妊娠特异性糖蛋白9 (PSG9) 促进乳腺癌发生发展的功能及机制研究

Breast cancer is the most commonly diagnosed type of cancer and is a leading cause of cancer-related mortality in women worldwide, but its underlying molecular mechanism remains poorly understood. Pregnancy-specific glycoprotein 9 (PSG9) is an unique glycoprotein in maternal serum during pregnancy and plays a key role in the physiological pregnancy of mammals. However, the functional role and its underlying molecular mechanism for PSG9 in breast cancer development and progression have not yet been explored to date. Our preliminary experimental results show that the expression levels of PSG9 are negatively associated with the prognosis of patients with breast cancer and PSG9 promotes the growth, migration and invasion potential of breast cancer cells, but the underlying molecular mechanism remains unknown. Bioinformatic analysis showed that the promoter region of the PSG9 gene contains multiple transcription factor Smad-binding elements and the PSG9 protein contains one arginine-glycine-aspartate (RGD) tripeptide sequence which can bind to integrin, suggesting that PSG9 may be a downstream target gene of the Smad signaling pathway and may act a mediator of the integrin-mediated signaling. In this study, we are aimed to use a variety of experimental models and techniques to systematically examine the biological functions of PSG9 in breast cancer development and progression, reveal the upstream regulatory mechanism of PSG9 expression in breast cancer, and elucidate the downstream signaling pathways for PSG9 responsible for its oncogenic functions in breast cancer. The expected results of this study will provide an important clue to reveal the function and molecular mechanism of PSG9 protein in breast cancer development and progression.

乳腺癌是威胁女性健康最常见恶性肿瘤之一，其发生发展的分子机制目前尚不清楚。妊娠特异性糖蛋白9 (PSG9) 是妊娠期母体血清中一种特有的糖蛋白并在生理妊娠中发挥关键作用，但其在乳腺癌发生发展中的作用及分子机制尚未见报道。前期预实验结果证实，PSG9促进乳腺癌细胞生长、迁移及侵袭, 并且其表达水平与临床乳腺癌病人不良预后有关。生物信息学分析显示PSG9基因启动子区含有转录因子Smad结合元件以及PSG9蛋白含有能与细胞粘附分子整合素结合的精氨酸-甘氨酸-天冬氨酸 (RGD) 三肽序列，提示PSG9可能是Smad通路下游靶基因以及介导整合素信号。本研究拟采用多种实验模型和技术，系统深入研究PSG9在乳腺癌发生发展中的功能、揭示PSG9基因上游调控机制以及阐明PSG9促进乳腺癌发生发展的下游信号通路。本课题的预期研究成果将为揭示PSG9在乳腺癌发生发展中的功能及其分子机制提供重要线索。

妊娠特异性糖蛋白9（PSG9）是一种胎盘糖蛋白，在维持哺乳动物正常妊娠过程中起着重要作用。在此，我们发现PSG9是转化生长因子β（TGFβ）/Smad途径的关键组成部分，并驱动乳腺癌的进展。PSG9在乳腺癌组织中表达上调，其表达水平与乳腺癌患者预后不良相关。功能缺失和获得研究表明，PSG9在体外促进细胞增殖、克隆形成、迁移和侵袭潜能，在体内促进肿瘤生长和肺转移。. 机制研究表明，TGFβ1通过向PSG9启动子中假定的Smad结合元件（SBE）募集Smad3/Smad4，在转录水平上激活PSG9。PSG9对TGFβ1诱导的上皮-间充质转化（EMT）、乳腺癌细胞迁移和侵袭的有显著影响。同时，PSG9在TGFβ-Smad途径中起重要作用。PSG9基因敲除降低了转移相关TGF-β靶基因的表达，如Snail家族转录抑制因子1（Snail1）、Snail家族转录抑制因子2（Slug）和锌指电子盒结合同源盒1（ZEB1）。. 总之，这些结果表明PSG9在TGFβ对乳腺癌发生和转移的协同作用中起着重要的作用，提示PSG9可能是乳腺癌治疗的潜在靶点。