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Effect of TENT2 knockdown on miRNA profiling in human lung endothelial cells

ABSTRACT: MiRNAs are generated through a finely tuned multi-step process that includes precise cropping and cleavage of their precursors. The mature miRNA is then loaded onto an argonaute (Ago) protein to form an RNA-induced silencing complex (RISC) and target messenger RNAs. Most of the mechanisms of miRNA regulation target one of the steps in the biogenesis. However, through analysis of miR-1 precursors, we demonstrate that VEGF stimulation induces degradation (decay) of mature miR-1-3p without affecting its precursors. This analysis also identified a specific miRNA 3’-adenylation pathway that targets the guide strand after RISC loading. VEGF induced the expression of terminal nucleotidyl transferase 2 (TENT2, also known as PAPD4 or GLD2), one of the main enzymes that mediate 3’ miRNA adenylation, and knockdown of TENT2 inhibited miR-1 decay. We examined the biological significance of TENT2 in VEGF-mediated EC proliferation, its pathogenic role in murine NSCLC models, and its expression and clinical significance in human NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE339083 | GEO | 2026/07/22

REPOSITORIES: GEO

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Project description:mRNA and microRNA expression was examined in global cellular fractions and in RNA-induced silencing complex (RISC)-immunoprecipitated cell fractions in cultured primary human astrocytes (ScienCell) and in cultured human U-87 MG astrocytoma cells (ATCC). ABSTRACT: Background: GW/P bodies are cytoplasmic ribonucleoprotein-rich foci that are involved in microRNA (miRNA)-mediated messenger RNA (mRNA) silencing and degradation. These mRNA regulatory functions within GW/P bodies are mediated by GW182 and its binding partner hAgo2 when bound to miRNA within the RNA-induced silencing complex (RISC). Although miRNAs and mRNAs are known to be localized to RISC in a variety of cells, to date no published study has examined the profile of specific miRNA and mRNA targeted to the RISC. Methodology/Principle Findings: In this study, RISC mRNA and miRNA components were profiled by microarray analysis of human U-87 astrocytoma cells and primary human astrocytes with total RNA extracted from the RISC as well as the global cellular fractions. The novel findings of this study were fourfold: (1) miRNAs are highly enriched in primary astrocyte RISC compared to U-87 astrocytoma RISC, (2) astrocytoma cells and primary astrocytes each contain unique RISC miRNA profiles as compared to their respective cellular miRNA profiles, (3) miR-195, 10b, 29b, 19b, 34a and 455-3p were upregulated and miR-181b was downregulated in U-87 astrocytoma RISC as compared to primary astrocyte RISC, and (4) RISC contain mostly downregulated mRNAs in primary astrocytes and U-87 astrocytoma cells. Conclusions/Significance: We show that in U-87 astrocytoma cells, miR-34a and miR-195 were upregulated in RISC suggesting an oncogenic role for these miRNAs. Three miR34a-targeted mRNAs and two miR-195-targeted mRNAs were downregulated. One miR-195-targeted mRNA was upregulated. Biological pathway analysis of RISC mRNA components suggests that the RISC plays a pivotal role in cancer, inflammatory disease, immunological disease, the cell cycle, cellular movement and numerous cell signaling pathways. This study points to the importance of the RISC and ultimately GW/P body composition and function and in miRNA and mRNA deregulation in astrocytoma cells and possibly for other brain tumors.

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Effect of TENT2 knockdown on miRNA profiling in human lung endothelial cells

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