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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. [ABSTRACT FROM AUTHOR]

Introduction: IQGAP3 possesses oncogenic actions; its impact on prostate cancer (PC) remains unclear. Objective: We will investigate IQGAP3′s association with PC progression, key mechanisms, prognosis, and immune evasion. Methods: 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. Results: 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. Conclusions: 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.

Abstract 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.

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • IQGAP3 network (NW) regulates mitosis in prostate cancer (PC) and other cancers. • IQGAP3 correlates with PLK1 and TOP2A expression in PC and other cancers. • SigIQGAP3NW robustly predicts recurrence and poor prognosis in PC and other cancers. • RELT significantly correlates with immune checkpoint in PC and across human cancers. • SigQIGAP3NW and RELT predict cancer resistance to immune checkpoint blockage therapy. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Bladder cancer (BC) is the most common malignant tumour of the urinary system. The current conventional treatments for BC have certain limitations. It is very urgent and necessary to find new treatment strategies for BC. Our study elucidated the underlying regulatory mechanisms of cell division control protein 42 homologue (CDC42) to regulate the development of BC. Quantitative real-time polymerase chain reaction, Western blot, immunofluorescence and immunohistochemistry were used to assess the expression of CDC42 and IQ motif-containing GTPase-activating protein 3 (IQGAP3) in BC tissues and BC cells. We induced the knockdown or overexpression by transfecting sh-CDC42 or oe-IQGAP3 into BC cells. In addition, cell proliferation and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays, respectively. Moreover, proteins involved in the rat sarcoma (Ras)/extracellular regulated protein kinase (ERK) pathway were determined by Western blot. The expression of CDC42 and IQGAP3 was markedly upregulated in both BC tissues and BC cells. CDC42 silencing downregulated the expression of IQGAP3 and suppressed the Ras/ERK pathway. In addition, CDC42 silencing markedly promoted apoptosis and inhibited proliferation in BC cells. Further experiments showed that overexpression of IQGAP3 dramatically abolished the bioeffects mediated by CDC42 silencing on the proliferation and apoptosis of BC cells. All our results suggested that CDC42 promoted the Ras/ERK pathway by regulating IQGAP3, thus enhancing cell proliferation and suppressing cell apoptosis in BC cells and ultimately participating in the pathogenesis of BC. [ABSTRACT FROM AUTHOR]

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 expression is elevated in triple negative breast cancer. • IQGAP3 plays a key role in TNBC cellular behaviour relevant to cell adhesion, invasion and metastasis. • A novel IQGAP3:PAK6 interaction mediates RhoA contractility. [ABSTRACT FROM AUTHOR]

Background. 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. Methods. 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 H2AX recruitment test. Results. 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. [ABSTRACT FROM AUTHOR]

Quan Meng,1,* Can-Xuan Li,2,* Dan Long,3 Xiaobin Lin4 1Department of Clinical Laboratory, Shenzhen Traditional Chinese Medical Hospital, Shenzhen, Guangdong, People’s Republic of China; 2Department of urology, Shenshan Central Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, Guangdong, People’s Republic of China; 3Respiratory Medicine, Shenshan Central Hospital, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Shanwei, Guangdong, People’s Republic of China; 4Department of Breast Surgery and General Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaobin LinDepartment of Breast Surgery and General Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaEmail lxb826463580@163.comAim: The study was designed to mine the expression and roles of IQGAP3 in clear cell renal cell carcinoma (ccRCC).Methods: Expression profiles and clinical information were obtained from the Cancer Genome Atlas (TCGA) to estimate IQGAP3 expression in ccRCC, its relationship with patients’ clinicopathological variables and prognosis, and the potential biological mechanisms.Results: IQGAP3 was highly expressed in ccRCC and indicated advanced clinical outcome and poor prognosis. IQGAP3 affected the progression of ccRCC through several cancer-related pathways. IQGAP3 might play a vital role in the ccRCC tumor microenvironment.Conclusion: IQGAP3 could serve as a promising prognostic biomarker and therapeutic target.Keywords: IQGAP3, clear cell renal cell carcinoma, prognosis

IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the Rho family of guanosine-5′-triphosphatases (GTPases). IQGAP3 plays a crucial part in the development and progression of several types of cancer. However, the prognostic, upstream-regulatory, and immunological roles of IQGAP3 in human cancer types are not known. We found that IQGAP3 expression was increased in different types of human cancer. The high expression of IQGAP3 was correlated with tumor stage, lymph node metastasis, and a poor prognosis in diverse types of human cancer. The DNA methylation of IQGAP3 was highly and negatively correlated with IQGAP3 expression in diverse cancer types. High DNA methylation in IQGAP3 was correlated with better overall survival in human cancer types. High mRNA expression of IQGAP3 was associated with tumor mutational burden, microsatellite instability, immune cell infiltration, and immune modulators. Analyses of signaling pathway enrichment showed that IQGAP3 was involved in the cell cycle. IQGAP3 expression was associated with sensitivity to a wide array of drugs in cancer cells lines. We revealed that polypyrimidine tract–binding protein 1 (PTBP1) and an IQGAP3-associated lncRNA (IQGAP3AR)/let-7c-5p axis were potential regulations for IQGAP3 expression. We provided the first evidence to show that an IQGAP3AR/let-7c-5p/IQGAP3 axis has indispensable roles in the progression and immune response in different types of human cancer.

The voltage‐dependent potassium channel Kv1.3 has been implicated in proliferation in many cell types, based on the observation that Kv1.3 blockers inhibited proliferation. By modulating membrane potential, cell volume, and/or Ca2+ influx, K+ channels can influence cell cycle progression. Also, noncanonical channel functions could contribute to modulate cell proliferation independent of K+ efflux. The specificity of the requirement of Kv1.3 channels for proliferation suggests the involvement of molecule‐specific interactions, but the underlying mechanisms are poorly identified. Heterologous expression of Kv1.3 channels in HEK cells has been shown to increase proliferation independently of K+ fluxes. Likewise, some of the molecular determinants of Kv1.3‐induced proliferation have been located in the C‐terminus region, where individual point mutations of putative phosphorylation sites (Y447A and S459A) abolished Kv1.3‐induced proliferation. Here, we investigated the mechanisms linking Kv1.3 channels to proliferation exploring the correlation between Kv1.3 voltage‐dependent molecular dynamics and cell cycle progression. Using transfected HEK cells, we analyzed both the effect of changes in resting membrane potential on Kv1.3‐induced proliferation and the effect of mutated Kv1.3 channels with altered voltage dependence of gating. We conclude that voltage‐dependent transitions of Kv1.3 channels enable the activation of proliferative pathways. We also found that Kv1.3 associated with IQGAP3, a scaffold protein involved in proliferation, and that membrane depolarization facilitates their interaction. The functional contribution of Kv1.3‐IQGAP3 interplay to cell proliferation was demonstrated both in HEK cells and in vascular smooth muscle cells. Our data indicate that voltage‐dependent conformational changes of Kv1.3 are an essential element in Kv1.3‐induced proliferation. [ABSTRACT FROM AUTHOR]

Abstract Background The IQ-motif-containing GTPase-activating protein (IQGAP) family comprises three members, IQGAP1, IQGAP2 and IQGAP3. IQGAP3 is the latest addition to the family. This study mainly investigated the novel marker IQGAP3 at serum and tumor tissue levels compared with the markers B7-H4 and cyclooxygenase-2 (COX-2) in patients with colorectal cancer (CRC) and in healthy individuals, aiming to evaluate the diagnostic and prognostic value of IQGAP3 for CRC. Materials and methods Serum samples were collected prior to any therapy in 118 CRC patients and as part of a routine examination in 85 healthy individuals. Serum IQGAP3, B7-H4 and COX-2 levels were measured using commercially available ELISA kits. Immunohistochemistry was performed to detect the IQGAP3, B7-H4 and COX-2 in tumor tissues and normal para-carcinoma tissues. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) were used to evaluate and compare the diagnostic value of different serum tumor markers. Univariate and multivariate analyses were performed to identify the prognostic risk factors for CRC. Results IQGAP3, B7-H4 and COX-2 showed low or high expression in tumor tissues while no expression in normal para-carcinoma tissues. Serum levels of IQGAP3 in CRC group were significantly higher than those in healthy control group (P

Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest identified member of the IQGAP family, may act as a crucial factor in cancer development and progression; however, its clinical value in breast cancer remains unestablished. We explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer.Methods: IQGAP3 mRNA and protein levels were detected in breast cancer cell lines and tumor tissues by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was also evaluated immunohistochemically in archived paraffin-embedded specimens from 257 breast cancer patients, and the associations between IQGAP3 expression level, clinical characteristics, and prognosis were analyzed. We assessed the relationship between IQGAP3 expression and sensitivity to radiation therapy which was determined by subgroup analysis.Results: IQGAP3 was significantly upregulated in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to controls. Additionally, high levels of IQGAP3 expression were detected in 110/257 (42.8%) of archived paraffin-embedded breast cancer specimens. High IQGAP3 expression level was significantly related to clinical stage (p = 0.001), T category (p = 0.002), N category (p = 0.001), locoregional recurrence (p = 0.002), distant metastasis (p = 0.001), and vital status (p = 0.001). Univariate and multivariate statistical analysis showed that IQGAP3 expression was an independent prognostic factor among all 257 breast cancer patients in our cohort (p = 0.003, p = 0.001). Subgroup analysis revealed IQGAP3 expression correlated with radioresistance and was also an independent predictor of radiotherapy outcome.Conclusion: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radioresistance in breast cancer. Therefore, IQGAP3 may be a reliable prognostic biomarker in breast cancer and could be used to identify patients who may benefit from radiotherapy.

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., Competing Interests: No author has a conflict of interest with the contents of this article., (© 2024 Gao et al.)

IQ motif containing GTPase-activating protein 3 (IQGAP3) has been implicated in diverse cellular processes, including neuronal morphogenesis, cell proliferation and motility, and epithelial-mesenchymal transition. However, its role in cancer radioresistance is completely unknown. Here, we report that IQGAP3 is overproduced in lung cancer patients and correlates with poor clinical outcomes. Functionally, we demonstrate that depletion of IQGAP3 impairs oncogenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with Rad17 and controls its expression to activate the ATM/Chk2 and ATR/Chk1 signaling pathways by recruiting the Mre11-Rad50-Nbs1 (MRN) complex in response to DNA damage. Moreover, Rad17 is identified as the major downstream effector that mediates the functions of IQGAP3 in lung cancer. Clinically, IQGAP3 overexpression positively correlates with Rad17 upregulation in human lung cancer tissues. Collectively, these data support key role for IQGAP3 in promoting lung cancer radioresistance by interacting with Rad17 and suggest that targeting IQGAP3 may be an attractive strategy for lung cancer radiotherapy. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • CHDs from IQGAPs in different organisms bind distinct F-actin structures • MTA/CykF/IR in different IQGAPs associate with specific cytokinesis factors • IQGAPs employ a two-domain mechanism to regulate actomyosin ring assembly • IQGAP3 acts in parallel to myosin-IIs and septin 9 to regulate cytokinesis How the IQGAP family of proteins functions in cytokinesis is not well understood. Wang et al. report that IQGAPs from budding yeast, fission yeast, and mammalian cells use a two-domain strategy to control their own localization as well as the assembly and function of the actomyosin ring during cytokinesis. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers, including liver, ovary, lung, large intestine, gastric, bone marrow, and breast malignancies and is involved in the invasion and metastasis of cancer cells. Therefore, we aimed to determine the biological role and molecular mechanism of IQGAP3 in HCC. Methods We used 120 archived clinical HCC samples, 9 snap-frozen HCC tumor tissues, and 4 normal liver tissues. Expression of IQGAP3 mRNA and protein in HCC cell lines (Hep3B, SMMC-7721, HCCC-9810, HepG2, BEL-7404, HCCLM3, QGY-7701, Huh7, and MHCC97H) and normal liver epithelial cells LO2 was examined by western blot, quantitative polymerase chain reaction, and immunohistochemistry. In addition, wound-healing and transwell matrix penetration assays were used to assess the migratory and invasive abilities of HCC cells, respectively. Results Expression of the IQGAP3 was robustly upregulated in HCC cells and tissues. High expression of IQGAP3 in HCC correlated with aggressive clinicopathological features and was an independent poor prognostic factor for overall survival. Furthermore, ectopic expression of IQGAP3 markedly enhanced HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro and promoted metastasis of orthotopic hepatic tumors in nude mice. Conversely, silencing endogenous IQGAP3 showed an opposite effect. Mechanistically, IQGAP3 promoted EMT and metastasis by activating TGF-β signaling. Conclusions IQGAP3 functions as an important regulator of metastasis and EMT by constitutively activating the TGF-β signaling pathway in HCC. Our findings present new evidence of the role of IQGAP3 in EMT and metastasis, indicating its potential as a prognostic biomarker candidate and a therapeutic target against HCC.

