Breast cancer is a heterogeneous disease that remains the most common malignancy among women worldwide. During genomic analysis of breast tumours, mRNA levels of IQGAP3 were found to be upregulated in triple negative tumours. IQGAP3 was subsequently found to be expressed across a panel of triple negative breast cancer (TNBC) cell lines. Depleting expression levels of IQGAP3 delivered elongated cells, disrupted cell migration, and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. The morphological changes induced by IQGAP3 depletion were found to be dependent on RhoA. Indeed, reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. Interestingly, IQGAP3 was also found to interact with p-21 activated kinase 6 (PAK6); a protein already associated with the regulation of cell morphology. Moreover, PAK6 depletion phenocopied IQGAP3 depletion in these cells. Whereas PAK6 overexpression rescued the IQGAP3 depletion phenotype. Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients.

IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) is member of the IQGAP family of scaffold proteins, which are essential for assembling multiprotein complexes that coordinate various intracellular signaling pathways. Previous research has shown that IQGAP3 is overexpressed in psoriatic skin lesions. Given its involvement in processes like cell proliferation and chemokine signaling, we sought to explore its molecular role in driving the psoriatic phenotype of keratinocytes. By conducting transcriptome profiling of HaCaT keratinocytes, we identified numerous psoriasis-associated pathways that were affected when IQGAP3 was knocked down. These included alterations in NFkB signaling, EGFR signaling, activation of p38/MAPK and ERK1/ERK2, lipid metabolism, cytokine production, and the response to inflammatory cytokine stimulation. Real-time analysis further revealed changes in cell growth dynamics, including proliferation and wound healing. The balance between cell proliferation and apoptosis was altered, as were skin barrier functions and the production of IL-6 and IFNγ. Despite these significant findings, the diversity of the alterations observed in the knockdown cells led us to conclude that IQGAP3 may not be the best target for the therapeutic inhibition to normalize the phenotype of keratinocytes in psoriasis.

Background: IQGAP3 plays a crucial role in regulating cell proliferation, division, and cytoskeletal organization. Abnormal expression of IQGAP3 has been linked to various tumors, but its function in glioma is not well understood. Methods: Various methods, including genetic differential analysis, single-cell analysis, ROC curve analysis, Cox regression, Kaplan-Meier analysis, and enrichment analysis, were employed to analyze the expression patterns, diagnostic potential, prognostic implications, and biological processes involving IQGAP3 in normal and tumor tissues. The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence. Additionally, the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3. Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms. Results: High IQGAP3 expression in gliomas is associated with an unfavorable prognosis, particularly in wild-type IDH and 1p/19q non-codeleted gliomas. Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle, PI3K/AKT signaling, p53 signaling, and PLK1-related pathways. Furthermore, IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma. BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy. In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells, with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression. Conclusion: IQGAP3 shows promise as a valuable biomarker for diagnosis, prognosis, and immunotherapeutic strategies in gliomas.

BACKGROUND: The primary reason for tumor-related deaths worldwide is lung adenocarcinoma (LUAD). The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is crucial for contributing to tumor initiation and progression. However, the precise function and molecular mechanism of IQGAP3 in LUAD remain unknown. The present study aimed to investigate the expression, prognosis, mechanism and tumor immunity associated with IQGAP3 in LUAD.
METHODS: The relationship between IQGAP3 and the poor prognosis of LUAD was analyzed using The Cancer Genome Atlas (TCGA) database. This analysis was further validated on lung cancer tissues and cell lines. The function of IQGAP3 was investigated by silencing it in LUAD cell lines. To predict microRNA (miRNA) and long non-coding RNA associated with IQGAP3, the starBase database was utilized, and the predictions were verified by enhancing the function of miRNA. Finally, the relationship between IQGAP3 and tumor immunity was evaluated using Spearman\'s correlation analysis.
RESULTS: TCGA database revealed that higher levels of IQGAP3 were associated with advanced tumor stage, N stage and poor prognosis in LUAD patients. To confirm that, we conducted experiments on lung cancer tissues and cell lines and found that silencing IQGAP3 significantly inhibited tumor cell proliferation and migration. The expression of IQGAP3 showed a negative correlation with has-miR-101-3p and has-miR-135a-5p, whereas it showed a positive correlation with GSEC, AC005034.3 and TYMSOS. Furthermore, the introduction of miRNA-mimics into lung cancer cell resulted in a significant inhibition of cancer cell growth and migration. Following that, the level of IQGAP3 showed a positive correlation with the infiltration of immune cells in tumors.
CONCLUSIONS: These results reveal that IQGAP3 significantly promotes LUAD progression and could serve as a prognostic biomarker for LUAD. Furthermore, IQGAP3 is most likely regulated by the GSEC/TYMSOS-hsa-miR-101-3p axis and the AC005034.3-hsa-miR-135a-5p axis in LUAD.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of malignancy, with poor prognosis and rising incidence. IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the IQGAPs family of scaffolding proteins that govern multiple cellular activities like cytoskeletal remodeling and cellular signal transduction. This study aimed to analyze the expression and biological function of IQGAP3 in PDAC.
METHODS: We analyzed IQGAP3 expression in 81 PDAC samples by immunohistochemistry. RNA interference was used to inhibit IQGAP3 expression in PDAC cell lines.
RESULTS: Immunohistochemical analysis of IQGAP3 showed that 54.3% of PDACs were positive for cytoplasmic expression of IQGAP3, with no expression found in non-neoplastic tissue. Furthermore, IQGAP3 expression was an independent poor prognostic factor in our immunostaining-based studies and analyses of public databases. Our cohort and the Cancer Genome Atlas database indicated that IQGAP3 is co-localized with kinesin family member C1 (KIFC1), which we previously reported as a cancer stem cell-associated protein. IQGAP3 small interfering RNA treatment decreased PDAC cell proliferation and spheroid colony formation via ERK and AKT pathways.
CONCLUSIONS: These results suggest that IQGAP3, a transmembrane protein, is involved in survival and stemness and may be a promising new therapeutic target for PDAC.

