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Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196405 | GEO | 2022/09/16

REPOSITORIES: GEO

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Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer [RIP-Seq]

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

The Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homeostasis and repair [SMART-SeqII]

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

The Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homeostasis and repair [RNA-Seq]

2021-03-08 | GSE161442 | GEO

Single cell RNA-seq of Stmn1+ isthmal cells and Pgc+ chief cells to compare and characterize distinct gastric corpus stem cells at molecular level

Project description:The purpose of this single cell experiment is to compare and characterize at molecular level actively cycling stem cells in the isthmus and quiescent stem cells in the base of the mouse stomach corpus. The lineage tracing data from Stmn1-CreERT2 shows that Stmn1+ cells in the corpus isthmus include fast dividing isthmus stem cells with long-term potency. On the other hand, chief cells including Lgr5+ subpopulation can play as quiescent stem cells in the base that are largely quiescent in homeostasis, but are activated upon injury. The isthmus stem cells and chief cells are isolated by Stmn1 and Pgc, respectively, and were subject to single cell RNA-seq experiment.

2019-08-14 | E-MTAB-6879 | biostudies-arrayexpress

Expression profiling of Troy positive gastric cells

2013-10-23 | GSE44060 | GEO

Expression profiling of Troy positive gastric cells

Project description:Proliferation of the self-renewing epithelium of the gastric corpus occurs almost exclusively in the isthmus of the glands, from where cells migrate bi-directionally towards pit and base. The isthmus is therefore generally viewed as the stem cell zone. We find that the stem cell marker Troy is expressed at the gland base by a small subpopulation of chief cells. By lineage tracing using a Troy-eGFP-ires-CreERT2 allele, single marked cells are shown to generate entirely labeled gastric units over periods of months. This phenomenon accelerates upon tissue damage. Troy+ chief cells can be cultured to generate long-lived gastric organoids. Troy marks a specific, 'plastic' subset of differentiated chief cells capable of replenishing entire gastric units, essentially serving as a quiescent ‘reserve’ stem cell. An EGFP-ires-CreERT2 cassette was introduced into the transcriptional start side of Tnfrsf19 (Troy), resulting in the expression of EGFP and CreERT2 under the control of endogenous Troy-regulatory sequences. Troy is expressed in basally located chief and parietal cells. Using FACS, Troy positive chief and parietal cells can be isolated separately. Expression profiling was performed on these two cell types: three arrays of sorted chief cells, two arrays of sorted parietal cells. As a reference, two arrays of separately isolated whole gastric corpus glands were added. In addition, single sorted Troy positive chief cells can be placed in culture, forming 3D cultures called organoids. Three arrays were generated from different organoid cultures, one time in normal medium containing the factors EGF, Gastrin, FGF10, Noggin, Wnt3a and Rspondin (EGFNWR medium) and one time in medium containing only EGF and Rspondin (ER medium).

2013-10-23 | E-GEOD-44060 | biostudies-arrayexpress

IQGAP3 interacts with Rad17 to activate the MRN/ATM/Chk2 signaling and promote radioresistance in lung cancer

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

Effect of IQGAP3 silencing on HaCaT keratinocytes under normal conditions or inflammatory cytokine stimulation

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

Bulk RNA-seq of proliferating cells in the mouse stomach corpus epithelium from FUCCI mouse.

Project description:The purpose of this bulk RNA-seq experiment is to identify candidate genes that can mark proliferating isthmus progenitors in the mouse stomach corpus epithelium. The cycling isthmus progenitors were isolated based on mVenus expression in FUCCI mouse and used for bulk RNA-seq data generation. The corpus epithelium was stained with E-cadherin and E-cadherin+ cells were also sorted and used for the control.

2019-08-14 | E-MTAB-6850 | biostudies-arrayexpress

Oncofetal protein IGF2BP1 regulates IQGAP3 expression to maintain stem cell potential in cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-16 | GSE196406 | GEO