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CircPVT1 attenuates negative regulation of NRAS by let-7 and drives cancer cells towards oncogenicity.

ABSTRACT: Circular RNAs have emerged as functional regulatory molecules whose aberrant expression has been linked to diverse pathophysiological processes. Here, we report that circPVT1 interferes with let-7 binding to NRAS, confirming this axis as one route by which circPVT1 can instigate an oncogenic program in A549 lung cancer cells and HCT116 colorectal cancer cells. CircPVT1 knockdown significantly reduced NRAS levels and attenuated cancer hallmark phenotypes such as proliferation, migration, resistance to apoptosis, cytoskeletal disorganization, and epithelial-mesenchymal transition. The effects of circPVT1 knockdown were at least partially rescued by blocking binding of let-7 to NRAS 3'UTR with a target protector, suggesting that a circPVT1/let-7/NRAS axis exists and acts in cells to reverse NRAS downregulation and favor oncogenicity. While the phenotypic effects of circPVT1 knockdown may be attributable to the global action of circPVT1, the target protection assays resolved the relative contribution of the circPVT1/let-7/NRAS axis specifically.

SUBMITTER: Danac JMC

PROVIDER: S-EPMC8079436 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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CircPVT1 attenuates negative regulation of NRAS by let-7 and drives cancer cells towards oncogenicity.

Danac Joshua Miguel C JMC Garcia Reynaldo L RL

Scientific reports 20210427 1

Circular RNAs have emerged as functional regulatory molecules whose aberrant expression has been linked to diverse pathophysiological processes. Here, we report that circPVT1 interferes with let-7 binding to NRAS, confirming this axis as one route by which circPVT1 can instigate an oncogenic program in A549 lung cancer cells and HCT116 colorectal cancer cells. CircPVT1 knockdown significantly reduced NRAS levels and attenuated cancer hallmark phenotypes such as proliferation, migration, resistan ...[more]

PMID: 33907219

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Project description:BackgroundAngiogenesis, the formation of new blood vessels from pre-existing vasculature is essential in a number of physiological processes such as embryonic development, wound healing as well as pathological conditions like, tumor growth and metastasis. Hyaluronic acid (HA), a high molecular weight polysaccharide, major component of extracellular matrix is known to associate with malignant phenotypes in melanomas and various other carcinomas. Hyaluronic acid binding protein 1 (HABP1) has been previously reported to trigger enhanced cellular proliferation in human liver cancer cells upon its over-expression. In the present study, we have identified the HA mediated cellular behaviour of liver endothelial cells during angiogenesis.MethodsEndothelial cells have been isolated from perfused liver of mice. Cell proliferation was studied using microwell plates with tetrazole dye. Cell migration was evaluated by measuring endothelial monolayer wound repair as well as through transwell migration assay. Alterations in proteins and mRNA expression were estimated by immunobloting and quantitative real time PCR using Applied Biosystems. The paraformaldehyde fixed endothelial cells were used for immuno- florescence staining and F-actin detection with conjugated antibodies. The images were captured by using Olympus florescence microscope (IX71).ResultsWe observed that administration of HA enhanced cell proliferation, adhesion, tubular sprout formation as well as migration of liver endothelial cells (ECs). The effect of HA in the rearrangement of the actins confirmed HA -mediated cytoskeleton re-organization and cell migration. Further, we confirmed enhanced expression of angiogenic factors like VEGF-A and VEGFR1 in endothelial cells upon HA treatment. HA supplementation led to elevated expression of HABP1 in murine endothelial cells. It was interesting to note that, although protein levels of β- catenin remained unaltered, but translocation of this protein from membrane to nucleus was observed upon HA treatment, suggesting its role not only in vessel formation but also its involvement in angiogenesis signalling.ConclusionsThe elucidation of molecular mechanism (s) responsible for HA mediated regulation of endothelial cells and angiogenesis contributes not only to our understanding the mechanism of disease progression but also offer new avenues for therapeutic intervention.

Dataset Information

CircPVT1 attenuates negative regulation of NRAS by let-7 and drives cancer cells towards oncogenicity.

Publications

CircPVT1 attenuates negative regulation of NRAS by let-7 and drives cancer cells towards oncogenicity.

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