Abstract
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-mesenchymal 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, β-catenin transcriptional activity, β-catenin nuclear translocation and expression of the direct target genes of β-catenin (cyclin D1 and c-myc). In contrast, knockdown of IQGAP1 decreased the level of DVL2 and attenuated Wnt/β-catenin signaling. In vivo results revealed that IQGAP1 promoted tumor growth and metastasis. Co-immunoprecipitation studies demonstrated that IQGAP1 interacted with both DVL2 and β-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.
Highlights
Pancreatic cancer (PC) remains one of the most lethal malignancies with a 5-year survival rate of less than 5%1
As one of the evolutionally conserved scaffold protein family members, IQ motif-containing GTPase-activating protein 1 (IQGAP1) includes five domains, namely, the calponin homology domain interacting with F-actin, GAP-related domain interacting with small GTPases (Rac[1] and Cdc42), poly-proline protein-protein domain interacting with ERK, IQ domain interacting with four IQ motifs and RasGAP C-terminus[7]
We found that the percentage of high expression of IQGAP1 in pancreatic ductal adenocarcinoma (PDAC) tissues was significantly higher than that in adjacent normal tissues, in line with previous results that IQGAP1 is elevated in PC17
Summary
Pancreatic cancer (PC) remains one of the most lethal malignancies with a 5-year survival rate of less than 5%1. Several cellular functions are regulated by the multidomain structures of IQGAP1 through its binding with many other partners, which is mainly mediated by the RGCT or IQ regions[8,9]. IQGAP1 functions as a scaffold in the MEK/ERK cascade by binding to MEK1/2, ERK1/2 and B-Raf via its IQ region[10]. The function and underlying mechanism of IQGAP1 in PDAC have not been fully evaluated. The present study aimed to investigate the prognostic values and biological functions of IQGAP1 and the associated molecular mechanisms in PDAC. We first evaluated the expression level of IQGAP1 in PDAC tissues using immunohistochemistry (IHC) and investigated the association of IQGAP1 expression level with clinicopathological features and patient survival. We explored the effect of IQGAP1 on the Wnt/β-catenin signaling pathway in PDAC cells
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