Taxol‑resistant breast cancer cell‑derived exosome‑delivered miR‑187‑5p regulates the growth of breast cancer cells via ABCD2 and Wnt/β‑catenin signaling

Wu,Tieli; Zhu,Dandan; Wu,Xingyi; Zhang,Ningning; Zhang,Qingyuan

doi:10.3892/ol.2023.13705

Taxol‑resistant breast cancer cell‑derived exosome‑delivered miR‑187‑5p regulates the growth of breast cancer cells via ABCD2 and Wnt/β‑catenin signaling

Authors:
- Tieli Wu
- Dandan Zhu
- Xingyi Wu
- Ningning Zhang
- Qingyuan Zhang
View Affiliations

Affiliations: Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150000, P.R. China, Department of Medical Oncology, Daqing Oilfield General Hospital, Daqing, Heilongjiang 163000, P.R. China, Department of Internal Medicine, Qiqihar First Factory Hospital, Qiqihar, Heilongjiang 161000, P.R. China, School of Basic Medicine, Qiqihar Medical University, Qiqihar, Heilongjiang 161000, P.R. China
Published online on: February 7, 2023 https://doi.org/10.3892/ol.2023.13705
Article Number: 119
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acquired resistance to Taxol (TAX) contributes to clinical treatment failure and significantly reduces the survival rate of patients. The present study aimed to explore the effects of exosomal microRNA (miR)‑187‑5p on TAX resistance in breast cancer cells and its underlying mechanisms. Exosomes were isolated from MCF‑7 and TAX‑resistant MCF‑7/TAX cells, and the miR‑187‑5p and miR‑106a‑3p levels of the cells and exosomes were determined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Next, MCF‑7 cells were treated with TAX for 48 h and either treated with exosomes or transfected with miR‑187‑5p mimics. Cell viability, apoptosis, migration, invasion and colony formation were determined using Cell Counting Kit‑8, flow cytometry, Transwell and colony formation assays, and the expression levels of associated genes and proteins were detected by RT‑qPCR and western blotting, respectively. Finally, a dual‑luciferase reporter gene assay was performed to confirm the target of miR‑187‑5p. The results showed that miR‑187‑5p expression levels increased significantly in TAX‑resistant MCF‑7 cells and exosomes compared with normal MCF‑7 cells and exosomes (P<0.05). However, miR‑106a‑3p was not detected in the cells or exosomes. Therefore, miR‑187‑5p was selected for subsequent experiments. A series of cell assays showed that TAX inhibited the viability, migration, invasion and colony formation of MCF‑7 cells and promoted their apoptosis; however, these changes were reversed by resistant cell exosomes and miR‑187‑5p mimics. Additionally, TAX significantly upregulated ABCD2 and downregulated β‑catenin, c‑Myc and cyclin D1, whereas resistant exosomes and miR‑187‑5p mimics reversed the TAX‑induced changes in expression. Finally, ABCD2 was confirmed to directly bind with miR‑187‑5p. It may be concluded that TAX‑resistant cell‑derived exosomes delivering miR‑187‑5p may affect the growth of TAX‑induced breast cancer cells by targeting ABCD2 and c‑Myc/Wnt/β‑catenin signaling.

