IQGAP1 plays an important role in the invasiveness of thyroid cancer.
IQGAP1 plays an important role in the invasiveness of thyroid cancer.
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DOI：
10.1158/1078-0432.ccr-10-1627
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发表时间：
2010-12-15
期刊：
影响因子：
--
通讯作者：
Xing M
中科院分区：
文献类型：
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作者：
Liu Z;Liu D;Bojdani E;El-Naggar AK;Vasko V;Xing M
本研究旨在探讨IQGAP1在甲状腺癌侵袭性中的作用，以及其作为甲状腺癌新的预后标志物和治疗靶点的潜力。我们研究了IQGAP1拷贝获得及其与甲状腺癌临床病理结果的关系，并研究了其在细胞侵袭中的作用和参与该过程的分子。我们发现IQGAP1拷贝数增加≥3的分别为良性甲状腺肿瘤的1/30（3%）、24/74（32%）、44/107（41%）、8/16（50%）、27/41（66%）、滤泡变异型甲状腺乳头状癌（FVPTC）、滤泡性甲状腺癌（FTC）、高细胞型甲状腺癌和间变性甲状腺癌。拷贝数≥4的肿瘤也有类似的分布趋势。IQGAP1拷贝增益与IQGAP1蛋白表达呈正相关。它与FVPTC和FTC的甲状腺外和血管侵犯显著相关，并且BRAF突变阳性PTC的多灶性和复发率为50-60% （P分别= 0.01和0.02）。siRNA敲低IQGAP1可显著抑制甲状腺癌细胞的侵袭和集落形成。共免疫沉淀实验表明，IQGAP1与E-cadherin（一种已知的入侵抑制分子）直接相互作用，当IQGAP1被敲低时，E-cadherin被上调。这为IQGAP1在甲状腺癌中的侵袭作用提供了机制。相比之下，IQGAP3缺乏所有这些功能。IQGAP1通过基因拷贝获得，在甲状腺癌的侵袭性中发挥重要作用，可能是甲状腺癌新的预后标志物和治疗靶点。
This study was designed to explore the role of IQGAP1 in the invasiveness of thyroid cancer and its potential as a novel prognostic marker and therapeutic target in this cancer. We examined IQGAP1 copy gain and its relationship with clinicopathological outcomes of thyroid cancer and investigated its role in cell invasion and molecules involved in the process. We found IQGAP1 copy number gain ≥ 3 in 1/30 (3%), 24/74 (32%), 44/107 (41%), 8/16 (50%), and 27/41 (66%) of benign thyroid tumor, follicular variant papillary thyroid cancer (FVPTC), follicular thyroid cancer (FTC), tall cell PTC, and anaplastic thyroid cancer, respectively, in the increasing order of invasiveness of these tumors. A similar tumor distribution trend of copy number ≥ 4 was also seen. IQGAP1 copy gain was positively correlated with IQGAP1 protein expression. It was significantly associated with extrathyroidal and vascular invasion of FVPTC and FTC and, remarkably, a 50–60% rate of multifocality and recurrence of BRAF mutation-positive PTC (P = 0.01 and 0.02, respectively). siRNA knockdown of IQGAP1 dramatically inhibited thyroid cancer cell invasion and colony formation. Co-immunoprecipitation assay demonstrated direct interaction of IQGAP1 with E-cadherin, a known invasion-suppressing molecule, which was up-regulated when IQGAP1 was knocked down. This provided a mechanism for the invasive role of IQGAP1 in thyroid cancer. In contrast, IQGAP3 lacked all these functions. IQGAP1, through genetic copy gain, plays an important role in the invasiveness of thyroid cancer and may represent a novel prognostic marker and therapeutic target for this cancer.