Singh, Anukriti ; Srivastava, Nidhi ; Yadav, Anjali ; Ateeq, Bushra (2020) Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma Neoplasia, 22 (10). pp. 497-510. ISSN 14765586
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Official URL: http://doi.org/10.1016/j.neo.2020.08.002
Related URL: http://dx.doi.org/10.1016/j.neo.2020.08.002
Abstract
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.
Item Type: | Article |
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Source: | Copyright of this article belongs to Elsevier Inc. |
Keywords: | AGTR1; CXCR4; Glioblastoma; NF-κB signaling; miR-155 |
ID Code: | 127223 |
Deposited On: | 13 Oct 2022 09:16 |
Last Modified: | 13 Oct 2022 09:16 |
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