated ubiquitin-specific peptidase 49 (USP49) was upregulated in OR-CRC cells. Luciferase reporter assay showed that USP49 was verified to act as a downstream target gene of miR-5000-3p. From the results of TCGA database, miR-5000-3p expression was upregulated and USP49 was downregulated in patients with CRC. The function of miR-5000-3p was detected using MTT assay, wound healing, Transwell, and flow cytometry assays. Moreover, through in vitro and in vivo experiments, miR-5000-3p expression was confirmed to be upregulated in CRC cells or OR-CRC cells comparing to normal cell lines. Molecular mechanism assays revealed that USP49 binds to the miR-5000-3p promoter to increase the expression of miR-5000-3p, resulting in cancer cells sensitized to OXA. To sum up, these results suggest that miR-5000-3p may be a novel biomarker involved in drug-resistance progression of CRC. Moreover, the drug-resistance mechanism of miR-5000-3p/USP49 axis provides new treatment strategies for CRC in clinical trials.
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影响因子：
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作者：
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通讯作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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