RBM38 is negatively regulated by miR‑320b and enhances Adriamycin resistance in breast cancer cells

Ke,Jing; Ni,Kan; Xue,Huimin; Li,Jia

doi:10.3892/ol.2021.13145

RBM38 is negatively regulated by miR‑320b and enhances Adriamycin resistance in breast cancer cells

Authors:
- Jing Ke
- Kan Ni
- Huimin Xue
- Jia Li
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Affiliations: Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226021, P.R. China
Published online on: November 19, 2021 https://doi.org/10.3892/ol.2021.13145
Article Number: 27
Copyright: © Ke et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Breast cancer (BC) is a common type of malignant tumor that is frequently accompanied by drug resistance, which is a significant challenge in the treatment of BC. Adriamycin (ADM) is a commonly used drug for the treatment of BC. The aim of the present study was to demonstrate the association between RNA binding motif protein 38 (RBM38) and ADM resistance in BC. The results revealed that the expression levels of RBM38 were significantly upregulated in ADM‑resistant BC tissues and the ADM‑resistant cell line, MCF‑7/A, as demonstrated using reverse transcription‑quantitative PCR and western blotting. In addition, the results of the MTT assay revealed that the overexpression of RBM38 enhanced the resistance of MCF‑7/A cells to ADM, promoted invasiveness, as determined using a Transwell assay, inhibited the apoptosis of resistant cells, as determined using flow cytometry, and accelerated cell cycle progression from the G0 to the S phase. The results of the dual luciferase reporter assay demonstrated the binding relationship between microRNA (miR)‑320b and RBM38, and the expression levels of miR‑320b were significantly downregulated in ADM‑resistant BC tissues and MCF‑7/A cells. Overexpression of miR‑320b reversed ADM resistance, suppressed invasiveness, promoted apoptosis and arrested MCF‑7/A cells in the G0 phase. In addition, RBM38 was discovered to be negatively regulated by miR‑320b, which was able to restore the sensitivity of BC cells to ADM by downregulating RBM38. Further exploration of the underlying regulatory mechanism revealed that the miR‑320b/RBM38 signaling axis mediated the development of ADM resistance in BC by altering the expression of cell cycle‑, drug resistance‑ and PI3K/AKT signaling pathway‑related proteins. In conclusion, the results of the present study suggested that RBM38 may be negatively regulated by miR‑320b, which accelerates drug resistance in BC.