The IQGAP family of proteins plays a crucial role in cytokinesis across diverse organisms, but the underlying mechanisms are not fully understood. In this study, we demonstrate that IQGAPs in budding yeast, fission yeast, and human cells use a two-domain module to regulate their localization as well as the assembly and disassembly of the actomyosin ring during cytokinesis. Strikingly, the calponin homology domains (CHDs) in these IQGAPs bind to distinct cellular F-actin structures with varying specificity, whereas the non-conserved domains immediately downstream of the CHDs in these IQGAPs all target the division site, but differ in timing, localization strength, and binding partners. We also demonstrate that human IQGAP3 acts in parallel to septins and myosin-IIs to mediate the role of anillin in cytokinesis. Collectively, our findings highlight the two-domain mechanism by which IQGAPs regulate cytokinesis in distantly related organisms as well as their evolutionary conservation and divergence.

As a transcriptional factor, the Forkhead box (FOX) gene family is closely connected with apoptosis, proliferation, and other cellular processes. FOXD2, as one descendant of the FOX gene family, has been mentioned in many articles to show a high expression in several cancers. However, whether FOXD2 has a connection with gastric adenocarcinoma remains an unanswered question. Expression of FOXD2 and IQGAP3 in gastric adenocarcinoma was evaluated by bioinformatics analysis, which was further detected by real-time quantitative PCR (qRT-PCR) and western blot. The downstream target genes of FOXD2 were also mined by bioinformatics analysis. Pathway enrichment analysis was then performed on the target genes. Chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assay were conducted to validate the regulatory relationship between FOXD2 and its downstream target gene IQGAP3. Methyl thiazolyl tetrazolium assay (MTT), combined with cell colony formation assay, was employed to assess the effect of FOXD2 and IQGAP3 on the proliferation of gastric adenocarcinoma cells. Intracytoplasmic Ca2+ concentration was measured by Fluo-3 fluorescence staining. FOXD2 showed a high expression in gastric adenocarcinoma tissues and cells, and FOXD2 silencing considerably attenuated gastric adenocarcinoma cell proliferation. IQGAP3, a downstream target gene of FOXD2, had a positive connection with the expression of FOXD2. The binding relationship between FOXD2 and the promoter region of IQGAP3 was further verified by ChIP and dual-luciferase reporter assays. The results of cell function experiments indicated that FOXD2 could promote gastric adenocarcinoma cell proliferation by transcriptionally activating IQGAP3 to induce an increase in intracellular Ca2+ level. This study confirmed that FOXD2 increased intracellular Ca2+ level through transcriptional activation of IQGAP3, which in turn propelled the proliferation of gastric adenocarcinoma cells, revealing the considerable significance of FOXD2 in the development of gastric adenocarcinoma.

