Targeting AGTR1/NF-κB /CXCR4 axis by miR-155 attenuates oncogenesis in Glioblastoma
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ABSTRACT:
PROVIDER: PRJNA576925 | ENA |
REPOSITORIES: ENA
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Project description:MiR-155 show conserved binding on the 3’UTR of AGTR1, subsequently confirmed by AGTR1-3’UTR-luciferase reporter assay. To determine the pathways regulated by miR-155, we overexpressed miR-155 in SNB19 glioblastoma cells using pLemiR lentiviral constructs. pLemiR vector, with turbo RFP (Open Biosystems) was used as control. Furthermore, stable miR-155 overexpressing GBM cells show a decrease in AGTR1-mediated cell proliferation, invasion, foci formation, anchorage-independent growth, Epithelial to Mesenchymal Transition and stemness.
2020-11-01 | GSE138737 | GEO
Project description:Glioblastoma (GBM) represents the most aggressive malignancy of the central nervous system. Increased expression of Angiotensin II Receptor Type 1 (AGTR1) has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3'untranslated region (3'UTR) of AGTR1 for putative miRNA binding by using prediction algorithms. Interestingly, miR-155 showed conserved binding on the 3'UTR of AGTR1, subsequently confirmed by luciferase reporter assay. Furthermore, miR-155 overexpressing GBM cells show decrease in AGTR1 expression accompanied with reduced cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show negligible tumor growth. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 as well as AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated angiogenesis, epithelial-to-mesenchymal transition, stemness, and MAPK signaling. Similar effects were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex in multiple cell-based assays. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects in GBM. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies.
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Project description:The goal of this study was to identify signalling molecules downstream of CXCR4 in breast cancer cells. For this purpose, we sorted CXCR4-positive and CXCR4-negative cells from MDA-MB-231 breast cancer cell line by flow cytometry and performed microarrays analysis. Three sets of samples, each in quadruplicate, were analyzed. These include CXCR4-positive subpopulation, CXCR4-positive subpopulation treated with SDF-1 (ligand for CXCR4, also called CXCL12) for one hour and CXCR4-negative subpopulation.
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Project description:BRCA1, a well-known breast and ovarian cancer susceptibility gene with multiple interacting partners, is predicted to have diverse biological functions. However, to date its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate risk variant, and found that it does not impair DNA damage repair but abrogates the repression of miR-155, a bona fide oncomir. We further show that in the absence of functional BRCA1, miR-155 is up-regulated in BRCA1-deficient mouse mammary epithelial cells, human and mouse BRCA1-deficienct breast tumor cell lines as well as tumors. Mechanistically, we found that BRCA1 represses miR-155 expression via its association with HDAC2, which deacetylates H2A and H3 on the miR-155 promoter. Finally, we show that over-expression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Taken together, our findings demonstrate a new mode of tumor suppression by BRCA1 and reveal miR-155 as a potential therapeutic target for BRCA1-deficient tumors. This SuperSeries is composed of the following subset Series: GSE31611: Expression data from embryoid body with BRCA1 mutation [mRNA] GSE31636: Expression data from embryoid body with BRCA1 mutation [miRNA] Refer to individual Series
2011-12-31 | E-GEOD-31637 | biostudies-arrayexpress
Project description:BRCA1, a well-known breast and ovarian cancer susceptibility gene with multiple interacting partners, is predicted to have diverse biological functions. However, to date its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate risk variant, and found that it does not impair DNA damage repair but abrogates the repression of miR-155, a bona fide oncomir. We further show that in the absence of functional BRCA1, miR-155 is up-regulated in BRCA1-deficient mouse mammary epithelial cells, human and mouse BRCA1-deficienct breast tumor cell lines as well as tumors. Mechanistically, we found that BRCA1 represses miR-155 expression via its association with HDAC2, which deacetylates H2A and H3 on the miR-155 promoter. Finally, we show that over-expression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Taken together, our findings demonstrate a new mode of tumor suppression by BRCA1 and reveal miR-155 as a potential therapeutic target for BRCA1-deficient tumors. This SuperSeries is composed of the SubSeries listed below.
2011-12-31 | GSE31637 | GEO
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Project description:T-cell exhaustion (Tex) phenotype has limited the efficacy of single-agent immune checkpoint blockade (ICB) in cancer immunotherapy, underscoring the need to target upstream pathways. Clinical trials have indicated that CXCR4 antagonists enhance anti-cancer activity. However, the specific mechanisms through which CXCR4 contributes to immune cell phenotypes are not fully understood. By targeting CXCR4 using antagonists or transgenic mice (Cxcr4flox/flox LckCre), we effectively attenuated the Tex phenotype and enhanced the functional T-cell phenotype in vivo. Additionally, single-cell RNA/TCR-seq analyses demonstrated that CXCR4 inhibition promotes anti-PD-1 immunotherapy by reducing CD8+ Tex phenotype and enriching the abundance of TCR clonotypes in vivo. Mechanically, we found that CXCR4-blocking T cells mitigate Tex phenotype by regulating the JAK2-STAT3 pathway, reducing the interaction between p-STAT3 and TOX. Single-cell ATAC/RNA-seq validated that CXCR4 deficiency epigenetically orchestrates the transition from functional to exhausted phenotypes in CD8+ T cells. Altogether, we demonstrate a mechanism of targeting CXCR4 to orchestrate CD8+ Tex cells in cancers and provide a rationale for the combined CXCR4 antagonists and ICBs in clinical trials.
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