IQGAP2对胃癌细胞侵袭的靶向调控作用及分子机制研究

Tumor invasion and metastasis are the main causes of treatment failure in cancer. IQ motif-containing GTPase activating protein 1(IQGAP1) plays a pivotal role in tumor invasion. IQGAP2, the subfamily of IQGAPs, has been poorly studied. We discovered IQGAP2 can decrease the invasion capability of gastric cancer cells. However, the molecular mechanism is unclear. In this project, key gene target will be discovered using genechip technique to measure the gene changes of increaesment and decreasement of IQGAP2. Target gene was measured by molecular technique and tumor model was transplanted subcutaneously in Nude mice with cancer cell lines to confirm cell adhesion, migration and invasion. This study can clarify the molecular mechanism of targeted regulation of IQGAP2 to gastric cancer cell invasion, discuss the relationship between targeted gene and differentiation, invasion and metastasis of gastric cancer. The result can provide experimental evidence for individualized treatment in patients with gastric cancer, target gene treatment of anti-invasion and anti-metastasis. It also can supply effective markers of prognosis.

肿瘤的侵袭和转移是肿瘤患者治疗失败的最主要的原因。含IQ模体的GTP酶活化蛋白1（IQ motif-contaning GTPase activating protein1;IQGAP1）对肿瘤侵袭起关键作用。IQGAPs家族的另一个成员IQGAP2的研究甚少。我们在国际上首次发现，IQGAP2降低胃癌细胞的侵袭能力，其分子机制尚不明确。本研究为了针对性地深入研究IQGAP2的作用机制，采用基因芯片技术，检测IQGAP2增强或抑制表达前后的相关基因变化，发现关键靶点，用多种分子生物学方法观察、检测其靶基因，观察细胞粘附、迁移和侵袭改变，在胃癌细胞株裸鼠皮下移植瘤模型和原发性胃癌组织上加以证实，阐明IQGAP2对胃癌细胞侵袭的靶向调控作用及分子机制，探讨IQGAP2靶基因与胃癌分化、侵袭和转移的关系，为胃癌患者的个体化治疗及抗侵袭、抗转移的靶向治疗提供实验依据，为判断预后提供有效标志物。

肿瘤的侵袭和转移是肿瘤患者治疗失败的最主要的原因。含IQ模体的GTP酶活化蛋白1（IQ motif-contaning GTPase activating protein1;IQGAP1）对肿瘤侵袭起关键作用。IQGAPs家族的另一个成员 IQGAP2的研究甚少。细胞的粘附消失是肿瘤侵袭、转移的先决条件。E-cadherin是重要的细胞粘附分子，ERK信号通路是调节肿瘤细胞的迁移和侵袭的重要通路。IQGAP2与IQGAP1比较，RasGAP C末端（E-cadherin结合位点）和WW区（ERK1/2 结合位点）分别有70%和30%的同源，两者在结构、功能上即有相似之处，又有明显不同。我们在国际上首次发现，IQGAP2降低胃癌细胞的侵袭能力，其分子机制尚不明确。本研究为了针对性地深入研究IQGAP2对胃癌细胞侵袭的靶向调控作用及分子机制，采用siRNA技术，抑制IQGAP2表达，用多种分子生物学方法观察、检测IQGAP2抑制表达前后的相关基因变化。 结果，我们发现，在胃癌细胞株NUGC-4中，用免疫荧光染色法观察IQGAP2与E-cadherin均分布在细胞膜；转染IQGAP2 siRNA , 抑制IQGAP2表达，ERK1表达明显减少，E-cadherin表达无变化，提示IQGAP2参与E-cadherin介导的细胞黏粘附，通过ERK信号途径，调节胃癌细胞侵袭。另外，我们还发现，在结肠癌细胞株RKO中，IQGAP2甲基化引起基因沉默，增强IQGAP2表达，结肠癌细胞侵袭能力下降。为胃癌、结肠癌患者的抗侵袭、抗转移的靶向治疗提供实验依据，为判断预后有重要的临床意义。