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1	Akram M, Iqbal M, Daniyal M and Khan AU: Awareness and current knowledge of breast cancer. Biol Res. 50:332017. View Article : Google Scholar : PubMed/NCBI
2	Zaidi Z and Dib HA: The worldwide female breast cancer incidence and survival, 2018. Cancer Res. Jul 1–2019.(Epub ahead of print). doi: 10.1158/1538-7445.AM2019-4191.
3	Ellis LM and Hicklin DJ: Resistance to targeted therapies: Refining anticancer therapy in the era of molecular oncology. Clin Cancer Res. 15:7471–7478. 2009. View Article : Google Scholar : PubMed/NCBI
4	Network CGA; Cancer Genome Atlas Network, : Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI
5	Daniyal A, Santoso I, Gunawan NHP, Barliana MI and Abdulah R: Genetic Influences in Breast Cancer Drug Resistance. Breast Cancer (Dove Med Press). 13:59–85. 2021.PubMed/NCBI
6	Ji X, Lu Y, Tian H, Meng X, Wei M and Cho WC: Chemoresistance mechanisms of breast cancer and their countermeasures. Biomed Pharmacother. 114:1088002019. View Article : Google Scholar : PubMed/NCBI
7	Hu W, Tan C, He Y, Zhang G, Xu Y and Tang J: Functional miRNAs in breast cancer drug resistance. OncoTargets Ther. 11:1529–1541. 2018. View Article : Google Scholar : PubMed/NCBI
8	Khordadmehr M, Shahbazi R, Ezzati H, Jigari-Asl F, Sadreddini S and Baradaran B: Key microRNAs in the biology of breast cancer; emerging evidence in the last decade. J Cell Physiol. 234:8316–8326. 2019. View Article : Google Scholar : PubMed/NCBI
9	Hanna J, Hossain GS and Kocerha J: The potential for microRNA therapeutics and clinical research. Front Genet. 10:4782019. View Article : Google Scholar : PubMed/NCBI
10	Si W, Shen J, Zheng H and Fan W: The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics. 11:252019. View Article : Google Scholar : PubMed/NCBI
11	Tormo E, Ballester S, Adam-Artigues A, Burgués O, Alonso E, Bermejo B, Menéndez S, Zazo S, Madoz-Gúrpide J, Rovira A, et al: The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors. Sci Rep. 9:53162019. View Article : Google Scholar : PubMed/NCBI
12	Lu X, Liu R, Wang M, Kumar AK, Pan F, He L, Hu Z and Guo Z: MicroRNA-140 impedes DNA repair by targeting FEN1 and enhances chemotherapeutic response in breast cancer. Oncogene. 39:234–247. 2020. View Article : Google Scholar : PubMed/NCBI
13	Yu SJ, Yang L, Hong Q, Kuang XY, Di GH and Shao ZM: MicroRNA-200a confers chemoresistance by antagonizing TP53INP1 and YAP1 in human breast cancer. BMC Cancer. 18:742018. View Article : Google Scholar : PubMed/NCBI
14	Mulrane L, McGee SF, Gallagher WM and O'Connor DP: miRNA dysregulation in breast cancer. Cancer Res. 73:6554–6562. 2013. View Article : Google Scholar : PubMed/NCBI
15	Rupaimoole R and Slack FJ: MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 16:203–222. 2017. View Article : Google Scholar : PubMed/NCBI
16	Wang H, Cao F, Li X, Miao H, e J, Xing J and Fu CG: miR-320b suppresses cell proliferation by targeting c-Myc in human colorectal cancer cells. BMC Cancer. 15:7482015. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Tang X, He Q, Yang X, Ren X, Wen X, Zhang J, Wang Y, Liu N and Ma J: Overexpression of mitochondria mediator gene TRIAP1 by miR-320b loss is associated with progression in nasopharyngeal carcinoma. PLoS Genet. 12:e10061832016. View Article : Google Scholar : PubMed/NCBI
18	Lv GY, Miao J and Zhang XL: Long noncoding RNA XIST promotes osteosarcoma progression by targeting Ras-related protein RAP2B via miR-320b. Oncol Res. 26:837–846. 2018. View Article : Google Scholar : PubMed/NCBI
19	Wu X, Wang Y, Zhong W, Cheng H and Tian Z: RNA binding protein RNPC1 suppresses the stemness of human endometrial cancer cells via stabilizing MST1/2 mRNA. Med Sci Monit. 26:e9213892020.PubMed/NCBI
20	Cho SJ, Jung YS, Zhang J and Chen X: The RNA-binding protein RNPC1 stabilizes the mRNA encoding the RNA-binding protein HuR and cooperates with HuR to suppress cell proliferation. J Biol Chem. 287:14535–14544. 2012. View Article : Google Scholar : PubMed/NCBI
21	Shi L, Xia T-S, Wei X-L, Zhou W, Xue J, Cheng L, Lou P, Li C, Wang Y, Wei JF, et al: Estrogen receptor (ER) was regulated by RNPC1 stabilizing mRNA in ER positive breast cancer. Oncotarget. 6:12264–12278. 2015. View Article : Google Scholar : PubMed/NCBI
