Institute of Neuroscience, Kunming Medical University, Kunming, China.
Department of Neurosurgery, 1st Affiliated Hospital of Kunming Medical University, Kunming, China.
Cell Death Dis. 2021 Jun 5;12(6):580. doi: 10.1038/s41419-021-03861-y.
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.
长链非编码 RNA（lncRNAs）及其与其他 RNA 的相互作用与肿瘤的发生和发展密切相关，但它们在侵袭性垂体腺瘤（IPA）中的作用在很大程度上仍不清楚。在我们的研究中，通过全转录组 RNA 测序（RNA-Seq）鉴定 LINC00473 为 IPA 中上调最明显的 lncRNA。此外，通过构建竞争性内源性 RNA（ceRNA）调控网络，获得了其相关信号通路 LINC00473/miR-502-3p/KMT5A。通过 qRT-PCR 验证了它们在 IPA 和非侵袭性垂体腺瘤（NIPA）组织中的表达。然后，通过基因过表达或沉默技术结合 CCK-8 测定、EdU 染色、流式细胞术测定和双荧光素酶报告基因测定，在体外的 PA 细胞系 AtT-20 和 GT1-1 以及体内的异种移植模型中证实了 LINC00473 及其 ceRNA 网络对 PA 细胞增殖的影响和机制。LINC00473 在 IPA 中过度表达，并能促进 PA 细胞增殖。从机制上讲，LINC00473 的过表达通过 ceRNA 机制限制了 miR-502-3p，上调了 KMT5A 的表达，并促进了细胞周期蛋白 D1 和 CDK2 的表达，有利于细胞周期过程，从而促进了 PA 细胞的增殖，涉及 IPA 的进展。