View Figures

View References

1	McDonald ES, Clark AS, Tchou J, Zhang P and Freedman GM: Clinical diagnosis and management of breast cancer. J Nucl Med. 57 (Suppl 1):9S–16S. 2016. View Article : Google Scholar : PubMed/NCBI
2	Gupta N, Gupta P and Srivastava SK: Penfluridol overcomes paclitaxel resistance in metastatic breast cancer. Sci Rep. 9:50662019. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2021. CA Cancer J Clin. 71:7–33. 2021. View Article : Google Scholar : PubMed/NCBI
4	Hassan MS, Ansari J, Spooner D and Hussain SA: Chemotherapy for breast cancer (Review). Oncol Rep. 24:1121–1131. 2010. View Article : Google Scholar : PubMed/NCBI
5	Ghersi D, Willson ML, Chan MM, Simes J, Donoghue E and Wilcken N: Taxane-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 10:CD0033662015.PubMed/NCBI
6	Megerdichian C, Olimpiadi Y and Hurvitz SA: nab-Paclitaxel in combination with biologically targeted agents for early and metastatic breast cancer. Cancer Treat Rev. 40:614–625. 2014. View Article : Google Scholar : PubMed/NCBI
7	Bukowski K, Kciuk M and Kontek R: Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 21:32332020. View Article : Google Scholar : PubMed/NCBI
8	Koual M, Tomkiewicz C, Cano-Sancho G, Antignac JP, Bats AS and Coumoul X: Environmental chemicals, breast cancer progression and drug resistance. Environ Health. 19:1172020. View Article : Google Scholar : PubMed/NCBI
9	Wang X, Li Z, Cui Y, Cui X, Chen C and Wang Z: Exosomes isolated from bone marrow mesenchymal stem cells exert a protective effect on osteoarthritis via lncRNA LYRM4-AS1-GRPR-miR-6515-5p. Front Cell Dev Biol. 9:6443802021. View Article : Google Scholar : PubMed/NCBI
10	Zhang L and Yu D: Exosomes in cancer development, metastasis, and immunity. Biochim Biophys Acta Rev Cancer. 1871:455–468. 2019. View Article : Google Scholar : PubMed/NCBI
11	Crow J, Atay S, Banskota S, Artale B, Schmitt S and Godwin AK: Exosomes as mediators of platinum resistance in ovarian cancer. Oncotarget. 8:11917–11936. 2017. View Article : Google Scholar : PubMed/NCBI
12	Yang F, Ning Z, Ma L, Liu W, Shao C, Shu Y and Shen H: Exosomal miRNAs and miRNA dysregulation in cancer-associated fibroblasts. Mol Cancer. 16:1482017. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Li S, Li L, Li M, Guo C, Yao J and Mi S: Exosome and exosomal microRNA: Trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 13:17–24. 2015. View Article : Google Scholar : PubMed/NCBI
14	Ebert MS and Sharp PA: Roles for microRNAs in conferring robustness to biological processes. Cell. 149:515–524. 2012. View Article : Google Scholar : PubMed/NCBI
15	Geretto M, Pulliero A, Rosano C, Zhabayeva D, Bersimbaev R and Izzotti A: Resistance to cancer chemotherapeutic drugs is determined by pivotal microRNA regulators. Am J Cancer Res. 7:1350–1371. 2017.PubMed/NCBI
16	Fu X, Liu M, Qu S, Ma J, Zhang Y, Shi T, Wen H, Yang Y, Wang S, Wang J, et al: Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway. J Exp Clin Cancer Res. 37:522018. View Article : Google Scholar : PubMed/NCBI
17	Fornari F, Pollutri D, Patrizi C, Bella TL, Marinelli S, Gardini AS, Marisi G, Toaldo MB, Baglioni M, Salvatore V, et al: In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis. Clin Cancer Res. 23:3953–3965. 2017. View Article : Google Scholar : PubMed/NCBI
18	Uhr K, Prager-van der Smissen WJC, Heine AAJ, Ozturk B, van Jaarsveld MTM, Boersma AWM, Jager A, Wiemer EAC, Smid M, Foekens JA and Martens JWM: MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines. PLoS One. 14:e02164002019. View Article : Google Scholar : PubMed/NCBI
19	Thery C, Amigorena S, Raposo G and Clayton A: Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3. Unit 3.22. 2006.PubMed/NCBI
20	Lee YS, Kim SY, Ko E, Lee JH, Yi HS, Yoo YJ, Je J, Suh SJ, Jung YK, Kim JH, et al: Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. Sci Rep. 7:37102017. View Article : Google Scholar : PubMed/NCBI
21	Martins TS, Catita J, Rosa IK, Silva OA and Henriques AG: Exosome isolation from distinct biofluids using precipitation and column-based approaches. PLoS One. 13:e01988202018. View Article : Google Scholar : PubMed/NCBI
22	Wu M, Ouyang Y, Wang Z, Zhang R, Huang PH, Chen C, Li H, Li P, Quinn D, Dao M, et al: Isolation of exosomes from whole blood by integrating acoustics and microfluidics. Proc Natl Acad Sci USA. 114:10584–10589. 2017. View Article : Google Scholar : PubMed/NCBI
23	Liao Z, Chen Y, Duan C, Zhu K, Huang R, Zhao H, Hintze M, Pu Q, Yuan Z, Lv L, et al: Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted cdip1 silencing to improve angiogenesis following myocardial infarction. Theranostics. 11:268–291. 2021. View Article : Google Scholar : PubMed/NCBI
24	Yang C, Liu X, Zhao K, Zhu Y, Hu B, Zhou Y, Wang M, Wu Y, Zhang C, Xu J, et al: miRNA-21 promotes osteogenesis via the PTEN/PI3K/Akt/HIF-1alpha pathway and enhances bone regeneration in critical size defects. Stem Cell Res Ther. 10:652019. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Park ST and Kim J: Trends in next-generation sequencing and a new era for whole genome sequencing. Int Neurourol J. 20:S76–S83. 2016. View Article : Google Scholar : PubMed/NCBI
