Long Noncoding RNA TRPM2-AS Promotes the Growth, Migration, and Invasion of Retinoblastoma via miR-497/WEE1 Axis.

Aipeng Li,Lin Li,Ting Zhang,Jingpu Yang,Miyang Li

doi:10.3389/fphar.2021.592822

Aipeng Li, Lin Li + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2021.592822

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Abstract

Long noncoding RNAs (lncRNAs) exhibit vital roles in many types of cancer, including retinoblastoma (RB), the most common primary intraocular malignancy tumor of infancy. A novel lncRNA TRPM2-AS has been demonstrated to be related to multiple cancers; however, its role in RB remains unclear. Here, we aimed to investigate the function of TRPM2-AS in RB. In this study, TRPM2-AS expression in 35 human RB tissues and RB cell lines was detected by real-time PCR. And, the relationship between its expression and clinicopathological characteristics of RB patients was analyzed. RB cells’ proliferation, migration, invasion, apoptosis, and cell cycle were explored after silencing TRPM2-AS. The mechanism of TRPM2-AS in RB was focused on miR-497/WEE1 axis. Additionally, the role and mechanism of TRPM2-AS were confirmed in a xenograft mouse model. We found TRPM2-AS expression was enhanced in RB tissues and cells. And, higher TRPM2-AS expression was related to advanced clinical stage and optic nerve invasion in patients. Downregulation of TRPM2-AS significantly inhibited proliferation, migration, and invasion, elevated apoptosis, attenuated G2/M phase arrest in RB cells, and suppressed tumor growth in vivo. TRPM2-AS acted as a ceRNA for miR-497 to positively regulate WEE1 expression. miR-497 inhibitor or WEE1 overexpression dramatically reversed the effects of TRPM2-AS downregulating on the malignant phenotypes of RB cells. Therefore, TRPM2-AS is an oncogenic lncRNA in RB, and it functions largely through the miR-497/WEE1 pathway. Despite the limited sample size, this study indicates that TRPM2-AS may be a candidate target in RB therapies.

Highlights

Retinoblastoma (RB) is the most frequently occurring primary intraocular malignancy tumor of infancy all over the world
The results indicated that the enrichment of TRPM2-AS was higher in Weri-Rb1 cells transfected with biotin-labeled (Bio)-miR-497 than cells transfected with BioNC (Figure 3D). miR-497 expression assay in human tissues revealed that the relative expression of miR-497 was lower in human RB tissues than that in normal retinal tissues (Figure 3E)
We demonstrated that the increase of TRPM2-AS in RB could promote cell’s proliferative, migrative, and invasive abilities and elevate G2/ M cell cycle arrest, yet suppress cell apoptosis

Summary

Introduction

Retinoblastoma (RB) is the most frequently occurring primary intraocular malignancy tumor of infancy all over the world. It accounts for 6% of cancers in children and with an incidence of one in 15,000 to 20,000 live births worldwide (Dimaras et al, 2015; Fabian et al, 2018). Treatment strategies for RB contain surgical enucleation, intravenous chemoreduction and intraarterial chemotherapy, and external beam radiotherapy (Mendoza and Grossniklaus, 2016). With these treatments, the 5-year survival rate of RB patients has greatly improved. Antisense noncoding RNA in the INK4 locus (ANRIL) was elevated and acted as onco-lncRNA in RB (Wang et al, 2019b; Yu et al, 2019)

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