细胞-细胞外基质信号转导枢纽IPP复合物在肿瘤发生发展中的作用及其作为抗肿瘤靶体的研究

Cancer is a major public health problem in China and the world. Determining the molecular mechanisms govenining cancer development and progression is important for developing effective anti-cancer therapies. Cell-extreacellular matrix (ECM) interactions are critically involved in cancer development and progression. Previous studies by the applicant’s laboratory have identified a focal adhesion complex consisting of integrin-linked kinase (ILK), PINCH and parvin (the IPP complex) that plays important roles in controlling integrin-mediated cell-ECM adhesion and signaling. Recent studies suggest that increased level of the IPP complex may be intimately involved in driving tumor development and progression. Thus, down-regulation of the IPP complex may represent an effective strategy for inhibition of tumor development and progression. Despite the accumulating evidence for a critical role of the IPP complex in tumor development and progression, thus far most of the studies were in cultured cells or on individual component of the IPP complex, and the underlying molecular mechanisms remain incompletely understood. In the proposed studies, we will employ a combination of molecular and genetic approaches to define the roles of the IPP complex in tumor growth and metastasis in vivo, and determine whether the IPP complex functions in these processes through influencing both tumor cell behavior and tumor microenvironment. Furthermore, we will investigate the molecular mechanism by which the IPP complex regulates tumor development and progression. Finally, we will test the efficacy of a novel small compound inhibitor of the IPP complex (IPP-I), which was recently developed through a collaborative effort by us and Professor Jun Qin, in suppression of tumor growth and metastasis in vivo and determine the molecular and cellular mechanisms whereby it functions. These studies will significantly improve our fundamental understanding of the functions and mechanism of the IPP signaling axis in cancer development and progression, and provide a strong scientific rationale for targeting the IPP complex in anti-cancer therapy.

细胞与细胞外基质相互作用在癌症发生发展中起关键作用。申请人前期发现的ILK-PINCH-parvin（IPP）复合物是细胞与细胞外基质相互作用和信号传导的重要控制因素。近年来研究提示IPP复合物可能在癌症发生和转移中发挥重要作用。因此，抑制IPP复合物有望成为治疗癌症的有效手段。然而，迄今IPP复合物的研究多基于体外实验且其分子机制尚不明确, 同时IPP复合物作为抗肿瘤靶体亟待深入研究。本项目旨在明确IPP复合物在体内肿瘤形成和转移中的作用，阐明IPP复合物是否通过调控肿瘤细胞本身及其微环境这二个方面来影响肿瘤发生发展并研究其分子和细胞调控机制。另外，我们最近成功研发出一个IPP复合物小分子抑制剂（IPP-I），我们将运用动物模型来研究IPP-I是否在体内抑制肿瘤发生发展并在细胞和分子水平上研究IPP-I对关键信号通路和过程的影响，从而为确立IPP复合物作为癌症治疗新靶点提供重要科学依据。

项目背景： 我们前期研究发现的ILK-PINCH-parvin（IPP）复合物是细胞与细胞外基质相互作用和信号传导的重要控制因素。近年来研究提示IPP复合物可能在癌症发生和转移中发挥重要作用。因此，抑制IPP复合物有望成为治疗癌症的有效手段。然而，迄今IPP复合物的研究多基于体外实验且其分子机制尚不明确, 同时IPP复合物作为抗肿瘤靶体亟待深入研究。.主要研究内容：（1）明确了IPP 复合物（PINCH1和ILK结合蛋白Kindlin-2）在肿瘤发生发展中起着极其重要的作用；（2）阐明了IPP复合物通过影响肿瘤微环境中的血管细胞生成来调节肿瘤发生发展；（3）发现了IPP 复合物调控肿瘤演进的一些关键信号通路并阐明了其作用分子机制。.重要结果：（1）以肺癌移植和转基因肺癌小鼠为动物模型，从体外和体内实验两方面阐明 IPP复合物这一功能单元在肿瘤发生发展中的作用；（2）研究 IPP复合物是否影响细胞外微环境和肿瘤细胞本身特性这二方面来调节肿瘤发生发展；（3）进一步解析 IPP 复合物对于控制肿瘤演进的关键信号通路和细胞过程的影响及其作用的分子机制；.关键数据：（1）明确了IPP 复合物（PINCH1和ILK结合蛋白Kindlin-2）在肿瘤发生发展中起着极其重要的作用；（2）在肺癌细胞系 A549中敲低PINCH1或Kindlin-2显著抑制了肺癌细胞的生长、迁移和黏附，敲低PINCH1可以抑制血管形成；（3）PINCH-1在肺腺癌中高度表达，通过调节线粒体动力学促进脯氨酸合成；kindlin-2定位于线粒体并与吡咯啉-5-羧酸还原酶1 (PYCR1)相互作用，PYCR1是脯氨酸合成的关键酶；PINCH1与Ras抑制因子-1（RSU-1）相互作用；RNA 聚合酶 I 介导的 rRNA 合成是细胞生长的关键决定性因素；Kindlin-2可以形成双聚体，从而促进整合素的聚集，调节整合素的活性；.科学意义：为确立IPP复合物作为癌症创新治疗的策略和新靶点提供重要科学依据。