miR-142-3p靶向HMGB1逆转乳腺癌细胞MCF-7对阿霉素的耐药性  

miR-142-3p target HMGB1 reverses adriamycin resistance of breast cancer cell MCF-7

作　　者：梁璐 岑慧裕 洪超 蔡晓彤 林忠晓 杜玲然 余细勇 LIANG Lu;CEN Hui-yu;HONG Chao;CAI Xiao-tong;LIN Zhong-xiao;DU Ling-ran;YU Xi-yong(School of Pharmaceutical Sciences,Guangzhou Medical University,Guangdong Key Lab of Molecular Target&Clinical Pharmacology,Guangzhou 511436,China)

机构地区：[1]广州医科大学药学院、广东省分子靶标与临床药理学重点实验室,广东广州511436

出　　处：《中国药理学通报》2020年第2期191-197,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金重点项目(No 81330007,U1601227);广东省重大科技计划资助项目(No 2015B020225006);广州市高等学校第八批教育教学改革课题(No 2017C06)。

摘　　要：目的化疗耐药是乳腺癌复发转移、治疗效果不理想的主要因素。本文探讨miR-142-3p通过靶向高迁移率族蛋白1(high-mobility group box 1,HMGB1)提高乳腺癌化疗敏感性的分子机制。方法实时荧光定量PCR检测人乳腺癌MCF-7细胞及阿霉素耐药株MCF-7/DOX细胞中的miR-142-3p水平;MTT法检测阿霉素(doxorubicin,DOX)处理后各组的增殖情况、流式细胞术检测凋亡率、Western blot检测HMGB1和自噬有关蛋白的表达水平;双荧光素酶报告实验评价miR-142-3p对HMGB1的靶向调控作用。结果阿霉素耐药株MCF-7/DOX细胞中的miR-142-3p水平明显下调。miR142-3p的过度表达增强了乳腺癌细胞对阿霉素的敏感性和提高阿霉素诱导的凋亡比率。HMGB1是乳腺癌细胞中miR-142-3p的直接功能靶点,HMGB1的过表达可以明显解除由miR-142-3p上调所产生的细胞凋亡和自噬抑制。结论miR-142-3p的过表达可能通过抑制自噬靶向HMGB1,增强乳腺癌细胞对阿霉素的化学敏感性。miR-142-3p/HMGB1为提高乳腺癌对药物的敏感性提供了新的靶点,具有一定价值。Aim To explore the molecular mechanism of miR-142-3p involved in the regulation of chemosensitivity of breast cancer by targeting high-mobility group box 1(HMGB1).Methods Real-time quantitative PCR(QPCR)was employed to detect the levels of miR-142-3p in human breast cancer MCF-7 cells and doxorubicin-resistant MCF-7/DOX cells.MTT was used to detect the proliferation of doxorubicin(DOX)-treated groups.Flow cytometry was applied to detect the apoptotic rate of each group after transfection.Western blot was used to detect the expression of HMGB1 and autophagy-related proteins.Double Luciferase Report experiment was carried out to evaluate the targeting effect of miR-142-3p on HMGB1.Results The level of miR-142-3p in MCF-7/DOX cells was significantly down-regulated.Overexpression of miR-142-3p enhanced the sensitivity of breast cancer cells to DOX and increased the apoptotic rate induced by DOX.HMGB1 was the direct functional target of miR-142-3p in breast cancer cells,and the overexpression of HMGB1 could significantly relieve the promotion of apoptosis and inhibition of autophagy by miR-142-3p uP-regulation.Conclusions The overexpression of miR-142-3p may enhance the chemosensitivity of breast cancer cells to DOX by inhibiting autophagy and targeting HMGB1.miR-142-3p/HMGB1 provides a new target for reversing the drug resistance of breast cancer.

关 键 词：miR-142-3p HMGB1 MCF-7 乳腺癌 自噬 阿霉素耐药 

分 类 号：R329.24[医药卫生—人体解剖和组织胚胎学] R342.2[医药卫生—基础医学]