Depleting Hsa_circ_0000567 Suppresses Acquired Gefitinib Resistance and Proliferation of Lung Adenocarcinoma Cells Through Regulating the MiR-377-3p / ZFX Axis: an in Vitro and in Vivo Study

Overview

Journal Histol Histopathol

Specialties Anatomy & Histology
Pathology

Date 2022 Feb 8

PMID 35133000

Authors

Lanjun Wang

Mengqi Li

Rong Lian

Affiliations

Soon will be listed here.

Abstract

Background: Circular RNAs (circRNAs) expression profile has been reported in lung adenocarcinoma (LUAD) cells resistant to gefitinib, and hsa_circ_0000567 was abnormally upregulated. However, its precise role in gefitinib resistance remains unclarified.

Methods: Levels of hsa_circ_0000567, microRNA (miR)-377-3p and zinc finger protein X-linked (ZFX) were detected by real-time quantitative PCR. Direct attachment was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Gefitinib resistance was measured by MTT assay, colony formation assay, flow cytometry, western blotting, and xenograft in mice.

Results: Expression of hsa_circ_0000567 was upreguated in human gefitinib-resistant human LUAD tissues and cells (HCC827/GR and PC9/GR). Clinically, higher hsa_circ_0000567 correlated with advanced tumor burden. Blockage of hsa_circ_0000567 suppressed cell viability, half maximal inhibitory concentration (IC₅₀) value, colony formation ability, and expression of Bcl-2 and proliferating cell nuclear antigen (PCNA) in HCC827/GR and PC9/GR cells under gefitinib treatment or not, accompanied with enhanced apoptosis rate and Bax expression. In vivo, tumor growth of PC9/GR cells untreated and treated with gefitinib was restrained by silencing hsa_circ_0000567. miR-377-3p was directly regulated by hsa_circ_0000567, and then targeted ZFX. Similar to hsa_circ_0000567 knockdown, overexpressing miR-377-3p inhibited chemoresistance in genitinib-resistant LUAD cells in vitro, whereas, depleting miR-377-3p was able to promote gefitinib resistance in spite of hsa_circ_0000567 knockdown. Moreover, restoring ZFX abrogated miR-377-3p-mediated chemosensitivity in genitinib-resistant LUAD cells in vitro.

Conclusion: The hsa_circ_0000567/miR-377-3p/ZFX axis might contribute to acquired gefitinib resistance in LUAD cells both in vitro and in vivo, suggesting hsa_circ_0000567 as a novel therapeutic target in treatment of gefitinib-resistant LUAD.

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References

Cai L, Tsai Y, Wang P, Wang J, Li D, Fan H . ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. Mol Cell. 2018; 72(2):341-354.e6. PMC: 6214474. DOI: 10.1016/j.molcel.2018.08.029. View

Chen T, Luo J, Gu Y, Huang J, Luo Q, Yang Y . Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. Thorac Cancer. 2019; 10(4):930-941. PMC: 6449233. DOI: 10.1111/1759-7714.13032. View

Dai C, Dong Q, Lu Q, Liu F, Zhu Z . Prognostic value of Zinc-finger protein X-linked in patients with solid tumors. Minerva Chir. 2016; 72(1):81-88. DOI: 10.23736/S0026-4733.16.07198-4. View

Di X, Jin X, Li R, Zhao M, Wang K . CircRNAs and lung cancer: Biomarkers and master regulators. Life Sci. 2019; 220:177-185. DOI: 10.1016/j.lfs.2019.01.055. View

Drula R, Braicu C, Harangus A, Nabavi S, Trif M, Slaby O . Critical function of circular RNAs in lung cancer. Wiley Interdiscip Rev RNA. 2020; 11(5):e1592. DOI: 10.1002/wrna.1592. View

Garg A, Batra U, Choudhary P, Jain D, Khurana S, Malik P . Clinical predictors of response to EGFR-tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer: A real-world multicentric cohort analysis from India. Curr Probl Cancer. 2020; 44(3):100570. DOI: 10.1016/j.currproblcancer.2020.100570. View

