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SNORD99 通过 2'-O-甲基化修饰抑制 GSDMD 介导热激原性细胞死亡促进子宫内膜癌的发展。

SNORD99 promotes endometrial cancer development by inhibiting GSDMD-mediated pyroptosis through 2'-O-methylation modification.

机构信息

Department of Obstetrics and Gynecology, Guangzhou Key Laboratory of Targeted Therapy for Gynecologic Oncology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Department of Gynecologic Oncology Research Office, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

出版信息

J Cell Mol Med. 2024 Jun;28(12):e18500. doi: 10.1111/jcmm.18500.

DOI:10.1111/jcmm.18500

PMID:39450788

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11193114/

Abstract

Eukaryotic cells possess multiple mechanisms of self-destruction, including pyroptosis and necroptosis. Pyroptosis is a type of programmed cell death characterized by cellular rupture and linked to inflammation. SnoRNA, a small non-coding RNA in the nucleolus, can dysregulate specific RNAs through 2'-O-methylation, contributing to tumorigenesis. Our StarBase and qRT-PCR analysis revealed SNORD99 upregulation in endometrial cancer (EC) tissue compared to normal tissue, suggesting its role in pathogenesis. SNORD99 overexpression enhanced migration and proliferation of EC cells, while ASO-mediated suppression reduced malignant cell spread and division. RNA-seq and base-comparing analysis identified GSDMD's differential expression upon SNORD99 overexpression, forming the SNORD99-FBL RNP complex. RTL-P experiments showed SNORD99 increased GSDMD's 2'-O-methylation. SNORD99 reduced GSDMD, caspase-1, and NLRP3 protein levels, implicating its role in pyroptosis. Optical and electron microscopy confirmed enhanced pyroptosis features. In summary, SNORD99 modifies GSDMD via 2'-O-methylation, suppressing pyroptosis and promoting EC progression. Developing pyroptosis-inducing drugs may offer new cancer treatment avenues.

摘要

真核细胞拥有多种自我毁灭的机制，包括细胞焦亡和坏死性凋亡。细胞焦亡是一种程序性细胞死亡形式，其特征是细胞破裂，并与炎症有关。核仁中的小核仁 RNA（snoRNA）可以通过 2'-O-甲基化来调节特定的 RNA，从而促进肿瘤的发生。我们的 StarBase 和 qRT-PCR 分析显示，与正常组织相比，子宫内膜癌（EC）组织中 SNORD99 的表达上调，表明其在发病机制中的作用。SNORD99 的过表达增强了 EC 细胞的迁移和增殖，而 ASO 介导的抑制减少了恶性细胞的扩散和分裂。RNA-seq 和碱基比较分析发现，SNORD99 过表达时 GSDMD 的表达存在差异，形成 SNORD99-FBL RNP 复合物。RTL-P 实验表明，SNORD99 增加了 GSDMD 的 2'-O-甲基化。SNORD99 降低了 GSDMD、半胱天冬酶-1 和 NLRP3 蛋白水平，表明其在细胞焦亡中发挥作用。光学和电子显微镜证实了增强的细胞焦亡特征。总之，SNORD99 通过 2'-O-甲基化修饰 GSDMD，抑制细胞焦亡并促进 EC 的进展。开发细胞焦亡诱导药物可能为癌症治疗提供新途径。