PTBP1调控的intersectin 1选择性剪接促进人脑胶质瘤进展,Cell Death & Disease

当前位置： X-MOL 学术 › Cell Death Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PTBP1调控的intersectin 1选择性剪接促进人脑胶质瘤进展
Cell Death & Disease ( IF 8.1 ) Pub Date : 2022-09-28 , DOI: 10.1038/s41419-022-05238-1
Chungen Lan _{1,

2,

3,

4,

5} , Huikun Zhang _{2,

3,

4,

5} , Kezhen Wang _{1,

3,

4,

5} , Xiaoli Liu _{2,

3,

4,

5} , Yawen Zhao _{2,

3,

4,

5} , Zhifang Guo _{2,

3,

4,

5} , Ning Zhang _{2,

3,

4,

5} , Yongxia Zhou _{2,

3,

4,

5} , Manzhi Gao _{2,

3,

4,

5} , Feng Gu _{1,

3,

4,

5} , Yongjie Ma _{2,

3,

4,

5}

Affiliation

Intersectin 1 (ITSN1) 包含两种亚型：ITSN1-S 和 ITSN1-L，它们受选择性剪接的高度调控。我们之前的结果表明，ITSN1 的两种亚型表现出相反的功能：ITSN1-S 促进胶质瘤的发展，而 ITSN1-L 在胶质瘤进展中发挥抑制作用。在这项研究中，我们使用大型神经胶质瘤队列进行的转录组分析表明，ITSN1-S/ITSN1-L 的比率与神经胶质瘤分级和不良预后呈正相关。我们将 RNA 结合蛋白聚嘧啶束结合蛋白 1 (PTBP1) 鉴定为ITSN1通过 RNA pull-down 测定和 RNA 免疫沉淀测定的 pre-mRNA 相互作用蛋白。PTBP1 的击倒降低了 ITSN1-S/ITSN1-L 的比率。Minigene 报告基因分析和突变分析进一步证实了 PTBP1 靶向 ITSN1 外显子 30 (TTGCACTTCAGTATTTT) 上的多聚嘧啶序列并促进了 ITSN1 外显子 30 的包含。随后，沉默 PTBP1 通过下调 ITSN1- S/ITSN1-L。综上所述，我们的研究提供了一种新机制，即 PTBP1 通过上调 ITSN1-S/ITSN1-L 的比例调节 ITSN1 的选择性剪接并促进神经胶质瘤增殖和运动，从而强调 PTBP1 可能是神经胶质瘤的一个有吸引力的治疗靶点.

"点击查看英文标题和摘要"

The alternative splicing of intersectin 1 regulated by PTBP1 promotes human glioma progression

Intersectin 1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which are highly regulated by alternative splicing. Our previous results showed that the two isoforms of ITSN1 displayed opposite functions: ITSN1-S promoted glioma development, while ITSN1-L exerted an inhibitory role in glioma progression. In this study, our transcriptome analysis using a large glioma cohort indicated that the ratio of ITSN1-S/ITSN1-L was positively correlated with glioma grading and poor prognosis. We identified the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as an ITSN1 pre-mRNA interaction protein through RNA pull-down assay and RNA immunoprecipitation assay. Knockdown of PTBP1 decreased the ratio of ITSN1-S/ITSN1-L. Minigene reporter assay and mutation analyses further confirmed PTBP1 targeted polypyrimidine sequences on ITSN1 exon 30 (TTGCACTTCAGTATTTT) and promoted the inclusion of ITSN1 exon 30. Subsequently, silencing PTBP1 inhibited glioma cell proliferation, migration, and invasion by down-regulating the ratio of ITSN1-S/ITSN1-L. Taken together, our study provides a novel mechanism that PTBP1 modulates the alternative splicing of ITSN1 and promotes glioma proliferation and motility by up-regulating the ratio of ITSN1-S/ITSN1-L, thereby highlighting that PTBP1 may be an attractive therapeutic target for gliomas.

更新日期：2022-09-29

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南