Gupta S, Silveira D, Barbe-Tuana F, Mombach J . Integrative data modeling from lung and lymphatic cancer predicts functional roles for miR-34a and miR-16 in cell fate regulation. Sci Rep. 2020; 10(1):2511. PMC: 7018995. DOI: 10.1038/s41598-020-59339-y. View

Herbst R, Morgensztern D, Boshoff C . The biology and management of non-small cell lung cancer. Nature. 2018; 553(7689):446-454. DOI: 10.1038/nature25183. View

Hu S, Cao P, Kong K, Han P, Deng Y, Li F . MicroRNA-449a delays lung cancer development through inhibiting KDM3A/HIF-1α axis. J Transl Med. 2021; 19(1):224. PMC: 8157436. DOI: 10.1186/s12967-021-02881-8. View

10.

Huang L, Liu Z, Hu J, Luo Z, Zhang C, Wang L . MiR-377-3p suppresses colorectal cancer through negative regulation on Wnt/β-catenin signaling by targeting XIAP and ZEB2. Pharmacol Res. 2020; 156:104774. DOI: 10.1016/j.phrs.2020.104774. View

11.

Huang Y, Dai Y, Wen C, He S, Shi J, Zhao D . circSETD3 Contributes to Acquired Resistance to Gefitinib in Non-Small-Cell Lung Cancer by Targeting the miR-520h/ABCG2 Pathway. Mol Ther Nucleic Acids. 2020; 21:885-899. PMC: 7452060. DOI: 10.1016/j.omtn.2020.07.027. View

12.

Jiang M, Xu S, Yue W, Zhao X, Zhang L, Zhang C . The role of ZFX in non-small cell lung cancer development. Oncol Res. 2013; 20(4):171-8. DOI: 10.3727/096504012x13548165987493. View

13.

Lai K, Chen J, He M, Ching A, Lau C, Lai P . Overexpression of ZFX confers self-renewal and chemoresistance properties in hepatocellular carcinoma. Int J Cancer. 2014; 135(8):1790-9. DOI: 10.1002/ijc.28819. View

14.

Leonetti A, Assaraf Y, Veltsista P, Hassouni B, Tiseo M, Giovannetti E . MicroRNAs as a drug resistance mechanism to targeted therapies in EGFR-mutated NSCLC: Current implications and future directions. Drug Resist Updat. 2018; 42:1-11. DOI: 10.1016/j.drup.2018.11.002. View

15.

Li K, Zhu Z, Liu Y, Liu J, Wang H, Xiong Z . ZFX knockdown inhibits growth and migration of non-small cell lung carcinoma cell line H1299. Int J Clin Exp Pathol. 2013; 6(11):2460-7. PMC: 3816815. View

16.

Li L, Zhang Q, Lian K . Circular RNA circ_0000284 plays an oncogenic role in the progression of non-small cell lung cancer through the miR-377-3p-mediated PD-L1 promotion. Cancer Cell Int. 2020; 20:247. PMC: 7298744. DOI: 10.1186/s12935-020-01310-y. View

17.

Rhie S, Yao L, Luo Z, Witt H, Schreiner S, Guo Y . ZFX acts as a transcriptional activator in multiple types of human tumors by binding downstream from transcription start sites at the majority of CpG island promoters. Genome Res. 2018; 28(3):310-320. PMC: 5848610. DOI: 10.1101/gr.228809.117. View

18.

Shah R, Lester J . Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clin Lung Cancer. 2020; 21(3):e216-e228. DOI: 10.1016/j.cllc.2019.12.003. View

19.

Shi Y, Au J, Thongprasert S, Srinivasan S, Tsai C, Khoa M . A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014; 9(2):154-62. PMC: 4132036. DOI: 10.1097/JTO.0000000000000033. View

20.

Song L, Cui Z, Guo X . Comprehensive analysis of circular RNA expression profiles in cisplatin-resistant non-small cell lung cancer cell lines. Acta Biochim Biophys Sin (Shanghai). 2020; 52(9):944-953. DOI: 10.1093/abbs/gmaa085. View