Exosomes Derived from Tumor Cells Initiate Breast Cancer Cell Metastasis and Chemoresistance Through a MALAT1-Dependent Mechanism

Overview

Journal J Oncol

Specialty Oncology

Date 2022 Jul 11

PMID 35813865

Authors

Shuang Tao

ZhengYang Bai

Yaobang Liu

YaLi Gao

Jia Zhou

Yangyang Zhang

Jinping Li

Affiliations

Soon will be listed here.

Abstract

Background: Chemoresistance poses a great hindrance in the treatment of breast cancer (BC). Interestingly, exosome (Exo)-mediated transfer of long noncoding RNAs (lncRNAs) has been reported to regulate chemoresistance in diverse diseases. We herein investigate the potential role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) transferred by BC cell-derived Exo in chemoresistance of BC cells.

Methods: BC-related lncRNAs were identified. Exosomes were isolated and verified from BC cells. The expression patterns of MALAT1 were then examined in the adriamycin (ADR)-sensitive and resistant cells and the isolated Exo, followed by the analysis of the downstream microRNA (miRNA) of MALAT1. The role and mechanism of MALAT1 transmitted by BC cell-derived Exo in BC cell metastasis and chemoresistance were assessed.

Results: MALAT1 was highly expressed in BC cells and their Exo. In addition, MALAT1 delivered by BC cell-derived Exo augmented the malignant properties and chemoresistance of BC cells. Mechanistically, MALAT1 bound to miR-1-3p and limited the miR-1-3p expression, which sequentially targeted the vasodilator-stimulated phosphoprotein (VASP) protein. Moreover, silencing of VASP inhibited the activation of the RAP1 member of RAS oncogene family (Rap1) signaling pathway, which led to the attenuation of BC cell malignant properties and chemoresistance. assay further validated the tumor-promoting effect of Exo-MALAT1 regulation of the miR-1-3p/VASP/Rap1 axis.

Conclusion: Collectively, MALAT1 loaded by BC cell-derived Exo can accelerate BC cell metastasis and chemoresistance disruption of miR-1-3p-mediated inhibition of the VASP/Rap1 signaling axis.

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References

Hu W, Liu C, Bi Z, Zhou Q, Zhang H, Li L . Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology. Mol Cancer. 2020; 19(1):102. PMC: 7273667. DOI: 10.1186/s12943-020-01199-1. View

Zhang L, Yu D . Exosomes in cancer development, metastasis, and immunity. Biochim Biophys Acta Rev Cancer. 2019; 1871(2):455-468. PMC: 6542596. DOI: 10.1016/j.bbcan.2019.04.004. View

Tao S, Li H, Ma X, Ma Y, He J, Gao Y . Elevating microRNA-1-3p shuttled by cancer-associated fibroblasts-derived extracellular vesicles suppresses breast cancer progression and metastasis by inhibiting GLIS1. Cancer Gene Ther. 2020; 28(6):634-648. DOI: 10.1038/s41417-020-00244-x. View

Benz P, Laban H, Zink J, Gunther L, Walter U, Gambaryan S . Vasodilator-Stimulated Phosphoprotein (VASP)-dependent and -independent pathways regulate thrombin-induced activation of Rap1b in platelets. Cell Commun Signal. 2016; 14(1):21. PMC: 5020514. DOI: 10.1186/s12964-016-0144-z. View

Arun G, Spector D . MALAT1 long non-coding RNA and breast cancer. RNA Biol. 2019; 16(6):860-863. PMC: 6546402. DOI: 10.1080/15476286.2019.1592072. View

Ye M, Dong S, Hou H, Zhang T, Shen M . Oncogenic Role of Long Noncoding RNAMALAT1 in Thyroid Cancer Progression through Regulation of the miR-204/IGF2BP2/m6A-MYC Signaling. Mol Ther Nucleic Acids. 2020; 23:1-12. PMC: 7711188. DOI: 10.1016/j.omtn.2020.09.023. View

Khattar E, Maung K, Chew C, Ghosh A, Mok M, Lee P . Rap1 regulates hematopoietic stem cell survival and affects oncogenesis and response to chemotherapy. Nat Commun. 2019; 10(1):5349. PMC: 6911077. DOI: 10.1038/s41467-019-13082-9. View

Dai X, Liang Z, Liu L, Guo K, Xu S, Wang H . Silencing of MALAT1 inhibits migration and invasion by sponging miR‑1‑3p in prostate cancer cells. Mol Med Rep. 2019; 20(4):3499-3508. PMC: 6755148. DOI: 10.3892/mmr.2019.10602. View

Teo H, Ghosh S, Luesch H, Ghosh A, Wong E, Malik N . Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression. Nat Cell Biol. 2010; 12(8):758-67. DOI: 10.1038/ncb2080. View

10.

