miR-221/222-Wnt/β-catenin正反馈环路促进三阴性乳腺癌发生发展的机制研究

The incidence and mortality of breast cancer ranked top one in female malignancy. Triple negative breast cancer is a subtype of breast cancer, accounting for about 15% of all breast cancers, because of the lack of endocrine and anti-HER2 therapeutic targets, there is no specific standard treatment. Studies have shown that Wnt/β-catenin signaling pathway is over-activated in triple negative breast cancer, and is closely related to triple negative breast cancer cell growth, proliferation, migration. However, the molecular mechanism of Wnt/β-catenin signaling pathway abnormal activation is still unclear. Our preliminary study found that the highly expressed miR-221/222 in triple negative breast cancer is possible by suppressing different Wnt signaling pathway inhibitors and form a positive feedback loop with Wnt/β-catenin to promote the activation of the Wnt signaling pathway, thereby promoting the occurrence and development of triple negative breast cancer. In this research project, we will use various molecular biology methods to reveal the molecular mechanism of miR-221/222 regulating Wnt signaling pathway. From the cellular level and animal models to reveal that miR-221/222 promote the development of triple negative breast cancer by regulating the activation of Wnt signaling pathways, which will provide new molecular targets and theoretical basis for triple negative breast cancer treatment and diagnosis.

目前，乳腺癌的发病率占女性恶性肿瘤的首位。三阴性乳腺癌约占所有乳腺癌的15%，因其缺乏内分泌及抗HER2治疗的靶点，尚无针对性的治疗方案。研究表明Wnt/β-catenin信号通路在三阴性乳腺癌中高度激活，与三阴性乳腺癌的生长、增殖、迁移密切相关。然而，其异常激活的机制仍不清楚。我们初步的研究发现，在三阴性乳腺癌中高度表达的miR-221/222有可能通过降低位于不同层面的Wnt信号通路抑制因子，并与Wnt信号通路形成正反馈环路，全方位促进Wnt信号通路的激活，从而促进三阴性乳腺癌的发生和发展。在本项目中，我们将利用各种分子生物学手段，从分子层面深入阐释miR-221/222调控Wnt信号通路激活的分子机制，从细胞层面和动物模型上揭示miR-221/222通过调控Wnt信号通路的激活从而促进三阴性乳腺癌发生发展的作用机制，为三阴性乳腺癌的治疗和诊断提供新的分子靶标和理论依据。

三阴性乳腺癌（TNBC）以雌激素受体、孕激素受体和人类表皮生长因子受体2的表达缺失为特征，由于治疗选择有限和缺乏有效的靶向治疗，导致其预后很差。研究表明，Wnt/β-catenin信号通路在三阴性乳腺癌中高度激活，与三阴性乳腺癌的生长、增殖、迁移密切相关。然而，TNBC中Wnt/β-catenin信号通路异常激活的分子机制仍不清楚。我们发现miR-221/222特异性地在三阴性乳腺癌中高度表达。通过体外和异种移植实验证明，抑制TNBC细胞系MDA-MB-231中miR-221/222的表达可抑制其增殖、上皮-间充质转化和迁移；而在非TNBC细胞系MCF7中过表达miR-221/222可促进MCF7细胞的增殖和迁移。此外，我们发现miR-221/222通过直接抑制Wnt/β-catenin信号通路的多种负性调节因子WIF1、SFRP2、DKK2和AXIN2从而激活该通路。值得注意的是，miR-221/222表达水平与患者生存率呈负相关，而WIF1、DKK2、SFRP2和AXIN2表达水平与患者生存率呈正相关。最后，我们的结果显示在他莫昔芬治疗组中抑制miR-221/222显著增加TNBC细胞的凋亡，而在环磷酰胺治疗组中抑制miR-221/222则没有此现象。通过该项目，我们从分子层面深入阐释了miR-221/222调控Wnt/β-catenin信号通路激活的分子机制，从细胞层面和动物模型上揭示了miR-221/222通过调控Wnt/β-catenin信号通路的激活从而促进三阴性乳腺癌发生发展的作用机制，为三阴性乳腺癌的治疗和诊断提供新的分子靶标和理论依据。