miR-153在三阴性乳腺癌中的功能和机制研究

Breast cancer is a common malignant tumor, which causes serious damage to the women's physical and mental health. The abnormal expression of microRNAs is closely related to the development of breast cancer. It has been confirmed that miR-153 could significantly inhibit the growth of triple negative breast cancer cells, promote apoptosis, and have the inhibitory effect on cancer stem cells. Our previous studies found that miR-153 was induced by ER stress, and it could obviously inhibit the tube formation of HUVEC cells. Therefore, miR-153 may play an important role in the development of breast cancer. Based on our previous findings, we will further investigate the function and clinical value of miR-153 in breast cancer, especially in TNBC. Firstly, we will detect the role of miR-153 in the tumor angiogenesis which is derived from TNBC cells lines and patients by using animal model; secondly, we will investigate the regulatory mechanisms of the up- and down-stream of miR-153 in TNBC. Finally, we will check the expression change of miR-153 in clinical breast tumor and serum samples to analyze whether miR-153 can serve as a diagnosis and prognosis biomarker and therapy target for breast cancer, especially for TNBC. We will further develop small molecules to kill TNBC by inducing miR-153. Our study will elucidate the potential of developing miR-153 as a new target of breast cancer diagnosis and therapies.

乳腺癌是一种常见的危害女性身心健康的恶性肿瘤，miRNA的异常表达与乳腺癌发生发展息息相关。研究证实miR-153能抑制TNBC细胞生长，促进凋亡，并对肿瘤干细胞有抑制作用。我们前期工作发现miR-153能被ER stress诱导，并显著抑制HUVEC细胞的管腔形成。因此miR-153可能参与乳腺癌血管生成的调控，并对乳腺癌发生发展起重要作用。本项目计划进一步研究 miR-153 在乳腺癌，尤其在TNBC中作用机制和临床应用价值：首先，我们将在动物体内验证miR-153对TNBC细胞株和临床来源乳腺癌移植瘤血管生成的作用；然后，我们将研究miR-153在乳腺癌的作用和受调控机制；最后，我们将在临床样本中检测 miR-153 表达，分析其在乳腺癌诊治中的应用价值，研发有效诱导 miR-153 的小分子药物。我们的研究将明确 miR-153 能否成为乳腺癌诊疗标志物，为后临床应用打下坚实基础。

乳腺癌是女性最常见的恶性肿瘤也是癌症相关死亡最常见的原因。miRNA的异常表达与乳腺癌发生发展息息相关。有研究证实miR-153能抑制TNBC细胞生长，促进凋亡，并对肿瘤干细胞有抑制作用。本项目研究了 miR-153 对乳腺癌血管生成的调控，尤其在TNBC中作用机制和临床应用价值。内皮细胞的萌发是肿瘤血管生成的第一步，有充分的证据表明，低氧激活低氧诱导因子1-α(HIF1α)/血管内皮生长因子A (VEGFA)轴促进乳腺癌血管生成。在本研究中，我们证明了miR-153通过与HIF1A mRNA的3'UTR结合，直接抑制HIF1α的表达，并通过减少VEGFA的分泌，抑制人脐原代血管内皮细胞(HUVECs)的管形成和乳腺癌血管生成。重要的是，低氧刺激内质网应激激活IRE1α及其下游转录因子X-box结合蛋白1 (XBP1)，诱导miR-153的表达。X-box结合蛋白1直接与miR-153宿主基因PTPRN的启动子结合并激活转录。我们还证明了miR-153也可以通过直接靶向乳腺癌细胞中的血管生成素1 (ANG1)来抑制内皮细胞的迁移和管腔的形成。miR-153与ANG1水平在乳腺癌中呈负相关。miR-153通过结合ANG1 mRNA阻断乳腺癌细胞中ANG1的表达和分泌。乳腺癌细胞MCF7的条件培养基经miR-153处理后对HUVECs的增殖无影响，但显著抑制HUVECs的迁移和管的形成，过表达ANG1可挽救HUVECs的迁移和管的形成。此外，miR-153还通过下调ANG1直接抑制MCF7的增殖和迁移。这些结果表明，缺氧诱导miR-153调节HIF1α/VEGFA轴，并且miR-153也可通过沉默ANG1抑制肿瘤细胞的活性以及内皮细胞的迁移和管状形成。体内体外实验以及临床样本的检测均证实了miR-153在乳腺癌中的作用。说明miR-153在乳腺癌诊治中有潜在的应用价值，可用于乳腺癌抗血管生成治疗。