ITGB1 Enhances the Radioresistance of Human Non-small Cell Lung Cancer Cells by Modulating the DNA Damage Response and YAP1-induced Epithelial-mesenchymal Transition

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2021 Feb 22

PMID 33613118

Citations 40

Authors

Yuexian Li

Cheng Sun

Yonggang Tan

Heying Zhang

Yuchao Li

Huawei Zou

Affiliations

Soon will be listed here.

Abstract

Radiotherapy has played a limited role in the treatment of non-small cell lung cancer (NSCLC) due to the risk of tumour radioresistance. We previously established the radioresistant non-small cell lung cancer (NSCLC) cell line H460R. In this study, we identified differentially expressed genes between these radioresistant H460R cells and their radiosensitive parent line. We further evaluated the role of a differentially expressed gene, ITGB1, in NSCLC cell radioresistance and as a potential target for improving radiosensitivity. The radiosensitivity of NSCLC cells was evaluated by flow cytometry, colony formation assays, immunofluorescence, and Western blotting. Bioinformatics assay was used to identify the effect of ITGB1 and YAP1 expression in NSCLC tissues. ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells. We observed lower clonogenic survival and cell viability and a higher rate of apoptosis of ITGB1-knockdown A549 and H460R cells than of wild type cells post-irradiation. Transfection with an ITGB1 short hairpin (sh) RNA enhanced radiation-induced DNA damage and G2/M phase arrest. Moreover, ITGB1 induced epithelial-mesenchymal transition (EMT) of NSCLC cells. Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1. ITGB1 may induce radioresistance via affecting DNA repair and YAP1-induced EMT. Taken together, our data suggest that ITGB1 is an attractive therapeutic target to overcome NSCLC cell radioresistance.

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References

Salama J, Vokes E . New radiotherapy and chemoradiotherapy approaches for non-small-cell lung cancer. J Clin Oncol. 2013; 31(8):1029-38. DOI: 10.1200/JCO.2012.44.5064. View

Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X . Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci. 2010; 101(5):1279-85. PMC: 11158334. DOI: 10.1111/j.1349-7006.2010.01511.x. View

Smith J, Tho L, Xu N, Gillespie D . The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010; 108:73-112. DOI: 10.1016/B978-0-12-380888-2.00003-0. View

Jean C, Gravelle P, Fournie J, Laurent G . Influence of stress on extracellular matrix and integrin biology. Oncogene. 2011; 30(24):2697-706. DOI: 10.1038/onc.2011.27. View

Zhou F, Huang X, Zhang Z, Chen Y, Liu X, Xing J . Functional polymorphisms of ITGB1 are associated with clinical outcome of Chinese patients with resected colorectal cancer. Cancer Chemother Pharmacol. 2015; 75(6):1207-15. DOI: 10.1007/s00280-015-2745-4. View

Seguin L, Desgrosellier J, Weis S, Cheresh D . Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015; 25(4):234-40. PMC: 4380531. DOI: 10.1016/j.tcb.2014.12.006. View

Ghasemi H, Mousavibahar S, Hashemnia M, Karimi J, Khodadadi I, Mirzaei F . Tissue stiffness contributes to YAP activation in bladder cancer patients undergoing transurethral resection. Ann N Y Acad Sci. 2020; 1473(1):48-61. DOI: 10.1111/nyas.14358. View

Yin H, Wu C, Lin C, Chai C, Hou M, Chang S . β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer. Int J Mol Sci. 2016; 17(9). PMC: 5037711. DOI: 10.3390/ijms17091432. View

Howe G, Addison C . β1 integrin: an emerging player in the modulation of tumorigenesis and response to therapy. Cell Adh Migr. 2012; 6(2):71-7. PMC: 3499315. DOI: 10.4161/cam.20077. View

10.

Eke I, Cordes N . Focal adhesion signaling and therapy resistance in cancer. Semin Cancer Biol. 2014; 31:65-75. DOI: 10.1016/j.semcancer.2014.07.009. View

11.

Chen H, Lin Y, Cheng Y, Wing L, Tsai S . Overexpression of integrin-β1 in leiomyoma promotes cell spreading and proliferation. J Clin Endocrinol Metab. 2013; 98(5):E837-46. DOI: 10.1210/jc.2012-3647. View

12.

Cooper J, Giancotti F . Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell. 2019; 35(3):347-367. PMC: 6684107. DOI: 10.1016/j.ccell.2019.01.007. View

13.

Wang D, Muller S, Amin A, Huang D, Su L, Hu Z . The pivotal role of integrin β1 in metastasis of head and neck squamous cell carcinoma. Clin Cancer Res. 2012; 18(17):4589-99. PMC: 3462074. DOI: 10.1158/1078-0432.CCR-11-3127. View

14.

Lo Sardo F, Strano S, Blandino G . YAP and TAZ in Lung Cancer: Oncogenic Role and Clinical Targeting. Cancers (Basel). 2018; 10(5). PMC: 5977110. DOI: 10.3390/cancers10050137. View

15.

Ju L, Zhou C, Li W, Yan L . Integrin beta1 over-expression associates with resistance to tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. J Cell Biochem. 2010; 111(6):1565-74. DOI: 10.1002/jcb.22888. View

16.

Sun C, Li Y, Tan Y, Zhang H, Liang Y, Zeng J . A novel role for NFIA in restoring radiosensitivity in radioresistant NSCLC cells by downregulating the AKT and ERK pathways. Biochem Biophys Res Commun. 2019; 515(4):558-564. DOI: 10.1016/j.bbrc.2019.06.011. View

17.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

18.

Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi A . Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J Biol Chem. 2001; 276(18):15164-73. DOI: 10.1074/jbc.M010484200. View

19.

Kanda R, Kawahara A, Watari K, Murakami Y, Sonoda K, Maeda M . Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling. Cancer Res. 2013; 73(20):6243-53. DOI: 10.1158/0008-5472.CAN-12-4502. View

20.

Siddiqui M, Francois M, Fenech M, Leifert W . Persistent γH2AX: A promising molecular marker of DNA damage and aging. Mutat Res Rev Mutat Res. 2015; 766:1-19. DOI: 10.1016/j.mrrev.2015.07.001. View