miR-1204下调ER-α表达促进乳腺癌细胞EMT和侵袭转移的作用及机制研究

Distant metastasis is one of the leading causes of death in breast cancer，however, its mechanism is far from illuminated. Our previous studies found that miR-1204 is frequently amplified in breast cancer. Our preliminary in vitro data further showed that miR-1204 promoted the epithelial mesenchymal transformation (EMT), migration and invasion of breast cancer cells and inhibit the expression of ER-α, which was reported to inhibit EMT of breast cancer cells. Therefore, this proposal is proposed to further explore the mechanistic roles of miR-1204 in inhibition of ER-α expression and promotion of breast cancer cell EMT, invasion and metastasis: 1) validate the functional roles of miR-1204 on breast cancer cells by establishing stable cell lines with up- and down-expression of miR-1204 and in mouse models; 2) explore the mechanistic regulation of miR-1204 on ER-α expression and verify if ER-α mediates the function of miR-1204 on breast cancer cells; 3) check the expression of miR-1204 and ER-α in collected breast cancer tissues and analyze the correlations among miR-1204, ER-α and clinical characteristics in breast cancer. This study will shed lights on the mechanisms of invasion and metastasis of breast cancer, and may lay a foundation to find new therapeutic targets.

远处转移是乳腺癌死亡主要病因之一，其机制远未阐明。我们前期研究发现miR-1204在乳腺癌中频繁扩增，并促进体外培养乳腺癌细胞的上皮间质转化（EMT）和迁移侵袭，而且抑制ER-α的表达，而ER-α具有抑制乳腺癌细胞EMT的功能。本课题拟在前期研究的基础上，从分子、细胞、小鼠、临床乳腺癌病例分析检测等层面综合探讨miR-1204通过下调ER-α促进乳腺癌细胞EMT及侵袭转移的作用、机制及临床意义：①确认miR-1204对乳腺癌细胞EMT、侵袭、转移的作用；②分析miR-1204下调ER-α的作用和机制，并确认ER-α介导miR-1204对乳腺癌细胞的作用；③在人乳腺癌组织检测并分析miR-1204、ER-α表达、乳腺癌分级分期之间的相关性，进一步明确miR-1204的临床意义。本研究的顺利实施将可能揭示乳腺癌侵袭转移的新机制，为寻找新的治疗靶点奠定基础。

Plasmacytoma variant translocation 1 (PVT1)是在乳腺癌中发挥重要作用的一种lncRNA。近年来，越来越多的研究发现位于PVT1区域的microRNA在PVT1致癌过程中发挥重要作用。然而miR-1204在乳腺癌中的致癌作用及潜在的机制仍不明确。在本研究中，我们发现过表达的miR-1204与乳腺癌预后有关。而且，miR-1204能够促进乳腺癌细胞增殖、EMT和侵袭迁移。机制研究证实VDR是miR-1204的直接靶基因。此外，干扰VDR的表达能够逆转miR-1204对乳腺癌增殖、肿瘤形成和转移的影响。总之，我们的研究结果证明miR-1204-VDR信号途径在乳腺癌中具有致癌作用，并为乳腺癌的防治提供新的依据。