Introduction: 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., Discussion/conclusion: These results suggest that IQGAP3, a transmembrane protein, is involved in survival and stemness and may be a promising new therapeutic target for PDAC., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

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 Ca 2+ 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 Ca 2+ level. This study confirmed that FOXD2 increased intracellular Ca 2+ 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., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Although gastric cancer is one of the most common causes of cancer death in the world, mechanisms underlying this type of tumor have not been fully understood. In this study, we found that IQGAP3, a member of the IQGAP gene family, was significantly up-regulated in human gastric cancer starting from the early stages of tumor progression. Overexpression of IQGAP3 in 293T and NIH3T3 cells, which have no endogenous IQGAP3 expression, resulted in morphological change with multiple dendritic-like protrusions and enhanced migration. Overexpression of IQGAP3 also led to reduced cell–cell adhesion in 293T cells, likely as a result of its interactions with e-cadherin or β-catenin proteins. Additionally, IQGAP3 accumulated along the leading edge of migrating cells and at the cleavage furrow of dividing cells. In contrast, suppression of IQGAP3 by short-interfering RNA (siRNA) markedly reduced invasion and anchorage-independent growth of MKN1 and TMK-1 gastric cancer cells. We further confirmed that IQGAP3 interacted with Rho family GTPases, and had an important role in cytokinesis. Taken together, we demonstrated that IQGAP3 plays critical roles in migration and invasion of human gastric cancer cells, and regulates cytoskeletal remodeling, cell migration and adhesion. These findings may open a new avenue for the diagnosis and treatment of gastric cancer.

Aims After birth mammalian cardiomyocytes initiate a last cell cycle which results in binucleation due to cytokinesis failure. Despite its importance for cardiac regenerative therapies, this process is poorly understood. Here, we aimed at a better understanding of the difference between cardiomyocyte proliferation and binucleation and providing a new tool to distinguish these two processes. Methods and results Monitoring of cell division by time-lapse imaging revealed that rat cardiomyocyte binucleation stems from a failure to properly ingress the cleavage furrow. Astral microtubule required for actomyosin ring anchorage and thus furrow ingression were not symmetrically distributed at the periphery of the equatorial region during anaphase in binucleating cardiomyocytes. Consequently, RhoA, the master regulator of actomyosin ring formation and constriction, non-muscle myosin IIB, a central component of the actomyosin ring, as well as IQGAP3 were abnormally localized during cytokinesis. In agreement with improper furrow ingression, binucleation in vitro and in vivo was associated with a failure of RhoA and IQGAP3 to localize to the stembody of the midbody. Conclusion Taken together, these results indicate that naturally occurring cytokinesis failure in primary cardiomyocytes is due to an aberrant mitotic microtubule apparatus resulting in inefficient anchorage of the actomyosin ring to the plasma cell membrane. Thus, cardiomyocyte binucleation and division can be discriminated by the analysis of RhoA as well as IQGAP3 localization. [ABSTRACT FROM AUTHOR]

