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. 2020 Aug 20:13:8299-8311.
doi: 10.2147/OTT.S257729. eCollection 2020.

Integrative Analysis of the IQ Motif-Containing GTPase-Activating Protein Family Indicates That the IQGAP3-PIK3C2B Axis Promotes Invasion in Colon Cancer

Zhuo Liu  1 , Xiao Li  2   3 , Jie Ma  4 , Dechuan Li  1 , Haixing Ju  1 , Yong Liu  1 , Yinbo Chen  1 , Xujun He  4 , Yuping Zhu  1
Affiliations

Integrative Analysis of the IQ Motif-Containing GTPase-Activating Protein Family Indicates That the IQGAP3-PIK3C2B Axis Promotes Invasion in Colon Cancer

Zhuo Liu et al. Onco Targets Ther. .

Abstract

Background: Colon cancer (CRC) is a common type of tumour, and IQGAP family proteins play an important role in many tumours. However, their roles in CRC remain unclear.

Methods: First, we searched many public databases to comprehensively analyze expression of IQGAPs in CRC. Next, real-time PCR, immunohistochemical (IHC), transwell, siRNA transfection and Western blot assays were used to evaluate relationships among IQGAP3 expression, clinical pathological parameters and CRC prognosis, and the underlying molecular mechanism was investigated.

Results: IQGAP3 was elevated in CRC tissues, whereas there was no significant change in expression of IQGAP1 or IQGAP2. Additionally, IQGAP3 expression in CRC tissues was associated with tumour progression, invasion and poor prognosis. In mechanistic studies, we found that IQGAP3 was positively coexpressed with PIK3C2B. In an in vitro assay, the PIK3C2B expression level was increased after exogenous overexpression of IQGAP3, resulting in the promotion of cell invasion, which was blocked by pretransfecting cells with PIK3C2B siRNA. Furthermore, we found that high expression of IQGAP3 and PIK3C2B correlated with tumour stage and vessel invasion in human CRC, whereby patients with high expression of both in tumours had a worse prognosis compared with patients with single-positive or double-negative tumours.

Conclusion: The results of our current study and corresponding previous studies provide evidence that IQGAP3 is elevated in CRC and promotes colon cancer growth and metastasis by regulating PIK3C2B activation.

Keywords: IQGAPs; PIK3C2B; colon cancer; invasion; prognosis.

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Conflict of interest statement

There is no conflict of interest in relation to this article for any of the authors.

Figures

Figure 1
Figure 1
Transcriptional levels of IQGAPs in different types of cancer public databases. (A) Transcriptional levels of IQGAPs in CRC in the ONCOMINE public database. (B and C) Transcriptional levels of IQGAPs in CRC in the GEPIA public database. Expression levels of IQGAP3 were higher in CRC tissues than in normal tissues; those of IQGAP1 and IQGAP2 showed no difference. Abbreviation: COAD, colon adenocarcinoma.
Figure 2
Figure 2
IQGAP gene expression and frequently altered neighbouring gene analysis in CRC (cBioPortal). (A) Real-time PCR analysis of IQGAP gene expression in 40 paired CRC tissues. P<0.05 was significant. (B) Correlations of IQGAPs with each other by analysing their mRNA expression (RNA Seq V2 RSEM) via the cBioPortal online tool for CRC (TCGA, Provisional). (C) The Venn diagram results show that PIK3C2B is positively associated with IQGAP alterations in CRC. Abbreviation: t, t value.
Figure 3
Figure 3
IQGAP3 promotes CRC invasiveness associated with PIK3C2B in vitro. (A) WB results of IQGAP3 and PIK3C2B. (B) Results of the invasion assay. CRC cell invasion abilities were significantly increased after exogenous overexpression of IQGAP3, and this invasion-promoting effect was blocked by pretransfecting the cells with PIK3C2B siRNA.
Figure 4
Figure 4
IHC staining of IQGAP3 and PIK3C2B in CRC tissue and Kaplan–Meier survival curves. (A) Typical TMA array images of IQGAP3 and PIK3C2B in CRC tissue and normal tissue. Original magnification, ×100 and ×400. (B–D) Kaplan–Meier survival curves of IQGAP3 and PIK3C2B expression in CRC.
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Grants and funding

The TMA production was funded by the Medicine and Health Research Foundation of Zhejiang (2018256123). All reagents for the in vitro experiments were supported by the China National Natural Science Foundation (81502090). The fees for technical staff and articles regarding English editing were funded by the Natural Science Foundation of Zhejiang Provincial (Y18H160037).