LncRNA LINC00473 is involved in the progression of invasive pituitary adenoma by upregulating KMT5A via ceRNA-mediated miR-502-3p evasion

Junjun Li,Jiazhi Guo,Wei Wang,Yisheng Qiao,Hao Song,Di Lu,Liyan Li,Xingli Deng,Chao Zhang,Yuan Qian

doi:10.1038/s41419-021-03861-y

Abstract

Long noncoding RNAs (lncRNAs) and their crosstalks with other RNAs have been revealed to be closely related to tumorigenesis and development, but their role in invasive pituitary adenoma (IPA) remains largely unclear. In our study, LINC00473 was identified as the most upregulated lncRNA in IPA by whole transcriptome RNA sequencing (RNA-Seq). Further, its related signaling pathway LINC00473/miR-502-3p/KMT5A was obtained by constructing a competing endogenous RNA (ceRNA) regulatory network. Their expression in IPA and non-invasive pituitary adenoma (NIPA) tissues was verified by qRT-PCR. Then the effects and mechanisms of LINC00473 and its ceRNA network on the proliferation of pituitary adenoma (PA) cells were confirmed by gene overexpression or silencing techniques combined with CCK-8 assay, EdU staining, flow cytometry assay, and double luciferase reporter gene assay in PA cell lines AtT-20 and GT1-1 in vitro and in a xenograft model in vivo. LINC00473 is overexpressed in IPA and can promote PA cells proliferation. Mechanistically, overexpression of LINC00473 restricts miR-502-3p through the ceRNA mechanism, upregulates KMT5A expression, and promotes the expression of cyclin D1 and CDK2, which is conducive to the cell cycle process, thereby promoting the proliferation of PA cells, involving IPA progression.

Highlights

pituitary adenoma (PA) is one of the most common primary brain tumor and account for ~16% of intracranial tumors[1]
Analysis of Long noncoding RNAs (lncRNAs) characterization revealed that the average length of lncRNAs was 1346nt, which was shorter than the length of mRNA (2206nt) (Fig. 1c)
Multiple studies have found that the noncoding RNAs (ncRNAs) are frequently dysregulated in tumors and their complex interactions with mRNA may be involved in tumor occurrence and development[7,8]

Summary

Introduction

PA is one of the most common primary brain tumor and account for ~16% of intracranial tumors[1]. Investigations on the molecular pathogenesis of IPA are LncRNAs are RNAs with a transcript length of > 200 nucleotides[5], and microRNAs (miRNAs) are singlestranded RNAs with a length of about 22 nucleotides[6] Both of them belong to noncoding RNAs (ncRNAs) and do not contain protein-coding sequences, but they play important regulatory roles in various cellular processes, including transcriptional regulation, RNA modification, chromosome remodeling, protein transport, etc[5,6]. Increasing evidence has shown that their mutation and dysregulation are closely related to tumor progression, recurrence, and resistance to treatment[7,8,9] It has been confirmed in many cancers that lncRNAs play important roles as ceRNAs competitively binding to shared miRNAs10.

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Results

Conclusion