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 Kras G12D 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 Kras G12D 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., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

IQGAP scaffold proteins are evolutionarily conserved in eukaryotes and facilitate the formation of complexes that regulate cytoskeletal dynamics, intracellular signaling, and intercellular interactions. Fungal and mammalian IQGAPs are implicated in cytokinesis. IQGAP1, IQGAP2, and IQGAP3 have diverse roles in vertebrate physiology, operating in the kidney, nervous system, cardio-vascular system, pancreas, and lung. The functions of IQGAPs can be corrupted during oncogenesis and are usurped by microbial pathogens. Therefore, IQGAPs represent intriguing candidates for novel therapeutic agents. While modulation of the cytoskeletal architecture was initially thought to be the primary function of IQGAPs, it is now clear that they have roles beyond the cytoskeleton. This review describes contributions of IQGAPs to physiology at the organism level. [ABSTRACT FROM AUTHOR]

Since its discovery in 1994, recognized cellular functions for the scaffold protein IQGAP1 have expanded immensely. Over 100 unique IQGAP1-interacting proteins have been identified, implicating IQGAP1 as a critical integrator of cellular signaling pathways. Initial research established functions for IQGAP1 in cell–cell adhesion, cell migration, and cell signaling. Recent studies have revealed additional IQGAP1 binding partners, expanding the biological roles of IQGAP1. These include crosstalk between signaling cascades, regulation of nuclear function, and Wnt pathway potentiation. Investigation of the IQGAP2 and IQGAP3 homologs demonstrates unique functions, some of which differ from those of IQGAP1. Summarized here are recent observations that enhance our understanding of IQGAP proteins in the integration of diverse signaling pathways. [ABSTRACT FROM AUTHOR]

Background: 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., Methods: 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., Results: 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., Competing Interests: The authors declare there are no competing interests., (©2022 Li et al.)

Abstract: The IQGAP family comprises three proteins in humans. The best characterized is IQGAP1, which participates in protein–protein interactions and integrates diverse signaling pathways. IQGAP2 and IQGAP3 harbor all the domains identified in IQGAP1, but their biological roles are poorly defined. Proteins that bind IQGAP1 include Cdc42 and Rac1, E-cadherin, β-catenin, calmodulin and components of the mitogen-activated protein kinase pathway, all of which are involved in cancer. Here, we summarize the biological functions of IQGAPs that may contribute to neoplasia. Additionally, we review published data which implicate IQGAPs in cancer and tumorigenesis. The cumulative evidence suggests IQGAP1 is an oncogene while IQGAP2 may be a tumor suppressor. [Copyright &y& Elsevier]

IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the Rho family of guanosine-5'-triphosphatases (GTPases). IQGAP3 plays a crucial part in the development and progression of several types of cancer. However, the prognostic, upstream-regulatory, and immunological roles of IQGAP3 in human cancer types are not known. We found that IQGAP3 expression was increased in different types of human cancer. The high expression of IQGAP3 was correlated with tumor stage, lymph node metastasis, and a poor prognosis in diverse types of human cancer. The DNA methylation of IQGAP3 was highly and negatively correlated with IQGAP3 expression in diverse cancer types. High DNA methylation in IQGAP3 was correlated with better overall survival in human cancer types. High mRNA expression of IQGAP3 was associated with tumor mutational burden, microsatellite instability, immune cell infiltration, and immune modulators. Analyses of signaling pathway enrichment showed that IQGAP3 was involved in the cell cycle. IQGAP3 expression was associated with sensitivity to a wide array of drugs in cancer cells lines. We revealed that polypyrimidine tract-binding protein 1 (PTBP1) and an IQGAP3-associated lncRNA (IQGAP3AR)/let-7c-5p axis were potential regulations for IQGAP3 expression. We provided the first evidence to show that an IQGAP3AR/let-7c-5p/IQGAP3 axis has indispensable roles in the progression and immune response in different types of human cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuan, Jiang, Tang, Yang, Wang, Zhang and Duan.)

