雌激素受体-α- miR-1271-SNAI2 反馈环调控转化生长因子-β诱导的乳腺癌进展。
Estrogen receptor-α-miR-1271-SNAI2 feedback loop regulates transforming growth factor-β-induced breast cancer progression.
机构信息
The First Department of Breast Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan-Hu-Xi Road, Hexi District, Tianjin, 300060, China.
Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
出版信息
J Exp Clin Cancer Res. 2019 Mar 1;38(1):109. doi: 10.1186/s13046-019-1112-4.
BACKGROUND
Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-β (TGF-β) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited.
METHODS
The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop.
RESULTS
miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-β-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2.
CONCLUSIONS
Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-β network in breast cancer progression.
背景
乳腺癌是全世界女性最常见的癌症，约 70%的乳腺癌为激素受体阳性，表达雌激素受体-α（ERα）和/或孕激素受体。ERα 已被证实可促进原发性乳腺癌的生长，但也可拮抗导致上皮间质转化（EMT）的信号通路，包括转化生长因子-β（TGF-β）信号通路。miRNA 的改变或功能障碍与癌症的发生和发展有关。虽然 miR-1271 已被确定为多种癌症的肿瘤抑制因子，但 miR-1271 在乳腺癌中的作用仍有限。
方法
通过体外和体内实验研究了 miR-1271 对乳腺癌进展的影响。通过 Western blot 和免疫荧光分别分析 EMT 相关蛋白的表达水平和定位。染色质免疫沉淀和双荧光素酶报告基因实验用于验证 ERα-miR-1271-SNAI2 反馈环的调控。
结果
miR-1271 通过靶向 SNAI2 抑制乳腺癌的体外和体内进展以及 EMT 表型。雌激素以 miR-1271 依赖的方式逆转 TGF-β 诱导的 EMT。此外，ERα 可反式激活 miR-1271 的表达，同时也被 SNAI2 转录抑制。
结论
我们的数据揭示了 ERα-miR-1271-SNAI2 反馈环，并提供了一种机制来解释 TGF-β 网络在乳腺癌进展中的作用。
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