LncRNA SPRY4‐IT1 facilitates cell proliferation and angiogenesis of glioma via the miR‐101‐3p/EZH2/VEGFA signaling axis

Abstract

Background SPRY4‐IT1 (SPRY4 intronic transcript 1) is a long non‐coding RNA (lncRNA) that has been identified as a novel oncogene in various cancers, including glioma. However, its function and underlying mechanism in glioma remain largely unclear. Here, we investigated the role of SPRY4‐IT1 in the development of glioma and its underlying mechanism. Methods Bioinformatics analysis and RT‐qPCR assay were used to examine the expression of SPRY4‐IT1 in glioma tissues. The CCK‐8, EdU, and Xenograft tumor assays wereperformed to assess the proliferation effect of glioma cells. The tube forming assay and Chick Embryo Chorioallantoic Membrane (CAM) assay were conducted to detect the angiogenesis effect of HUVECs. RNA‐sequencing, western blotting, RT‐qPCR, ELISA, and IHC assays were employed to verify the regulatory mechanism of the SPRY4‐IT1/ miR‐101‐3p/EZH2/VEGFA axis. Results Analysis of the TCGA dataset and data from our own cohort demonstrated that SPRY4‐IT1 was overexpressed in patients with glioma, and high SPRY4‐IT1 expression correlated with poor prognosis. In vitro and in vivo experiments showed that SPRY4‐IT1 promoted the proliferation of glioma cells. RNA sequencing and Gene Ontology (GO) enrichment analysis indicated significant enrichment of angiogenesis. HUVEC tube forming assay and CAM assay confirmed that SPRY4‐IT1 could induce angiogenesis of glioma cells in vitro and in vivo. Mechanistically, SPRY4‐IT1 upregulated EZH2 expression by sponging miR‐101‐3p to induce VEGFA expression in glioma cells. Moreover, SPRY4‐IT1 activated the VEGFR2/AKT/ERK1/2 pathway in HUVECs mediated by glioma cells. Rescue experiments further confirmed that SPRY4‐IT1 promoted glioma cell proliferation and angiogenesis via the miR‐101‐3p/EZH2/VEGFA signaling axis. Conclusions Our findings provide compelling evidence showing that SPRY4‐IT1 upregulated EZH2 to induce VEGFA by sponging miR‐101‐3p, thereby achieving cell proliferation and angiogenesis in glioma. Therefore, targeting SPRY4‐IT1/miR‐101‐3p/EZH2/VEGFA axis may improve the outcomes of patients with glioma.

EZH2: A Critical Competing Endogenous RNA in Cancer Research - A Scoping Review

“…SPRY4-IT1 has been reported in three of the included studies (22)(23)(24) and in all of them it competes with EZH2 for binding to the miR-101-3p. lncRNA SPRY4-IT1 is a critical RNA in cancer.…”

“…SPRY4-IT1 -miR-101-3p -EZH2 ceRNA axis has been reported in glioma, bladder cancer, and cholangiocarcinoma (22)(23)(24). SPRY4-IT1 has been identified as an oncogene in bladder cancer.…”

“…Knockdown of SPRY4-IT1 in cholangiocarcinoma, promotes apoptosis and decreases proliferation, invasion and migration (24). In these cancers, SPRY4-IT1 regulates the expression of EZH2 via sponging miR-101-3p (22)(23)(24).…”

“…For instance, it is overexpressed in prostate cancer and through the PI3K/AKT signaling pathway, promotes proliferation of cancerous cells (97). In breast cancer, upregulation of SPRY4-IT1 induces NF-κB signaling pathway by which promotes cell proliferation and inhibits apoptosis (98).…”

Nanotherapeutic approaches for delivery of long non-coding RNAs: an updated review with emphasis on cancer

“…50 Sponging miR-101-3p, SPRY4-IT1 upregulated EZH2 to induce VEGFA and angiogenesis in gliomas. 51 Additionally, the lincRNA H19 promotes Wnt5a expression and angiogenesis by sponging miR-342 in malignant gliomas. 52 Angiogenesis in TNBC may be mediated by exosomal MALAT1 via miR-140-5p-JAG1/VEGFA signaling.…”