IQGAP3 interacts with Rad17 to activate the MRN/ATM/Chk2 signaling and promote radioresistance in lung cancer
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ABSTRACT:
PROVIDER: PRJNA573096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10156190_1.fastq.gz | Fastqsanger.gz | |||
| SRR10156190_2.fastq.gz | Fastqsanger.gz | |||
| SRR10156191_1.fastq.gz | Fastqsanger.gz | |||
| SRR10156191_2.fastq.gz | Fastqsanger.gz | |||
| SRR10156192.fastq.gz | Fastqsanger.gz |
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Project description:IQ motif containing GTPase activating protein 3 (IQGAP3) has been implicated in diverse cellular processes including neuronal morphogenesis, cell proliferation and motility as well as epithelial-mesenchymal transition. However, its roles in DNA damage and repair remain to be clarified. Here, we demonstrate that IQGAP3 is frequently overproduced and predicts poor prognosis in lung cancer patients. Functionally, we provide evidence that depletion of IQGAP3 impairs tumorigenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with and controls the stability of Rad17 to activate the ATM/Chk2 signaling by recruiting 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 protein levels in human lung cancer tissues. Collectively, these data support key roles for IQGAP3 in promoting tumorigenesis and radioresistance in lung cancer by stabilizing the Rad17 protein and suggest targeting IQGAP3 is a promising therapeutic strategy for lung cancer radiotherapy.
2019-09-21 | GSE137802 | GEO
Project description:We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach. Furthermore, we observed robust induction of IQGAP3 expression in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated expression of IQGAP3 in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes the upregulation of IQGAP3 in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both showing decreases during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon reexpression of IGF2BP1 during carcinogenesis. We found that IGF2BP1 binds and stabilizes m 6 A-modified IQGAP3 transcripts. Furthermore, downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
2022-09-16 | GSE196405 | GEO
Project description:We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach. Furthermore, we observed robust induction of IQGAP3 expression in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated expression of IQGAP3 in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes the upregulation of IQGAP3 in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both showing decreases during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon reexpression of IGF2BP1 during carcinogenesis. We found that IGF2BP1 binds and stabilizes m 6 A-modified IQGAP3 transcripts. Furthermore, downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
2022-09-16 | GSE196238 | GEO
Project description:Objective: Tissue stem cells are central regulators of organ homeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. Design: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridization. We performed lineage tracing and transcriptomic analysis of Iqgap3+ isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumors from patient samples. Results: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homeostasis. Iqgap3+ isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. Conclusion: IQGAP3 is a major regulator of stomach epithelial tissue homeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
2021-03-08 | GSE161443 | GEO
Project description:Objective: Tissue stem cells are central regulators of organ homeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. Design: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridization. We performed lineage tracing and transcriptomic analysis of Iqgap3+ isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumors from patient samples. Results: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homeostasis. Iqgap3+ isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. Conclusion: IQGAP3 is a major regulator of stomach epithelial tissue homeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
2021-03-08 | GSE161442 | GEO
Project description:Radioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGFβ2 expression by directly reducing H3K9me3 level at the TGFβ2 promoter and then activates TGF-β/Smad/ATM signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner which deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.
2021-07-14 | GSE136404 | GEO
Project description:Background: Cancer cells inevitably develop resistance to radiation in lung cancer radiotherapy. However, the underlying mechanisms remain to be fully clarified. This study aimed to explore the roles and mechanisms of FGF1 intracellular binding protein (FIBP)?in lung cancer radioresistance. Methods: Expression levels of FIBP in human lung cancer and adjacent tissues were analyzed by immunohistochemical (IHC) staining. Cell growth and proliferation, EdU and CFSE assays, Neutral comet and clonogenic survival analysis as well as mouse xenograft model were performed to explore the functions of FIBP in vitro and in vivo. The underlying mechanisms were investigated by RNA sequencing, co-immunoprecipitation and dual luciferase reporter assays. Results: The expression levels of FIBP in lung cancer tissues were significantly upregulated compared with adjacent normal tissues and associated with worse overall survival. Functionally, we found that depletion of FIBP impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we uncovered that FIBP interacts with STAT3 to enhance the transcriptional activity of STAT3, thereby inducing the expression of downstream target gene Eme1. Importantly, we also demonstrated that the biological effects of FIBP were partially dependent on Eme1 in lung cancer. Conclusions: These results reveal that FIBP modulates STAT3/Eme1 axis to drive lung cancer progression and radioresistance, indicating targeting FIBP may be a novel intervention strategy for lung cancer radiotherapy.
2022-06-06 | GSE196635 | GEO
Project description:Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays. Results: We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of β-catenin, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer. Conclusions: These findings suggest that Cyclin K positively modulates the β-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.
2020-01-07 | GSE143147 | GEO
Project description:Scaffold protein IQGAP3 mediates assembly of multiprotein complexes, orchestrating intracellular signaling pathways. Earlier we have found it to be overexpressed in lesional psoriatic skin. IQGAP3 is involved in cell proliferation and chemokine signaling that are key processes in psoriasis, so we decided to investigate the molecular basis of its role in psoriatic phenotype of keratinocytes. Transcriptome profiling of HaCaT keratinocytes allowed us to identify a wide range of psoriasis-associated pathways to be altered in IQGAP3-knockdown cells. NFkB signaling, EGFR signaling, p38/MAPK and ERK1/ERK2 activation, lipid metabolism and cytokine production as well as the response to the inflammatory cytokine stimulation were altered in the knockdown cells. Real-time analysis of cell growth revealed the alterations of proliferation and wound healing. The balance between proliferation and apoptosis of skin cells was altered, as well as the skin barrier functions and the production of IL-6 and IFNg. However, the diversity of the pathway alterations in the knockdown cells led us to the conclusion that IQGAP3 may not be the best target for the therapeutic inhibition to normalize the phenotype of keratinocytes in psoriasis.
2024-04-22 | GSE248548 | GEO
Project description:NK/T cell lymphoma (NKTCL) is a highly aggressive subtype of non-Hodgkin lymphoma. GELOX (gemcitabine, oxaliplatin, and L-asparaginase) is one of the first-line chemotherapy regimens of NKTCL. Yet, the prognosis of NKTCL is poor. Icaritin (ICT) is an herb-derived monomer from icariin with antitumor effects. We found that icaritin induced proliferation inhibition and apoptosis of NKTCL both in vitro and in vivo. Moreover, icaritin inhibited the dissemination of NKTCL in vivo. RNA sequencing (RNA-seq) revealed the polo-like kinase 1 (PLK1) gene and DNA damage response (DDR) as the targets of icaritin. Mechanistically, icaritin inhibited PLK1 to promote checkpoint kinase 2 (Chk2) homodimerization and its T387 phosphorylation, which further activated p53, leading to the activation of the DDR pathway. Moreover, inhibiting PLK1 increased Forkhead box O3a (FOXO3a) nuclear localization, the latter of which activated Ataxia-telangiectasia mutated (ATM), an early sensor of DNA damage. Then ATM phosphorylated Chk2 T68 and initiated Chk2 activation. Remarkably, combined treatment of icaritin and GELOX achieved better antitumor efficacy than single treatment in vivo. In summary, our results proved the efficacy of icaritin treating NKTCL, and provided insights into its antitumor molecular mechanism, and revealed the application value of icaritin in facilitating clinical NKTCL treatment.
2022-05-04 | GSE201959 | GEO