22	Zheng L, Zhang Z, Zhang S, Guo Q, Zhang F, Gao L, Ni H, Guo X, Xiang C and Xi T: RNA binding protein RNPC1 inhibits breast cancer cell metastasis via activating STARD13-correlated ceRNA network. Mol Pharm. 15:2123–2132. 2018. View Article : Google Scholar : PubMed/NCBI
23	Hernandez-Aya LF and Gonzalez-Angulo AM: Adjuvant systemic therapies in breast cancer. Surg Clin North Am. 93:473–491. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ponnusamy L, Mahalingaiah PKS and Singh KP: Treatment schedule and estrogen receptor-status influence acquisition of doxorubicin resistance in breast cancer cells. Eur J Pharm Sci. 104:424–433. 2017. View Article : Google Scholar : PubMed/NCBI
25	Xue J-Q, Xia T-S, Liang X-Q, Zhou W, Cheng L, Shi L, Wang Y and Ding Q: RNA-binding protein RNPC1: Acting as a tumor suppressor in breast cancer. BMC Cancer. 14:3222014. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Zhong ZF, Yu HB, Wang CM, Qiang WA, Wang SP, Zhang JM, Yu H, Cui L, Wu T, Li DQ, et al: Furanodiene induces extrinsic and intrinsic apoptosis in doxorubicin-resistant MCF-7 breast cancer cells via NF-κB-independent mechanism. Front Pharmacol. 8:6482017. View Article : Google Scholar : PubMed/NCBI
28	Gao HL, Xia YZ, Zhang YL, Yang L and Kong LY: Vielanin P enhances the cytotoxicity of doxorubicin via the inhibition of PI3K/Nrf2-stimulated MRP1 expression in MCF-7 and K562 DOX-resistant cell lines. Phytomedicine. 58:1528852019. View Article : Google Scholar : PubMed/NCBI
29	Li YS, Zhao DS, Liu XY, Liao YX, Jin HW, Song GP and Cui ZN: Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell. Eur J Med Chem. 151:546–556. 2018. View Article : Google Scholar : PubMed/NCBI
30	Muss HB, White DR, Richards F II, Cooper MR, Stuart JJ, Jackson DV, Rhyne L and Spurr CL: Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: A randomized trial. Cancer. 42:2141–2148. 1978. View Article : Google Scholar : PubMed/NCBI
31	Valero V, Jones SE, Von Hoff DD, Booser DJ, Mennel RG, Ravdin PM, Holmes FA, Rahman Z, Schottstaedt MW, Erban JK, et al: A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol. 16:3362–3368. 1998. View Article : Google Scholar : PubMed/NCBI
32	Riggins RB, Schrecengost RS, Guerrero MS and Bouton AH: Pathways to tamoxifen resistance. Cancer Lett. 256:1–24. 2007. View Article : Google Scholar : PubMed/NCBI
33	Chen X, Lu P, Wang DD, Yang SJ, Wu Y, Shen H-Y, Zhong SL, Zhao JH and Tang JH: The role of miRNAs in drug resistance and prognosis of breast cancer formalin-fixed paraffin-embedded tissues. Gene. 595:221–226. 2016. View Article : Google Scholar : PubMed/NCBI
34	Majumder S and Jacob ST: Emerging role of microRNAs in drug-resistant breast cancer. Gene Expr. 15:141–151. 2011. View Article : Google Scholar : PubMed/NCBI
35	Lu TX and Rothenberg ME: MicroRNA. J Allergy Clin Immunol. 141:1202–1207. 2018. View Article : Google Scholar : PubMed/NCBI
36	Du F, Yu L, Wu Y, Wang S, Yao J, Zheng X, Xie S, Zhang S, Lu X, Liu Y, et al: miR-137 alleviates doxorubicin resistance in breast cancer through inhibition of epithelial-mesenchymal transition by targeting DUSP4. Cell Death Dis. 10:9222019. View Article : Google Scholar : PubMed/NCBI
37	Liu T, Guo J and Zhang X: MiR-202-5p/PTEN mediates doxorubicin-resistance of breast cancer cells via PI3K/Akt signaling pathway. Cancer Biol Ther. 20:989–998. 2019. View Article : Google Scholar : PubMed/NCBI
38	Huang JF, Wen CJ, Zhao GZ, Dai Y, Li Y, Wu LX and Zhou HH: Overexpression of ABCB4 contributes to acquired doxorubicin resistance in breast cancer cells in vitro. Cancer Chemother Pharmacol. 82:199–210. 2018. View Article : Google Scholar : PubMed/NCBI
39	Zhang R, Qin Y, Zhu G, Li Y and Xue J: Low serum miR-320b expression as a novel indicator of carotid atherosclerosis. J Clin Neurosci. 33:252–258. 2016. View Article : Google Scholar : PubMed/NCBI
40	Lv QL, Du H, Liu YL, Huang YT, Wang GH, Zhang X, Chen SH and Zhou HH: Low expression of microRNA-320b correlates with tumorigenesis and unfavorable prognosis in glioma. Oncol Rep. 38:959–966. 2017. View Article : Google Scholar : PubMed/NCBI