Simple Summary: The inhibitors of BET proteins represent a promising class of therapeutic agents that target the oncogenic activity of MYC and repress DLBCL cell migration, but the mechanism of such repression remains elusive. Herein, we found that BET inhibitor JQ1 abrogated the amoeboid movement of DLBCL cells through a small GTPase-driven mechanism, including both restrained RAS signaling and MYC-mediated suppression of GTP-RhoA activity. BET inhibition drastically increased the expression of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3), in DLBCL. Proteomics-based re-stratification identified a specific subgroup of DLBCL patients whose tumors harbored an enhanced PI3K activity and had an inferior survival, whereas a lower IQGAP3 expression level further portended a very dismal outcome for those patients. The inhibitors of both BET and RAS (through attenuated PI3K signaling) activities effectively ameliorated the outspread of in vivo DLBCL tumors, indicating the potential of their synergism in the treatment of specific DLBCL subtypes. Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL. [ABSTRACT FROM AUTHOR]

Background: IQ motif-containing GTPase activating protein 3 (IQGAP3), the latest identified member of the IQGAP family, may act as a crucial factor in cancer development and progression; however, its clinical value in breast cancer remains unestablished. We explored the correlation between IQGAP3 expression profile and the clinicopathological features in breast cancer. Methods: IQGAP3 mRNA and protein levels were detected in breast cancer cell lines and tumor tissues by real-time PCR and western blotting and compared to the normal control groups. Protein expression of IQGAP3 was also evaluated immunohistochemically in archived paraffin-embedded specimens from 257 breast cancer patients, and the associations between IQGAP3 expression level, clinical characteristics, and prognosis were analyzed. We assessed the relationship between IQGAP3 expression and sensitivity to radiation therapy which was determined by subgroup analysis. Results: IQGAP3 was significantly upregulated in breast cancer cell lines and human tumor tissues at both the mRNA and protein level compared to controls. Additionally, high levels of IQGAP3 expression were detected in 110/257 (42.8%) of archived paraffin-embedded breast cancer specimens. High IQGAP3 expression level was significantly related to clinical stage (p = 0.001), T category (p = 0.002), N category (p = 0.001), locoregional recurrence (p = 0.002), distant metastasis (p = 0.001), and vital status (p = 0.001). Univariate and multivariate statistical analysis showed that IQGAP3 expression was an independent prognostic factor among all 257 breast cancer patients in our cohort (p = 0.003, p = 0.001). Subgroup analysis revealed IQGAP3 expression correlated with radioresistance and was also an independent predictor of radiotherapy outcome. Conclusion: Our findings suggest that high IQGAP3 expression predicts poor prognosis and radioresistance in breast cancer. Therefore, IQGAP3 may be a reliable prognostic biomarker in breast cancer and could be used to identify patients who may benefit from radiotherapy. [ABSTRACT FROM AUTHOR]