Identification of unique gene markers of normal and cancer stem cells is an effective strategy to study cells of origin and understand tumor behavior. Lineage tracing experiments using the Cre recombinase driven by a stem cell-specific promoter in the CreERT2 reporter mouse model enables identification of adult stem cells and delineation of stem cell activities in vivo. In our recent research on the mouse stomach, Iqgap3 was identified as a homeostatic stem cell marker located in the isthmus of the stomach epithelium. Lineage tracing with the Iqgap3-2A-CreERT2;Rosa26-LSL-tdTomato mouse model demonstrated stem cell activity in Iqgap3-expressing cells. Using the Iqgap3-2A-CreERT2 mouse model to target oncogenic KrasG12D expression to Iqgap3-expressing cells, we observed the rapid development of precancerous metaplasia in the stomach and proposed that aberrant Iqgap3-expressing cells may be critical determinants of early carcinogenesis. In this chapter, we detail a lineage tracing protocol to assess stem cell activity in the murine stomach. We also describe the procedure of inducing KrasG12D expression in Iqgap3-expressing homeostatic stem cells to explore their role as cells of origin and to trace the early cellular changes that precede neoplastic transformation.

IQGAP3 possesses oncogenic actions; its impact on prostate cancer (PC) remains unclear.
We will investigate IQGAP3\'s association with PC progression, key mechanisms, prognosis, and immune evasion.
IQGAP3 expression in PC was examined by immunohistochemistry and using multiple datasets. IQGAP3 network was analyzed for pathway alterations and used to construct a multigene signature (SigIQGAP3NW). SigIQGAP3NW was characterized using LNCaP cell-derived castration-resistant PCs (CRPCs), analyzed for prognostic value in 26 human cancer types, and studied for association with immune evasion.
Increases in IQGAP3 expression associated with PC tumorigenesis, tumor grade, metastasis, and p53 mutation. IQGAP3 correlative genes were dominantly involved in mitosis. IQGAP3 correlated with PLK1 and TOP2A expression at Spearman correlation/R = 0.89 (p ≤ 3.069e-169). Both correlations were enriched in advanced PCs and Taxane-treated CRPCs and occurred at high levels (R > 0.8) in multiple cancer types. SigIQGAP3NW effectively predicted cancer recurrence and poor prognosis in independent PC cohorts and across 26 cancer types. SigIQGAP3NW stratified PC recurrence after adjustment for age at diagnosis, grade, stage, and surgical margin. SigIQGAP3NW component genes were upregulated in PC, metastasis, LNCaP cell-produced CRPC, and showed an association with p53 mutation. SigIQGAP3NW correlated with immune cell infiltration, including Treg in PC and other cancers. RELT, a SigIQGAP3NW component gene, was associated with elevations of multiple immune checkpoints and the infiltration of Treg and myeloid-derived suppressor cells in PC and across cancer types. RELT and SigIQGAP3NW predict response to immune checkpoint blockade (ICB) therapy.
In multiple cancers, IQGAP3 robustly correlates with PLK1 and TOP2A expression, and SigIQGAP3NW and/or RELT effectively predict mortality risk and/or resistance to ICB therapy. PLK1 and TOP2A inhibitors should be investigated for treating cancers with elevated IQGAP3 expression. SigIQGAP3NW and/or RELT can be developed for clinical applications in risk stratification and management of ICB therapy.

Clear cell renal clear cell carcinoma (ccRCC) is resistant to most chemotherapeutic drugs and the molecular mechanisms have not been fully revealed. Genomic instability and the abnormal activation of bypass DNA repair pathway is the potential cause of tumor resistance to radiotherapy and chemotherapy. IQ-motif GTPase activating protein 3 (IQGAP3) regulates cell migration and intercellular adhesion. This study aims to analysis the effects of IQGAP3 expression on cell survival, genome stability and clinical prognosis in ccRCC.
Multiple bioinformatics analysis based on TCGA database and IHC analysis on clinical specimens were included. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) were used to determine protein expression level. MTT assay and 3D spheroid cell growth assay were used to assess cell proliferation and drug resistance in RNAi transfected ccRCC cells. Cell invasion capacity was evaluated by transwell assay. The influence of IQGAP3 on genome instability was revealed by micronuclei number and γ H2AX recruitment test.
The highly expressed IQGAP3 in multiple subtypes of renal cell carcinoma has a clear prognostic value. Deletion of IQGAP3 inhibits cell growth in 3D Matrigel. IQGAP3 depletion lso increases accumulated DNA damage, and improves cell sensitivity to ionizing radiation and chemotherapeutic drugs. Therefore, targeting DNA damage repair function of IQGAP3 in tumorigenesis can provide ideas for the development of new targets for early diagnosis.