Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion
Overexpression of IQGAP1 in advanced colorectal cancer correlates with poor prognosis-critical role in tumor invasion
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DOI：
10.1002/ijc.24987
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发表时间：
2010-06-01
影响因子：
6.4
通讯作者：
Iwasaki, Hiroshi
中科院分区：
文献类型：
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作者：
Hayashi, Hiroyuki;Nabeshima, Kazuki;Iwasaki, Hiroshi
IQGAP1是一种多功能蛋白，参与肌动蛋白细胞骨架的组装和E-钙粘附素介导的细胞黏附。我们以前报道过IQGAP1在人类结直肠癌中的过度表达，特别是在侵袭前沿(IF)，这种过度表达往往与晚期病例的淋巴转移相关。因此，本研究探讨了85例pt2-3结直肠癌组织中IQGAP1表达的临床病理意义，并分析了IQGAP1在肿瘤体外侵袭中的作用。定量逆转录-聚合酶链式反应显示IQGAP1在结直肠癌组织中的表达明显上调。免疫组织化学将IQGAP1表达分为弥漫型(20%)、IF相关型(35.3%)和局灶型(44.7%)。弥漫型与较高的远处转移率相关。IQGAP1过表达和弥漫型患者的生存期显著短于其他患者(p<；0.0001)，多因素分析显示弥漫型是预后不良的独立预测因素。体外侵袭实验表明，IQGAP1 siRNA能显著抑制肝细胞生长因子(HGF)刺激的细胞侵袭。HGF减少膜上α-连环素的定位，但不改变E-钙粘附素、β-连环素和IQGAP1在膜上的定位。即使在HGF存在的情况下，siRNA抑制IQGAP1的表达也不会改变α-连环蛋白的膜定位。我们的结果表明，IQGAP1在结肠癌细胞侵袭中起关键作用，因此IQGAP1的弥漫性和高表达预示着结直肠癌患者预后不良。
IQGAP1 is a multifunctional protein involved in actin cytoskeleton assembly and E-cadherin-mediated cell adhesion. We reported previously IQGAP1 overexpression in human colorectal carcinomas especially at the invasion front (IF) and that such overexpression tended to correlate with lymph node metastasis in advanced cases. Thus, in this study, we investigated the clinicopathological significance of IQGAP1 expression in 85 cases of pT2-3 colorectal carcinomas with special reference to its expression pattern and prognosis, followed by analysis of the role of IQGAP1 in cancer invasion in vitro. Quantitative reverse transcription-PCR showed significant upregulation of IQGAP1 in colorectal carcinomas compared with normal mucosa. Immunohistochemically, IQGAP1 expression pattern was classified into diffuse (20%), IF-associated (35.3%) and focal (44.7%). The diffuse pattern was associated with higher rates of distant metastasis. Patients with IQGAP1 overexpression and diffuse pattern had significantly shorter survival (p < 0.0001) than others, and the diffuse pattern was an independent predictor of poor survival by multivariate analysis. In vitro invasion assays using three human colon carcinoma cell lines showed that IQGAP1 siRNA significantly suppressed hepatocyte growth factor (HGF)-stimulated cell invasion. HGF reduced membranous localization of alpha-catenin, but did not alter localization of E-cadherin, beta-catenin and IQGAP1 in membranes. Suppression of IQGAP1 expression by siRNA did not alter membranous localization of alpha-catenin even in the presence of HGF. Our results indicate that IQGAP1 plays a critical role in colon cancer cell invasion, and therefore diffuse and high expression of IQGAP1 predicts poor prognosis in patients with colorectal carcinoma.