IQGAP1 promotes pancreatic cancer progression and epithelial-mesenchymal transition (EMT) through Wnt/β-catenin signaling
IQGAP1 promotes pancreatic cancer progression and epithelial-mesenchymal transition (EMT) through Wnt/β-catenin signaling
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IQGAP1 通过 Wnt/β-catenin 信号传导促进胰腺癌进展和上皮间质转化 (EMT)
DOI：
10.1038/s41598-019-44048-y
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发表时间：
2019-05-17
影响因子：
4.6
通讯作者：
Jiang, Chunping
中科院分区：
文献类型：
--
作者：
Hu, Wei;Wang, Zhongxia;Jiang, Chunping
含有IQ基序的GTP酶激活蛋白1（IQGAP 1）是一种支架蛋白，其参与多种细胞功能，包括细胞骨架调节、细胞粘附、基因转录和细胞极化。IQGAP 1与几种人类癌症的肿瘤发生和进展有关。然而，IQGAP 1在胰腺导管腺癌（PDAC）中的作用仍然未知。我们发现IQGAP 1表达是PDAC的独立预后因素。IQGAP 1上调显著促进细胞增殖、迁移、侵袭和上皮-间充质转化（EMT），而IQGAP 1下调损害其致癌功能。IQGAP 1的过表达增加了Dishevelled 2（DVL 2）的蛋白水平，并增强了经典Wnt信号传导，如通过增加的DVL 2水平、β-连环蛋白转录活性、β-连环蛋白核转位和β-连环蛋白的直接靶基因（细胞周期蛋白D1和c-myc）的表达所证明的。相反，IQGAP 1的敲低降低了DVL 2的水平并减弱了Wnt/β-连环蛋白信号传导。体内结果显示，IQGAP 1促进肿瘤生长和转移。免疫共沉淀研究表明，IQGAP 1与DVL 2和β-连环蛋白相互作用。此外，DVL 2的敲低逆转了IQGAP 1诱导的EMT。因此，我们的研究结果证实，IQGAP 1可以用作PDAC治疗的潜在靶点。
IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a scaffold protein that participates in several cellular functions, including cytoskeletal regulation, cell adhesion, gene transcription and cell polarization. IQGAP1 has been implicated in the tumorigenesis and progression of several human cancers. However, the role of IQGAP1 in pancreatic ductal adenocarcinoma (PDAC) is still unknown. We found that IQGAP1 expression was an independent prognostic factor for PDAC. IQGAP1 upregulation significantly promoted cell proliferation, migration, invasion and epithelial-mesenchyma I transition (EMT), whereas IQGAP1 downregulation impaired its oncogenic functions. Overexpression of IQGAP1 increased the protein level of Dishevelled2 (DVL2) and enhanced canonical Wnt signaling as evidenced by increased DVL2 level, beta-catenin transcriptional activity, beta-catenin nuclear translocation and expression of the direct target genes of beta-catenin (cyclin D1 and c-myc). In contrast, knockdown of IQGAP1 decreased the level of DVL2 and attenuated Wnt/beta-catenin signaling. In vivo results revealed that IQGAP1 promoted tumor growth and metastasis. Co-immunoprecipitation studies demonstrated that IQGAP1 interacted with both DVL2 and beta-catenin. Moreover, knockdown of DVL2 reversed IQGAP1-induced EMT. Our findings thus confirmed that IQGAP1 could be used as a potential target for PDAC treatment.