Although gastric cancer is one of the most common causes of cancer death in the world, mechanisms underlying this type of tumor have not been fully understood. In this study, we found that IQGAP3, a member of the IQGAP gene family, was significantly up-regulated in human gastric cancer starting from the early stages of tumor progression. Overexpression of IQGAP3 in 293T and NIH3T3 cells, which have no endogenous IQGAP3 expression, resulted in morphological change with multiple dendritic-like protrusions and enhanced migration. Overexpression of IQGAP3 also led to reduced cell–cell adhesion in 293T cells, likely as a result of its interactions with e-cadherin or β-catenin proteins. Additionally, IQGAP3 accumulated along the leading edge of migrating cells and at the cleavage furrow of dividing cells. In contrast, suppression of IQGAP3 by short-interfering RNA (siRNA) markedly reduced invasion and anchorage-independent growth of MKN1 and TMK-1 gastric cancer cells. We further confirmed that IQGAP3 interacted with Rho family GTPases, and had an important role in cytokinesis. Taken together, we demonstrated that IQGAP3 plays critical roles in migration and invasion of human gastric cancer cells, and regulates cytoskeletal remodeling, cell migration and adhesion. These findings may open a new avenue for the diagnosis and treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers. This study was designed to explore the expression and role of IQGAP3 in colorectal cancer., Methods: We first assessed the IQGAP3 expression level in colorectal cancer. The correlation of IQGAP3 expression with the clinicopathological characteristics and prognosis was then assessed. At last, we investigated the function of IQGAP3 in colorectal cancer by knocking down its expression in colorectal cancer cell lines., Results: Consistent with the conclusions drawn from The Cancer Genome Atlas database, IQGAP3 was upregulated in colorectal cancer at the tissue level and cellular level. Based on immunohistochemistry results of the tissue microarrays, we demonstrated that higher expression of IQGAP3 was associated with higher tumor node metastasis stage ( P = 0.005), higher incidence of lymph node metastasis ( P = 0.004), and shorter overall survival ( P = 0.022). Knockdown of IQGAP3 in colorectal cancer cell lines remarkably decreased their proliferation and migration abilities., Conclusion: Our data provide evidence that IQGAP3 significantly promote malignant progression of colorectal cancer and could serve as a potential therapeutic target.

For decades, E2F1 has been recognized as a retinoblastoma protein (RB) binding transcription factor that regulates the cell cycle. E2F1 binds preferentially to RB and accelerates the cell cycle in most cancer cells. However, it is thought that E2F1 modulates cell proliferation in other ways as well. Herein, it has been discovered that in pathological tissues derived from hepatocellular carcinoma (HCC) patients, E2F1 correlates positively with IQGAP3 and that both of these factors are highly expressed (N = 164, R = 0.6716). In addition, a high level of E2F1 or IQGAP3 predicted poor survival in HCC patients. Further study determined that E2F1 transactivates IQGAP3, the GTPase binding protein in MHCC-97H cells. Co-immunoprecipitation analysis indicated that IQGAP3 interacts with PKCδ and competitively inhibits the interaction between PKCδ and PKCα, resulting in phosphorylation of PKCα activation and promotion of cell proliferation. This study reveals that highly expressed E2F1 not only transactivates cell-cycle-related factors but also promotes HCC proliferation by activating the phosphorylation of PKCα., Competing Interests: None.

Objective: Spheroid colony formation is a useful method of cancer stem cell (CSC) characterization. We previously showed that the IQ motif containing the GTPase-activating protein 3 gene (IQGAP3) is upregulated in spheroid body-forming gastric cancer (GC) cells compared with parental cells. We investigated IQGAP3 expression in GC., Methods: IQGAP3 protein expression was analyzed by immunohistochemistry in 165 GC cases. RNA interference was used to inhibit IQGAP3 expression in GC cell lines., Results: In non neoplastic gastric mucosa, weak staining of IQGAP3 was observed in the foveolar epithelium, while GC tissue showed stronger, more extensive staining. Of the 165 GC cases, 34 (21%) were positive for IQGAP3 expression. GC cases positive for IQGAP3 were found more frequently in stage II/III/IV cases than in stage I cases. Univariate and multivariate analyses demonstrated that IQGAP3 expression is an independent prognostic classifier of GC patients. Both the number and size of the spheres formed by MKN-74 cells were significantly reduced by knockdown of IQGAP3. The phosphorylation of Akt and Erk1/2 was inhibited by knockdown of IQGAP3., Conclusion: These results suggest that IQGAP3 plays an important role in gastric CSCs. The location of IQGAP3 on the cell membrane makes it a potential therapeutic target for GC., (© 2017 S. Karger AG, Basel.)

Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers, including liver, ovary, lung, large intestine, gastric, bone marrow, and breast malignancies and is involved in the invasion and metastasis of cancer cells. Therefore, we aimed to determine the biological role and molecular mechanism of IQGAP3 in HCC., Methods: We used 120 archived clinical HCC samples, 9 snap-frozen HCC tumor tissues, and 4 normal liver tissues. Expression of IQGAP3 mRNA and protein in HCC cell lines (Hep3B, SMMC-7721, HCCC-9810, HepG2, BEL-7404, HCCLM3, QGY-7701, Huh7, and MHCC97H) and normal liver epithelial cells LO2 was examined by western blot, quantitative polymerase chain reaction, and immunohistochemistry. In addition, wound-healing and transwell matrix penetration assays were used to assess the migratory and invasive abilities of HCC cells, respectively., Results: Expression of the IQGAP3 was robustly upregulated in HCC cells and tissues. High expression of IQGAP3 in HCC correlated with aggressive clinicopathological features and was an independent poor prognostic factor for overall survival. Furthermore, ectopic expression of IQGAP3 markedly enhanced HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro and promoted metastasis of orthotopic hepatic tumors in nude mice. Conversely, silencing endogenous IQGAP3 showed an opposite effect. Mechanistically, IQGAP3 promoted EMT and metastasis by activating TGF-β signaling., Conclusions: IQGAP3 functions as an important regulator of metastasis and EMT by constitutively activating the TGF-β signaling pathway in HCC. Our findings present new evidence of the role of IQGAP3 in EMT and metastasis, indicating its potential as a prognostic biomarker candidate and a therapeutic target against HCC.

IQGAP3 (IQ motif containing GTPase activating protein3) belongs to IQGAP family. Recent studies have investigated that IQGAP3 was overexpressed in several tumor tissues. This study was designed to explore the expression and role of IQGAP3 in pancreatic cancer, a highly lethal disease. IQGAP3 mRNA expression was significantly increased in pancreatic cancer tissues, compared with non-cancerous tissues. Moreover, its expression was strongly associated with tumor size, differentiation, lymph node metastasis and patients' overall survival. Gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) dataset showed that cell apoptosis, metastasis and Cdc42 pathways were strongly associated with IQGAP3 expression in pancreatic cancer patients. Knocking down of IQGAP3 in two pancreatic cancer cell lines with high level of IQGAP3 (BXPC-3 and SW1990) significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis. Moreover, silencing of IQGAP3 also affected the expression of cell apoptosis-, metastasis- and Cdc42 pathway-related proteins. Cdc42 knockdown had similar inhibitory effects on the cellular behavior of BXPC-3 cells. In conclusion, IQGAP3 may act as an oncogene in pancreatic cancer through regulating Cdc42 expression. Our data suggest IQGAP3 might be a novel diagnostic marker and therapeutic target for this cancer.

IQGAPs are scaffolding proteins that regulate actin assembly, exocyst function, cell motility, morphogenesis, adhesion and division. Vertebrates express 3 family members: IQGAP1, IQGAP2, and IQGAP3. IQGAP1 is known to stimulate nucleation of branched actin filaments through N-WASP and the Arp2/3 complex following direct binding to cytoplasmic tails of ligand-activated growth factor receptors, including EGFR, VEGFR2 and FGFR1. By contrast, little is known about functions of IQGAP2 or IQGAP3. Using in situ hybridization on whole mount zebrafish (Danio rerio) embryos, we show that IQGAP1 and IQGAP2 are associated with discrete tissues and organs, while IQGAP3 is mainly expressed in proliferative cells throughout embryonic and larval development. Morpholino knockdowns of IQGAP1 and IQGAP2 have little effect on embryo morphology while loss of function of IQGAP3 affects both cell proliferation and cell motility. IQGAP3 morphant phenotypes are similar to those resulting from overexpression of dominant negative forms of Ras or of Fibroblast Growth Factor Receptor 1 (FGFR1), suggesting that IQGAP3 plays a role in FGFR1-Ras-ERK signaling. In support of this hypothesis, dominant negative forms of FGFR1 or Ras could be rescued by co-injection of zebrafish IQGAP3 mRNA, strongly suggesting that IQGAP3 acts as a downstream regulator of the FGFR1-Ras signaling pathway., (© 2015 Wiley Periodicals, Inc.)