IQGAP2对前列腺癌的抑制作用及其机制研究

Prostate cancer is the most common cancer affecting men and the second leading cause of cancer-related deaths in males in the developed world. Incidence of prostate cancer in china also shows a rapid growth recently. The improvement of clinical diagnosis and management is significant. It is useful that finding valuable tumor suppressor for prostate cancer to inhibit tumor metastasis. We have systemically examined IQGAP2 protein expression in normal prostatic glands, PINs, early stages of PC, and advanced stages of PC. Consistent with publications, we detected high and low levels of IQGAP2 protein in primary prostate cancers. Although IQGAP2 was expressed at levels that were either undetectable or low in non-tumorigenic prostate epithelial cells and prostatic glands, its expression was significantly increased in androgen-dependent PC cells and early states of prostate carcinomas. Further progression to advanced carcinomas or hormone-refractory PC was associated with significant reduction in IQGAP2 expression. Furthermore, ectopic expression of IQGAP2 inhibited DU145 prostate cancer cell invasion and serum-induced AKT activation, but increased E-Cadherin expression. It demonstrated that IQGAP2 is a candidate tumor suppressor for prostate cancer. The main goal of this project is to investigate the inhibitory effect and mechanism of IQGAP2 on prostate cancer in vivo and in vitro; to find out a crucial structure site in IQGAP2, which is different with IQGAP1, maybe it's valuable in clinic and in new anti-cancer drug discovery.

前列腺癌是男性生殖系最常见的恶性肿瘤，是欧美国家男性癌症死因的第二位，国内的前列腺癌发病率存在逐年增高趋势，改进前列腺癌的诊断和治疗具有重要意义。寻找前列腺癌的肿瘤抑制因子，抑制前列腺癌发生肿瘤转移，是前列腺癌治疗的重要措施。我们前期研究发现IQGAP2蛋白在恶性程度相对低的前列腺癌细胞中表达增高，恶性程度高的前列腺癌细胞中表达下降；IQGAP2具有抑制前列腺癌细胞增殖，减轻前列腺癌细胞侵袭力，下调E-Cadherin表达，减少前列腺癌细胞AKT活化的作用。提示，IQGAP2可能是前列腺癌的肿瘤抑制因子。我们将继续从整体动物和细胞分子水平，对E-Cadherin启动子抑制因子及PI3K/AKT信号通路进行研究，探讨IQGAP2对前列腺癌的抑制作用及其作用靶点；通过分子克隆技术，寻找IQGAP2区别于IQGAP1的抑癌结构位点，为IQGAP2在临床上的应用和其他抗肿瘤新药的开发提供理论基础。

前列腺癌是男性生殖系最常见的恶性肿瘤，是欧美国家男性癌症死因的第二位，国内的前列腺癌发病率存在逐年增高的趋势，改进前列腺癌的诊断和治疗具有重要意义。寻找前列腺癌的肿瘤抑制因子，抑制前列腺癌发生肿瘤转移，是前列腺癌治疗的重要措施。我们前期研究发现IQGAP2蛋白在恶性程度相对低的前列腺癌细胞中表达增高，恶性程度高的前列腺癌细胞中表达下降；IQGAP2具有抑制前列腺癌细胞的增殖，减轻前列腺癌细胞侵袭力，上调E-Cadherin表达，减少前列腺癌细胞AKT活化的作用。提示，IQGAP2可能是前列腺癌的肿瘤抑制因子。本研究体外实验证明IQGAP2可以通过抑制PIP3、PDK1的表达抑制AKT活化、上调E-Cadherin的表达；通过抑制E-Cadherin启动子抑制因子Snail1、ZEB1、SIP1、Twist1的蛋白表达提高E-Cadherin的转录及表达；通过分子克隆技术将IQGAP2区别于IQGAP1的ww结构域进行调换，nIQGAP2相对于nIQGAP1仍可以减轻前列腺癌细胞侵袭力，减少前列腺癌细胞AKT活化，上调E-Cadherin表达。在动物实验中也证明IQGAP2可以减少前列腺癌在肺脏的种植转移数目。本项目研究提示：IQGAP2通过抑制PI3K/AKT通路活化、抑制E-Cadherin启动子抑制因子的表达上调E-Cadherin的表达，减少前列腺癌细胞的侵袭力，从而达到抑制前列腺癌远处转移的作用；此外， IQGAP2作为前列腺癌抑制因子的作用，可能与其ww结构域无明显相关性。