27	Kolak A, Kaminska M, Sygit K, Budny A, Surdyka D, Kukiełka-Budny B and Burdan F: Primary and secondary prevention of breast cancer. Ann Agric Environ Med. 24:549–553. 2017. View Article : Google Scholar : PubMed/NCBI
28	Denkert C, Liedtke C, Tutt A and von Minckwitz G: Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 389:2430–2442. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zhang S, Zhang H, Ghia EM, Huang J, Wu L, Zhang J, Lam S, Lei Y, He J, Cui B, et al: Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody. Proc Natl Acad Sci U S A. 116:1370–1377. 2019. View Article : Google Scholar : PubMed/NCBI
30	Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F and Alahari SK: Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer. 18:752019. View Article : Google Scholar : PubMed/NCBI
31	Santos JC, Lima NDS, Sarian LO, Matheu A, Ribeiro ML and Derchain SFM: Exosome-mediated breast cancer chemoresistance via miR-155 transfer. Sci Rep. 8:8292018. View Article : Google Scholar : PubMed/NCBI
32	Zheng P, Chen L, Yuan X, Luo Q, Liu Y, Xie G, Ma Y and Shen L: Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J Exp Clin Cancer Res. 36:532017. View Article : Google Scholar : PubMed/NCBI
33	Kampan NC, Madondo MT, McNally OM, Quinn M and Plebanski M: Paclitaxel and its evolving role in the management of ovarian cancer. Biomed Res Int. 2015:4130762015. View Article : Google Scholar : PubMed/NCBI
34	Weaver BA: How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 25:2677–2681. 2014. View Article : Google Scholar : PubMed/NCBI
35	Li Z, Lin C, Zhao L, Zhou L, Pan X, Quan J, Peng X, Li W, Li H, Xu J, et al: Oncogene miR-187-5p is associated with cellular proliferation, migration, invasion, apoptosis and an increased risk of recurrence in bladder cancer. Biomed Pharmacother. 105:461–469. 2018. View Article : Google Scholar : PubMed/NCBI
36	Hu YB, Yan C, Mu L, Mi YL, Zhao H, Hu H, Li XL, Tao DD, Wu YQ, Gong JP and Qin JC: Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance. Oncogene. 38:1951–1965. 2019. View Article : Google Scholar : PubMed/NCBI
37	Qin X, Yu S, Zhou L, Shi M, Hu Y, Xu X, Shen B, Liu S, Yan D and Feng J: Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner. Int J Nanomedicine. 12:3721–3733. 2017. View Article : Google Scholar : PubMed/NCBI
38	Dey N, Barwick BG, Moreno CS, Ordanic-Kodani M, Chen Z, Oprea-Ilies G, Tang W, Catzavelos C, Kerstann KF, Sledge GW Jr, et al: Wnt signaling in triple negative breast cancer is associated with metastasis. BMC Cancer. 13:5372013. View Article : Google Scholar : PubMed/NCBI
39	Hlavac V, Brynychova V, Vaclavikova R, Ehrlichová M, Vrána D, Pecha V, Koževnikovová R, Trnková M, Gatěk J, Kopperová D, et al: The expression profile of ATP-binding cassette transporter genes in breast carcinoma. Pharmacogenomics. 14:515–529. 2013. View Article : Google Scholar : PubMed/NCBI
40	Soucek P, Hlavac V, Elsnerova K, Vaclavikova R, Kozevnikovova R and Raus K: Whole exome sequencing analysis of ABCC8 and ABCD2 genes associating with clinical course of breast carcinoma. Physiol Res. 64:S549–S557. 2015. View Article : Google Scholar : PubMed/NCBI
41	Park CY, Kim HS, Jang J, Lee H, Lee JS, Yoo JE, Lee DR and Kim DW: ABCD2 is a direct target of beta-catenin and TCF-4: Implications for X-linked adrenoleukodystrophy therapy. PLoS One. 8:e562422013. View Article : Google Scholar : PubMed/NCBI
42	Jia XX, Zhu TT, Huang Y, Zeng XX, Zhang H and Zhang WX: Wnt/β-catenin signaling pathway regulates asthma airway remodeling by influencing the expression of c-Myc and cyclin D1 via the p38 MAPK-dependent pathway. Exp Ther Med. 18:3431–3438. 2019.PubMed/NCBI
43	Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, Wen Y, Pestell RG and Hung MC: Beta-catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci USA. 97:4262–4266. 2000. View Article : Google Scholar : PubMed/NCBI
44	Shi Q, Li Y, Li S, Jin L, Lai H, Wu Y, Cai Z, Zhu M, Li Q, Li Y, et al: LncRNA DILA1 inhibits Cyclin D1 degradation and contributes to tamoxifen resistance in breast cancer. Nat Commun. 11:55132020. View Article : Google Scholar : PubMed/NCBI
45	Gosens R, Baarsma HA, Heijink IH, Oenema TA, Halayko AJ, Meurs H and Schmidt M: De novo synthesis of {beta}-catenin via H-Ras and MEK regulates airway smooth muscle growth. FASEB J. 24:757–768. 2010. View Article : Google Scholar : PubMed/NCBI
46	Xu J, Zhang P, Sun H and Liu Y: LINC01094/miR-577 axis regulates the progression of ovarian cancer. J Ovarian Res. 13:1222020. View Article : Google Scholar : PubMed/NCBI
47	Cheng R, Liu YJ, Cui JW, Yang M, Liu XL, Li P, Wang Z, Zhu LZ, Lu SY, Zou L, et al: Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells. Oncotarget. 8:30252–30264. 2017. View Article : Google Scholar : PubMed/NCBI