Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, 87 Ding Jiaqiao Rd., Nanjing, 210009, China.
Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Breast Cancer Res. 2020 Mar 6;22(1):26. doi: 10.1186/s13058-020-01264-z.
Breast cancer stem cells (BCSCs) are typically seed cells of breast tumor that initiate and maintain tumor growth. MiR-7, as a cancer inhibitor, decreases the BCSC subset and inhibits tumor progression through mechanisms that remain unknown.
We examined miR-7 expression in breast cancer and developed a BCSC-driven xenograft mouse model, to evaluate the effects of miR-7 overexpression on the decrease of the BCSC subset in vitro and in vivo. In addition, we determined how miR-7 decreased the BCSC subset by using the ALDEFLUOR, lentivirus infection, dual-luciferase reporter, and chromatin immunoprecipitation-PCR assays.
MiR-7 was expressed at low levels in breast cancer tissues compared with normal tissues, and overexpression of miR-7 directly inhibited lncRNA XIST, which mediates the transcriptional silencing of genes on the X chromosome, and reduced epithelium-specific antigen (ESA) expression by increasing miR-92b and inhibiting slug. Moreover, miR-7 suppressed CD44 and ESA by directly inhibiting the NF-κB subunit RELA and slug in breast cancer cell lines and in BCSC-driven xenografts, which confirmed the antitumor activity in mice injected with miR-7 agomir or stably infected with lenti-miR-7.
The findings from this study uncover the molecular mechanisms by which miR-7 inhibits XIST, modulates the miR-92b/Slug/ESA axis, and decreases the RELA and CD44 expression, resulting in a reduced BCSC subset and breast cancer growth inhibition. These findings suggest a potentially targeted treatment approach to breast cancer.
乳腺癌干细胞（BCSCs）通常是启动和维持肿瘤生长的乳腺肿瘤的起始细胞。miR-7 作为一种癌症抑制剂，通过未知的机制减少 BCSC 亚群并抑制肿瘤进展。
我们检查了乳腺癌中的 miR-7 表达，并开发了 BCSC 驱动的异种移植小鼠模型，以评估 miR-7 过表达对体外和体内 BCSC 亚群减少的影响。此外，我们通过 ALDEFLUOR、慢病毒感染、双荧光素酶报告基因和染色质免疫沉淀-PCR 检测确定了 miR-7 如何减少 BCSC 亚群。
miR-7 在乳腺癌组织中的表达水平低于正常组织，过表达 miR-7 可直接抑制 lncRNA XIST，介导 X 染色体上基因的转录沉默，并通过增加 miR-92b 和抑制 slug 来降低上皮特异性抗原（ESA）的表达。此外，miR-7 通过直接抑制 NF-κB 亚基 RELA 和 slug 在乳腺癌细胞系和 BCSC 驱动的异种移植中抑制 CD44 和 ESA，证实了 miR-7 agomir 注射或稳定感染 lenti-miR-7 的小鼠的抗肿瘤活性。
本研究的结果揭示了 miR-7 抑制 XIST、调节 miR-92b/Slug/ESA 轴以及降低 RELA 和 CD44 表达的分子机制，导致 BCSC 亚群减少和乳腺癌生长抑制。这些发现表明了一种针对乳腺癌的潜在靶向治疗方法。