Li K, Ma Y, Tian Y, Xu X, Gao Y, He Y . Silencing lncRNA SNHG6 suppresses proliferation and invasion of breast cancer cells through miR-26a/VASP axis. Pathol Res Pract. 2019; 215(10):152575. DOI: 10.1016/j.prp.2019.152575. View

11.

Shaath H, Vishnubalaji R, Elango R, Khattak S, Alajez N . Single-cell long noncoding RNA (lncRNA) transcriptome implicates MALAT1 in triple-negative breast cancer (TNBC) resistance to neoadjuvant chemotherapy. Cell Death Discov. 2021; 7(1):23. PMC: 7835365. DOI: 10.1038/s41420-020-00383-y. View

12.

Sun D, Zhong J, Wei W, Chen X, Liu J, Hu Z . Identification of microRNA expression in sentinel lymph nodes from patients with breast cancer via RNA sequencing for diagnostic accuracy. J Gene Med. 2019; 21(4):e3075. DOI: 10.1002/jgm.3075. View

13.

Liu L, Jiang Z, Jiang X, Wang S . Up-regulation of SNHG15 facilitates cell proliferation, migration, invasion and suppresses cell apoptosis in breast cancer by regulating miR-411-5p/VASP axis. Eur Rev Med Pharmacol Sci. 2020; 24(4):1899-1912. DOI: 10.26355/eurrev_202002_20368. View

14.

Zhao W, Geng D, Li S, Chen Z, Sun M . LncRNA HOTAIR influences cell growth, migration, invasion, and apoptosis via the miR-20a-5p/HMGA2 axis in breast cancer. Cancer Med. 2018; 7(3):842-855. PMC: 5852357. DOI: 10.1002/cam4.1353. View

15.

Mansoori B, Silvestris N, Mohammadi A, Khaze V, Baghbani E, Mokhtarzadeh A . miR-34a and miR-200c Have an Additive Tumor-Suppressive Effect on Breast Cancer Cells and Patient Prognosis. Genes (Basel). 2021; 12(2). PMC: 7918749. DOI: 10.3390/genes12020267. View

16.

Liu P, Li X, Cui Y, Chen J, Li C, Li Q . LncRNA-MALAT1 mediates cisplatin resistance via miR-101-3p/VEGF-C pathway in bladder cancer. Acta Biochim Biophys Sin (Shanghai). 2019; 51(11):1148-1157. DOI: 10.1093/abbs/gmz112. View

17.

Xiao L, Lan X, Shi X, Zhao K, Wang D, Wang X . Cytoplasmic RAP1 mediates cisplatin resistance of non-small cell lung cancer. Cell Death Dis. 2017; 8(5):e2803. PMC: 5520727. DOI: 10.1038/cddis.2017.210. View

18.

Ou X, Gao G, Bazhabayi M, Zhang K, Liu F, Xiao X . MALAT1 and BACH1 are prognostic biomarkers for triple-negative breast cancer. J Cancer Res Ther. 2020; 15(7):1597-1602. DOI: 10.4103/jcrt.JCRT_282_19. View

19.

Dou D, Ren X, Han M, Xu X, Ge X, Gu Y . CircUBE2D2 (hsa_circ_0005728) promotes cell proliferation, metastasis and chemoresistance in triple-negative breast cancer by regulating miR-512-3p/CDCA3 axis. Cancer Cell Int. 2020; 20:454. PMC: 7491078. DOI: 10.1186/s12935-020-01547-7. View

20.

Li Z, Xu C, Ding B, Gao M, Wei X, Ji N . Long non-coding RNA MALAT1 promotes proliferation and suppresses apoptosis of glioma cells through derepressing Rap1B by sponging miR-101. J Neurooncol. 2017; 134(1):19-28. DOI: 10.1007/s11060-017-2498-5. View