CircNUP98 Suppresses the Maturation of miR-519a-3p in Glioblastoma.

Jun Lu,Lin Jiang,Jianxin Jiang,Xiaolin Wang,Xiaoxing Liu,Gaojie Lou

doi:10.3389/fneur.2021.679745

Jun Lu, Lin Jiang + Show 4 more

Open Access

https://doi.org/10.3389/fneur.2021.679745

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Abstract

Circular RNA (circNUP98) has been reported to promote renal cancer; however, its role in other cancers is unknown. The function of circNUP98 in glioblastoma (GB) cancer was explored in this study. A total of 58 GB tissue samples were collected to study the expression of circNUP98 and miR-519a-3p [both the mature and pre-mature microRNA (miRNA)] by quantitative real-time PCR (RT-qPCR) and heatmap analysis. The subcellular location that expresses circNUP98 was analyzed by nuclear fractionation assay. RNA pull-down assay was performed to evaluate the interaction between circNUP98 and pre-mature miR-519a-3p. Overexpression assays were performed to investigate the role of circNUP98 in the regulation of both the mature and pre-mature miR-519a-3p. The role of circNUP98 and miR-519a-3p in GB cell proliferation was explored by 5-bromo-2-deoxyuridine (BrdU) assay and was assessed in mouse xenograft model. Heatmap analysis showed that circNUP98 and pre-mature miR-519a-3p were upregulated in GB, while mature miR-519a-3p was downregulated in GB. Across the cancer tissues, circNUP98 was inversely correlated with mature miR-519a-3p, but positively correlated with pre-mature miR-519a-3p. In GB cells, circNUP98 was localized to both the nucleus and cytoplasm and it interacted with pre-mature miR-519a-3p. In GB cells, circNUP98 increased the expression levels of pre-mature miR-519a-3p and decreased the expression levels of mature miR-519a-3p. BrdU and cholecystokinin octapeptide (CCK-8) assays illustrated that overexpression of circNUP98 reduced the inhibitory effects of miR-519a-3p on cell proliferation. CircNUP98 contributed to larger tumors, which resulted in significantly reduced mice survival. CircNUP98 suppresses the maturation of miR-519a-3p to promote GB cell proliferation.

Highlights

Glioblastoma (GB), commonly known as GB multiforme (GBM), is a highly aggressive malignancy that originates from either spinal cord or the brain [1]
Upregulation of circNUP98 and the suppressed maturation of miR-519a-3p may be related to GBM
Nuclear fractionation assay showed that circNUP98 localized into both the nucleus and cytoplasm and pre-mature miR-519a3p mainly localized into the nucleus, while mature miR-519a-3p mainly localized into the cytoplasm (Figure 2A)

Summary

Introduction

Glioblastoma (GB), commonly known as GB multiforme (GBM), is a highly aggressive malignancy that originates from either spinal cord or the brain [1]. People in any age groups can develop GBM, this malignancy mainly affects patients older than 65 years old [2, 3]. Surgical resection followed by radiation therapy or oral chemotherapy is usually applied in the treatment of GBM [5]. Even with timely and effective treatment, only 25 and 5% of patients can survive for more than 1 and 5 years, respectively, and the average survival time is only 12–18 months [6, 7]. With the growth of aging population, incidence of GBM is increasing, leading to a serious

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