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环状PRKDC通过调控miR-375/FOXM1轴和Wnt/β-连环蛋白通路促进大肠癌细胞对5-氟尿嘧啶的耐药性。

Circ-PRKDC Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells by Regulating miR-375/FOXM1 Axis and Wnt/β-Catenin Pathway.

作者信息

Chen Hao, Pei Lingyu, Xie Peng, Guo Guancheng

机构信息

Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Department of Digestive System, Yongcheng People's Hospital, Shangqiu, Henan, People's Republic of China.

出版信息

Onco Targets Ther. 2020 Jun 23;13:5939-5953. doi: 10.2147/OTT.S253468. eCollection 2020.

DOI:10.2147/OTT.S253468
PMID:32606803
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7320885/
Abstract

PURPOSE

Diverse circular RNAs (circRNAs) participate in the regulation of drug resistance in human cancers. However, the role of circRNAs in drug resistance in colorectal cancer (CRC) is dismal. In this study, we aimed to explore the effect of circ-PRKDC on 5-fluorouracil (5-FU) resistance in CRC.

MATERIALS AND METHODS

The levels of circ-PRKDC, microRNA-375 (miR-375) and forkhead box protein M1 (FOXM1) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). IC of 5-FU, cell colony formation ability and invasion were assessed by Cell Counting Kit-8 (CCK-8) assay, colony formation assay and transwell assay, respectively. The protein levels of P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), FOXM1, β-catenin and c-Myc were measured via Western blot assay. The targeting relationship between miR-375 and circ-PRKDC or FOXM1 was investigated by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The effect of circ-PRKDC in vivo was explored by murine xenograft model assay.

RESULTS

Circ-PRKDC was upregulated in 5-FU-resistant CRC tissues and cells. Circ-PRKDC silencing repressed 5-FU resistance, cell colony formation and invasion in 5-FU-resistant CRC cells in vitro and inhibited 5-FU resistance in vivo. MiR-375 was a target of circ-PRKDC and miR-375 inhibition reversed the effects of circ-PRKDC silencing on 5-FU resistance, cell colony formation and invasion. FOXM1 was a direct target gene of miR-375. MiR-375 suppressed 5-FU resistance by targeting FOXM1. Moreover, circ-PRKDC knockdown decreased FOXM1 expression by targeting miR-375. Additionally, circ-PRKDC knockdown impeded wnt/β-catenin pathway by regulating miR-375 and FOXM1.

CONCLUSION

Circ-PRKDC enhanced 5-FU resistance in CRC by regulating FOXM1/miR-375 axis and wnt/β-catenin pathway.

摘要

目的

多种环状RNA（circRNA）参与人类癌症耐药性的调控。然而，circRNA在结直肠癌（CRC）耐药中的作用尚不明确。在本研究中，我们旨在探讨circ-PRKDC对CRC中5-氟尿嘧啶（5-FU）耐药性的影响。

材料与方法

通过定量实时聚合酶链反应（qRT-PCR）测定circ-PRKDC、微小RNA-375（miR-375）和叉头框蛋白M1（FOXM1）mRNA的水平。分别采用细胞计数试剂盒-8（CCK-8）法、集落形成试验和Transwell试验评估5-FU的半数抑制浓度（IC）、细胞集落形成能力和侵袭能力。通过蛋白质免疫印迹法检测P-糖蛋白（P-gp）、多药耐药蛋白1（MRP1）、FOXM1、β-连环蛋白和c-Myc的蛋白水平。通过双荧光素酶报告基因试验和RNA免疫沉淀（RIP）试验研究miR-375与circ-PRKDC或FOXM1之间的靶向关系。通过小鼠异种移植模型试验探讨circ-PRKDC在体内的作用。

结果

circ-PRKDC在5-FU耐药的CRC组织和细胞中上调。circ-PRKDC沉默可抑制体外5-FU耐药CRC细胞的5-FU耐药性、细胞集落形成和侵袭，并在体内抑制5-FU耐药性。miR-375是circ-PRKDC的靶点，miR-375抑制可逆转circ-PRKDC沉默对5-FU耐药性、细胞集落形成和侵袭的影响。FOXM1是miR-375的直接靶基因。miR-375通过靶向FOXM1抑制5-FU耐药性。此外，circ-PRKDC敲低通过靶向miR-375降低FOXM1表达。此外，circ-PRKDC敲低通过调节miR-375和FOXM1阻碍wnt/β-连环蛋白通路。

结论

circ-PRKDC通过调节FOXM1/miR-375轴和wnt/β-连环蛋白通路增强CRC中的5-FU耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3727/7320885/70c18a1a3c28/OTT-13-5939-g0008.jpg
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