MiR-873/PD-L1 axis regulates the stemness of breast cancer cells
MiR-873/PD-L1 axis regulates the stemness of breast cancer cells
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MiR-873/PD-L1轴调节乳腺癌细胞的干性
DOI：
10.1016/j.ebiom.2019.02.034
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发表时间：
2019-03-01
期刊：
影响因子：
11.1
通讯作者：
Zheng, Lufeng
中科院分区：
文献类型：
--
作者：
Gao, Lanlan;Guo, Qianqian;Zheng, Lufeng
背景：乳腺癌干细胞具有自我更新能力，对常规化疗具有抵抗力。PD-L1可促进乳腺癌干细胞中干细胞标志物（OCT 4和Nanog）的表达。然而，PD-L1调控乳腺癌细胞干细胞性的机制以及PD-L1在乳腺癌细胞中的调控机制尚不清楚。在临床样本中评价PD-L1与干性标志物表达之间的相关性。此外，荧光素酶报告基因试验结合RNA荧光原位杂交（RNA-FISH）和RNA结合蛋白免疫沉淀（RIP）试验用于验证miR-873与PD-L1的直接结合。并通过流式细胞术、乳腺球形成法结合裸鼠移植瘤模型检测miR-873/PDL 1轴对乳腺癌细胞干细胞性的影响。结果：PD-L1的表达与干细胞性标志物的表达呈正相关，PD-L1的过表达通过激活PI 3 K/Akt和ERK 1/2通路促进乳腺癌细胞的耐药和干细胞性。在机制上，miR-873通过直接结合PD-L1的3 '-非翻译区（UTR）来抑制PD-L1的表达，并且miR-873减弱乳腺癌细胞的干性和化疗耐药性，这依赖于PD-L1和下游PI 3 K/Akt和ERK 1/2信号传导。值得注意的是，重组PD-1（rPD-1）增强了PD-L1对干细胞性和化疗耐药性的促进作用，PD-1/PD-L1抑制剂减弱了这种作用。解读：miR-873/PD-L1调节轴可能作为增强乳腺癌细胞化疗敏感性和消除干细胞性的治疗靶点。本工作得到了国家自然科学基金项目81702957，中国博士后科学基金项目2017 M620230，江苏省博士后科研资助计划（2017）的资助，1701197 B号，以及江苏省高等教育机构优先学术计划发展（PAPD）。(c)2019年，任作家。由Elsevier B出版。V.这是CC BY-NC-ND许可证（http：//creativecommons.org/licenses/by-nc-nd/4.0/）下的开放获取文章。
Background: Breast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.Methods: Lentivirus infectionwas used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flowcytometry, mammosphere formation combined with nude mouse tumor xenograftmodel were carried out to examine the effects ofmiR-873/PDL1 axis on the stemness of breast cancer cells. Finally, MTT assay was performed to determine the effects of miR873/ PD-L1 axis on drug resistance.Findings: PD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3'-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor.Interpretation: miR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemosensitivity and eliminate the stemness of breast cancer cells.Fund: This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. (c) 2019 The Authors. Published by Elsevier B. V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).