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Circ_0000260通过靶向MiR-129-5p上调MMP11来调节顺铂耐药的胃腺癌的发展和恶化。

Circ_0000260 Regulates the Development and Deterioration of Gastric Adenocarcinoma with Cisplatin Resistance by Upregulating MMP11 via Targeting MiR-129-5p.

作者信息

Liu Shicheng, Wu Miao, Peng Mengyin

机构信息

Department of Gastrointestinal Surgery, The Second People's Hospital of Yibin, Yibin, Sichuan, 644000, People's Republic of China.

出版信息

Cancer Manag Res. 2020 Oct 23;12:10505-10519. doi: 10.2147/CMAR.S272324. eCollection 2020.

DOI:10.2147/CMAR.S272324
PMID:33122949
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7591103/
Abstract

BACKGROUND

Cisplatin (CDDP) plays a vital role in the treatment of advanced gastric adenocarcinoma (GAC); however, the development of chemoresistance depletes the overall benefit of CDDP. This study harbored the aim to investigate the role of a novel circular RNA (circRNA), circ_0000260, in DDP-resistant GAC and provide a potential mechanism to explain its function.

METHODS

The morphology of tumor tissues and normal tissues was observed by hematoxylin-eosin (HE) staining. The isolated exosomes were observed and examined using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The expression of circ_0000260, miR-129-5p and matrix metalloproteinase 11 (MMP11) mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of CD63, CD81, fibronectin, vitronectin and MMP11 were detected by Western blot. Cell viability, colony formation, cell apoptosis, migration, invasion and cell adhesion were monitored by cell counting kit-8 (CCK-8) assay, colony formation assay, flow cytometry assay, scratch assay, transwell assay and cell adhesion assay, respectively. The interaction between miR-129-5p and circ_0000260 or MMP11 predicted by bioinformatics analysis was verified by dual-luciferase reporter assay. Animal experiments were performed in nude mice to explore the role of circ_0000260 in vivo.

RESULTS

The expression of circ_0000260 was promoted in tumor tissues and serum-derived exosomes of GAC patients, and circ_0000260 expression in CDDP-resistant tumor tissues was higher than that in CDDP-sensitive tumor tissues. Circ_0000260 knockdown lessened CDDP chemoresistance, suppressed cell proliferation, migration, invasion and adhesion, and induced apoptosis. In mechanism, circ_0000260 regulated the expression of MMP11 by targeting miR-129-5p. MiR-129-5p inhibition could reverse the functions of circ_0000260 knockdown, and MMP11 knockdown could also reverse the effects of miR-129-5p inhibition. Besides, circ_0000260 knockdown attenuated CDDP resistance during tumor growth in vivo by regulating the expression of miR-129-5p and MMP11.

CONCLUSION

Circ_0000260 regulated CDDP chemoresistance of GAC by promoting MMP11 expression via targeting miR-129-5p.

摘要

背景

顺铂（CDDP）在晚期胃腺癌（GAC）治疗中发挥着至关重要的作用；然而，化疗耐药性的产生削弱了CDDP的整体疗效。本研究旨在探讨一种新型环状RNA（circRNA），即circ_0000260，在顺铂耐药性GAC中的作用，并提供一种潜在机制来解释其功能。

方法

采用苏木精-伊红（HE）染色观察肿瘤组织和正常组织的形态。使用透射电子显微镜（TEM）和纳米颗粒跟踪分析（NTA）观察和检测分离出的外泌体。通过定量实时聚合酶链反应（qRT-PCR）检测circ_0000260、miR-129-5p和基质金属蛋白酶11（MMP11）mRNA的表达。通过蛋白质免疫印迹法检测CD63、CD81、纤连蛋白、玻连蛋白和MMP11的蛋白水平。分别通过细胞计数试剂盒-8（CCK-8）法、集落形成试验、流式细胞术检测、划痕试验、Transwell试验和细胞黏附试验监测细胞活力、集落形成、细胞凋亡、迁移、侵袭和细胞黏附。通过双荧光素酶报告基因试验验证生物信息学分析预测的miR-129-5p与circ_0000260或MMP11之间的相互作用。在裸鼠中进行动物实验以探讨circ_0000260在体内的作用。

结果

circ_0000260在GAC患者的肿瘤组织和血清来源的外泌体中表达上调，且顺铂耐药肿瘤组织中circ_0000260的表达高于顺铂敏感肿瘤组织。circ_0000260敲低减轻了顺铂化疗耐药性，抑制了细胞增殖、迁移、侵袭和黏附，并诱导了细胞凋亡。机制上，circ_0000260通过靶向miR-129-5p调节MMP11的表达。抑制miR-129-5p可逆转circ_0000260敲低的作用，敲低MMP11也可逆转抑制miR-129-5p的作用。此外，circ_0000260敲低通过调节miR-129-5p和MMP11的表达减轻了体内肿瘤生长过程中的顺铂耐药性。

结论

circ_0000260通过靶向miR-129-5p促进MMP11表达来调节GAC的顺铂化疗耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5355/7591103/38aaf8063889/CMAR-12-10505-g0009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5355/7591103/38aaf8063889/CMAR-12-10505-g0009.jpg

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