细胞粘附分子Kindlin-2缺失在乳腺癌发生发展中的作用及机制研究

Breast cancer is the most frequently diagnosed cancer and is the sixth leading cause of cancer-related death in Chinese women. Determining the molecular mechanisms governing cancer development and progression is important for developing effective anti-cancer therapies. Kindlin-2 is an important component of cell-matrix adhesion. Recently, more studies suggested that Kindlin-2 is involved in multiple diseases, such as vascular diseases, bone and renal disease. In cancer, despite the accumulating evidence for a critical role of Kindlin-2 in tumor development and progression, thus far most of the studies were in cultured cells and the underlying molecular mechanisms remain incompletely understood. In the proposed studies, we will employ a conditional knockout strategy combined with spontaneous mammary tumor mouse model to determine the function of Kindlin-2 in tumor growth and metastasis in vivo, and determine whether the Kindlin-2 functions in these processes through influencing both tumor cell behavior and tumor microenvironment. Furthermore, we will investigate the molecular mechanism of the Kindlin-2 signaling axis in cancer development and progression, and provide a strong scientific rationale for targeting the Kindlin-2 in anti-cancer therapy.

乳腺癌是世界女性最常见的恶性肿瘤。我国乳腺癌发病率和死亡人数呈逐年上升趋势。揭示乳腺癌形成和转移的分子机制，是根治肿瘤的希望所在。Kindlin-2是近年来发现的一类极其重要的黏着斑蛋白，具有许多生物学功能。研究显示Kindlin-2在多种肿瘤组织中表达异常并且参与肿瘤细胞的增殖、存活和迁移。然而，迄今为止，Kindlin-2在肿瘤生物学的作用多集中于体外研究且分子机制尚不清楚。为在体内明确Kindlin-2在肿瘤发生发展中的作用，本研究首次将MMTV-PyMT乳腺癌模型小鼠与乳腺上皮特异敲除Kindlin-2小鼠杂交，旨在整体水平上观察Kindlin-2对乳腺肿瘤形成和转移的作用，并阐明Kindlin-2是否通过调控肿瘤细胞本身及微环境这二个方面来影响肿瘤演进。此外，我们运用IP/MS、RNA-seq和蛋白组学等技术寻找Kindlin-2调控乳腺癌发生发展的关键信号网络并探讨其作用机制。

雄激素受体对于乳腺肿瘤的发生发展非常重要。在本项目中，我们发现Kindlin-2可以诱导雄激素受体AR的信号通路，从而促进乳腺肿瘤发生发展。分子机制方面，Kindlin-2作为分子桥梁，介导Src酶和AR的结合，进而形成Kindlin-2-Src-AR复合体，促进AR534位酪氨酸磷酸化，以及AR下游信号通路。细胞中敲减Kindlin-2显著抑制Src对AR的磷酸化修饰，从而阻断AR信号通路，抑制AR介导的细胞增殖和迁移。破坏Kindlin-2-Src-AR复合体的形成，不能恢复敲低Kindlin-2对AR信号通路损伤及肿瘤细胞生长转移的抑制。在体内实验，该项目进一步验证了Kindlin-2对乳腺肿瘤发生发展和肺转移的重要作用，以及Kindlin-2对AR磷酸化和下游信号通路的作用。总而言之，本项目阐明了Kindlin-2对乳腺肿瘤发生发展和转移的重要作用，并明确了其作用分子机制。本项目的完成为Kindlin-2作为乳腺肿瘤治疗新靶点提供重要科学依据，同时发现了乳腺肿瘤形成和转移的重要调控途径和机制。