AZD9291-resistant Non-small Cell Lung Cancer Cell-derived Exosomal Lnc-MZT2A-5:1 Induces the Activation of Fibroblasts

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2021 Nov 18

PMID 34790799

Citations 7

Authors

Liwei Song

Gang Qian

Jia Huang

Tianxiang Chen

Yunhai Yang

Affiliations

Soon will be listed here.

Abstract

Background: AZD9291 resistance is still a challenge in the treatment of non-small cell lung cancer (NSCLC) and fibroblasts in the tumor microenvironment (TME) play a key role in the malignant phenotype of NSCLC. The study aimed to investigate the role of exosomes derived from AZD9291-resistant cells on the phenotypes of lung fibroblasts and the underlying mechanism.

Methods: The supernatants and exosomes of wild type and AZD9291-resistant NSCLC (H1975/PC9) cells were collected, and co-cultured with lung fibroblasts (MRC-5 cells) respectively. Transwell and quantitative real-time PCR (qRT-PCR) assays were used to evaluate migration and inflammation levels. Exosomes were collected by ultracentrifugation, and identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blots. Microarray was used to screen dysregulated exosomal lncRNAs from the resistant cells. Candidate lncRNAs were selected by bioinformatical annotation of their target genes and verified by qRT-PCR. The target lncRNA was then selected for further confirmation.

Results: Both the supernatant and exosomes from resistant cells significantly promoted the migration of MRC-5 cells, and the exosomes also upregulated mRNA levels of inflammation cytokines. Microarray identified 159 dysregulated exosomal lncRNAs. Fifteen candidate lncRNAs were selected following the biological roles of their target genes. qRT-PCR validation indicated that lnc-MZT2A-5:1 had the highest fold change. Finally, we found that lnc-MZT2A-5:1 could promote the migration ability and inflammation cytokines expression level of MRC-5 cells.

Conclusions: Our study clarified that lnc-MZT2A-5:1 from AZD9291-resistant NSCLC cell lines could promote the activation of MRC-5 cells, thus to uncover a new mechanism for AZD9291 resistance and provide new potential targets for the treatment of NSCLC.

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References

Chen X, Wang Z, Tong F, Dong X, Wu G, Zhang R . lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer. Mol Ther Nucleic Acids. 2020; 19:643-653. PMC: 6965519. DOI: 10.1016/j.omtn.2019.10.047. View

Gan R, Yang Y, Yang X, Zhao L, Lu J, Meng Q . Downregulation of miR-221/222 enhances sensitivity of breast cancer cells to tamoxifen through upregulation of TIMP3. Cancer Gene Ther. 2014; 21(7):290-6. DOI: 10.1038/cgt.2014.29. View

Yan W, Xu N, Han X, Zhou X, He B . The clinicopathological significance of FHIT hypermethylation in non-small cell lung cancer, a meta-analysis and literature review. Sci Rep. 2016; 6:19303. PMC: 4726317. DOI: 10.1038/srep19303. View

Yan P, Luo S, Lu J, Shen X . Cis- and trans-acting lncRNAs in pluripotency and reprogramming. Curr Opin Genet Dev. 2017; 46:170-178. DOI: 10.1016/j.gde.2017.07.009. View

Vancauwenberghe E, Noyer L, Derouiche S, Lemonnier L, Gosset P, Sadofsky L . Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF). Mol Carcinog. 2017; 56(8):1851-1867. DOI: 10.1002/mc.22642. View

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View

Xie F, Zhou X, Fang M, Li H, Su P, Tu Y . Extracellular Vesicles in Cancer Immune Microenvironment and Cancer Immunotherapy. Adv Sci (Weinh). 2019; 6(24):1901779. PMC: 6918121. DOI: 10.1002/advs.201901779. View

Terlizzi M, Colarusso C, Pinto A, Sorrentino R . Drug resistance in non-small cell lung Cancer (NSCLC): Impact of genetic and non-genetic alterations on therapeutic regimen and responsiveness. Pharmacol Ther. 2019; 202:140-148. DOI: 10.1016/j.pharmthera.2019.06.005. View

Bach D, Hong J, Park H, Lee S . The role of exosomes and miRNAs in drug-resistance of cancer cells. Int J Cancer. 2017; 141(2):220-230. DOI: 10.1002/ijc.30669. View

10.

Andrews Wright N, Goss G . Third-generation epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Transl Lung Cancer Res. 2019; 8(Suppl 3):S247-S264. PMC: 6894985. DOI: 10.21037/tlcr.2019.06.01. View

11.

Allavena G, Cuomo F, Baumgartner G, Bele T, Sellgren A, Oo K . Suppressed translation as a mechanism of initiation of CASP8 (caspase 8)-dependent apoptosis in autophagy-deficient NSCLC cells under nutrient limitation. Autophagy. 2017; 14(2):252-268. PMC: 5902222. DOI: 10.1080/15548627.2017.1405192. View

12.

Pan R, Zhou H . Exosomal Transfer of lncRNA H19 Promotes Erlotinib Resistance in Non-Small Cell Lung Cancer via miR-615-3p/ATG7 Axis. Cancer Manag Res. 2020; 12:4283-4297. PMC: 7294568. DOI: 10.2147/CMAR.S241095. View

13.

Che Y, Wang J, Li Y, Lu Z, Huang J, Sun S . Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance. Cell Death Dis. 2018; 9(7):759. PMC: 6037765. DOI: 10.1038/s41419-018-0808-2. View

14.

Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M . Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019; 121(9):725-737. PMC: 6889286. DOI: 10.1038/s41416-019-0573-8. View

15.

Zheng L, Wang Y, Xu Z, Yang Q, Zhu G, Liao X . Concurrent EGFR-TKI and Thoracic Radiotherapy as First-Line Treatment for Stage IV Non-Small Cell Lung Cancer Harboring EGFR Active Mutations. Oncologist. 2019; 24(8):1031-e612. PMC: 6693693. DOI: 10.1634/theoncologist.2019-0285. View

16.

Qin X, Yu S, Zhou L, Shi M, Hu Y, Xu X . Cisplatin-resistant lung cancer cell-derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100-5p-dependent manner. Int J Nanomedicine. 2017; 12:3721-3733. PMC: 5439933. DOI: 10.2147/IJN.S131516. View

17.

El Andaloussi S, Mager I, Breakefield X, Wood M . Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013; 12(5):347-57. DOI: 10.1038/nrd3978. View

18.

Poulet C, Njock M, Moermans C, Louis E, Louis R, Malaise M . Exosomal Long Non-Coding RNAs in Lung Diseases. Int J Mol Sci. 2020; 21(10). PMC: 7279016. DOI: 10.3390/ijms21103580. View

19.

Rajurkar S, Mambetsariev I, Pharaon R, Leach B, Tan T, Kulkarni P . Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies. J Clin Med. 2020; 9(6). PMC: 7356243. DOI: 10.3390/jcm9061870. View

20.

Mueller M, Fusenig N . Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004; 4(11):839-49. DOI: 10.1038/nrc1477. View