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Article

ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells

1
Department of Pharmacology, College of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Korea
2
Department of Convergence Medical Science (BK21 Plus), Gyeongsang National University, Jinju 52727, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(6), 1363; https://doi.org/10.3390/cancers12061363
Received: 14 April 2020 / Revised: 19 May 2020 / Accepted: 22 May 2020 / Published: 26 May 2020
The key barrier to the effectiveness of radiotherapy remains the radioresistance of breast cancer cells, resulting in increased tumor recurrence and metastasis. Thus, in this study, we aimed to clarify the difference between radiotherapy-resistant (RT-R) breast cancer (BC) and BC, and accordingly, analyzed gene expression levels between radiotherapy-resistant (RT-R) MDA-MB-231 cells and MDA-MB-231 cells. Gene expression array showed that ESM-1 was the most upregulated in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells. Then, we aimed to investigate the role of ESM-1 in the increased tumorigenesis of RT-R-BC cells. RT-R-MDA-MB-231, which showed an increased expression level of ESM1, exhibited significantly enhanced proliferation, colony forming ability, migration, and invasion compared to MDA-MB-231 cells, and ESM-1 knockdown effectively reversed these effects. In addition, compared to MDA-MB-231 cells, RT-R-MDA-MB-231 cells displayed improved adhesion to endothelial cells (ECs) due to the induction of adhesion molecules and increased MMP-9 activity and VEGF-A production, which were decreased by ESM-1 knockdown. Moreover, the expression of HIF-1α and activation of NF-κB and STAT-3 were increased in RT-R-MDA-MB-231 cells compared to MDA-MB-231 cells, and these effects were abolished by the knockdown of ESM-1. Finally, we confirmed the role of ESM-1 in tumorigenesis in an in vivo mouse model. Tumor volume, lung metastasis, and tumorigenic molecules (VEGF-A, HIF-1α, MMP-9, ICAM-1, VCAM-1, and phospho-NF-κB and phospho-STAT-3) were significantly induced in mice injected with ESM-1-overexpressing 4T1 cells and greatly enhanced in those injected with ESM-1-overexpressing RT-R-4T1 cells. Taken together, these results suggest for the first time that ESM-1 plays a critical role in tumorigenesis of breast cancer cells, especially RT-R-breast cancer cells, through the induction of cell proliferation and invasion. View Full-Text
Keywords: ESM-1; metastasis; tumorigenesis; radiotherapy-resistant; TNBC ESM-1; metastasis; tumorigenesis; radiotherapy-resistant; TNBC
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MDPI and ACS Style

Jin, H.; Rugira, T.; Ko, Y.S.; Park, S.W.; Yun, S.P.; Kim, H.J. ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells. Cancers 2020, 12, 1363. https://doi.org/10.3390/cancers12061363

AMA Style

Jin H, Rugira T, Ko YS, Park SW, Yun SP, Kim HJ. ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells. Cancers. 2020; 12(6):1363. https://doi.org/10.3390/cancers12061363

Chicago/Turabian Style

Jin, Hana, Trojan Rugira, Young S. Ko, Sang W. Park, Seung P. Yun, and Hye J. Kim. 2020. "ESM-1 Overexpression is Involved in Increased Tumorigenesis of Radiotherapy-Resistant Breast Cancer Cells" Cancers 12, no. 6: 1363. https://doi.org/10.3390/cancers12061363

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