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外生骨疣蛋白1调节耐阿霉素乳腺癌细胞中的癌细胞干性。

Exostosin 1 regulates cancer cell stemness in doxorubicin-resistant breast cancer cells.

作者信息

Manandhar Sarala, Kim Chang-Gu, Lee Sun-Hee, Kang Soo Hyun, Basnet Nikita, Lee You Mie

机构信息

BK21 Plus Multi-Omics Based Creative Drug Research Training Team (22A20154413076), National Basic Research Laboratory of Vascular Homeostasis Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, South Korea.

出版信息

Oncotarget. 2017 Jul 31;8(41):70521-70537. doi: 10.18632/oncotarget.19737. eCollection 2017 Sep 19.

DOI:10.18632/oncotarget.19737
PMID:29050299
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5642574/
Abstract

Cancer stem cells (CSCs) are associated with cancer recurrence following radio/chemotherapy owing to their high resistance to therapeutic intervention. In this study, we investigated the role of exostoxin 1 (EXT1), an endoplasmic reticulum (ER)-residing type II transmembrane glycoprotein, in cancer cell stemness. DNA microarray analysis revealed that doxorubicin-resistant MCF7/ADR cells have high levels of EXT1 expression compared to its parental cell line, MCF7. These cells showed significantly higher populations of CSCs and larger populations of aldehyde dehydrogenase (ALDH) and CD44/CD24cells, as compared to MCF7 cells. siRNA-mediated knockdown of EXT1 in MCF7/ADR cells significantly reduced cancer stem cell markers, populations of ALDHand CD44/CD24 cells, mRNA and protein expression for CD44, and mammosphere number. Furthermore, epithelial mesenchymal transition (EMT) markers and migratory behavior were also repressed with reduced EXT1. In an soft agar colony formation assay, EXT1 knockdown by short hairpin RNA (shRNA) reduced the colony formation ability of these cells. Based on these results, we suggest that EXT1 could be a promising novel target to overcome cancer cell stemness in anthracycline-based therapeutic resistance.

摘要

癌症干细胞（CSCs）因其对治疗干预具有高度抗性，与放化疗后的癌症复发相关。在本研究中，我们调查了外切毒素1（EXT1），一种内质网（ER）驻留的II型跨膜糖蛋白，在癌细胞干性中的作用。DNA微阵列分析显示，与亲代细胞系MCF7相比，阿霉素耐药的MCF7/ADR细胞具有高水平的EXT1表达。与MCF7细胞相比，这些细胞显示出显著更高比例的癌症干细胞以及更大比例的乙醛脱氢酶（ALDH）和CD44/CD24细胞。在MCF7/ADR细胞中，siRNA介导的EXT1敲低显著降低了癌症干细胞标志物、ALDH和CD44/CD24细胞群体、CD44的mRNA和蛋白表达以及乳腺球数量。此外，EXT1减少时，上皮间质转化（EMT）标志物和迁移行为也受到抑制。在软琼脂集落形成试验中，短发夹RNA（shRNA）介导的EXT1敲低降低了这些细胞的集落形成能力。基于这些结果，我们认为EXT1可能是克服蒽环类药物治疗抗性中癌细胞干性的一个有前景的新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/62c618399d3d/oncotarget-08-70521-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/11525cc8f199/oncotarget-08-70521-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/7582115091fa/oncotarget-08-70521-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/951f09f88ceb/oncotarget-08-70521-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/502bf44dac67/oncotarget-08-70521-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/df646919598c/oncotarget-08-70521-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/46ecf194a041/oncotarget-08-70521-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/62c618399d3d/oncotarget-08-70521-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/11525cc8f199/oncotarget-08-70521-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/7fffc5a62f6c/oncotarget-08-70521-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/7582115091fa/oncotarget-08-70521-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/951f09f88ceb/oncotarget-08-70521-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/502bf44dac67/oncotarget-08-70521-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/df646919598c/oncotarget-08-70521-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/46ecf194a041/oncotarget-08-70521-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/626b/5642574/62c618399d3d/oncotarget-08-70521-g008.jpg

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