DNMT1阻断SOX21抑制的CKS2转录以促进胃癌进展。

DNMT1 blocks SOX21-repressed CKS2 transcription to promote gastric cancer progression.

作者信息

Wei Jie, Xue Song, Du Xinglong, Dai Yuanfei, Ji Yuting, He Guangsi

机构信息

Department of Oncology, The Affiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou), No. 12, Zhongyou Lane, Gulou Street, Chuzhou, Anhui, 239001, P.R. China.

出版信息

BMC Cancer. 2025 Jul 17;25(1):1182. doi: 10.1186/s12885-025-14577-z.

DOI:10.1186/s12885-025-14577-z

PMID:40676553

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12273269/

Abstract

BACKGROUND

The dysregulation of SOXs is related to tumor invasion, metastasis, proliferation, apoptosis, and epithelial-mesenchymal transition. This research sought to investigate the function and mechanisms of SOX21 in gastric cancer (GC).

METHODS

Multiple databases were included to determine the hub transcription factors in GC. In addition, RT-qPCR and Western blot were used to validate gene expression in tissues from GC patients. CCK-8, EdU, colony formation, wound healing, Transwell assays, and a xenograft tumor model were used to determine the function of SOX21 in GC. The targets of SOX21 were predicted and verified using ChIP, dual-luciferase reporter, and functional assays. SOX21 DNA methylation in GC cells was determined by qMSP. Rescue experiments were carried out in GC cells with DNMT1 silencing alone or in combination with SOX21 silencing.

RESULTS

SOX21 was downregulated in GC tissues and cells. Ectopic expression of SOX21 inhibited cell growth, invasion, and migration, and induced apoptosis of GC cells. CKS2 was a target of SOX21, and overexpression of CKS2 promoted cell viability and mobility in GC cells overexpressing SOX21. The downregulation of SOX21 was related to the DNA hypermethylation catalyzed by DNMT1. The silencing of SOX21, by contrast, overturned the anti-tumor effects of sh-DNMT1 in vitro and in vivo.

CONCLUSION

Our data showed that DNMT1 overexpression upregulated CKS2 expression via hypermethylation of SOX21, thus promoting GC cell proliferation and growth, indicating that the DNMT1/SOX21/CKS2 axis could be a target for GC treatment.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1186/s12885-025-14577-z.

摘要

背景

SOX 蛋白家族的失调与肿瘤侵袭、转移、增殖、凋亡及上皮-间质转化有关。本研究旨在探究 SOX21 在胃癌（GC）中的功能及机制。

方法

纳入多个数据库以确定 GC 中的关键转录因子。此外，采用 RT-qPCR 和蛋白质免疫印迹法验证 GC 患者组织中的基因表达。使用 CCK-8、EdU、集落形成、伤口愈合、Transwell 实验及异种移植肿瘤模型来确定 SOX21 在 GC 中的功能。通过染色质免疫沉淀（ChIP）、双荧光素酶报告基因及功能实验预测并验证 SOX21 的靶标。采用定量甲基化特异性 PCR（qMSP）检测 GC 细胞中 SOX21 的 DNA 甲基化情况。在单独沉默 DNMT1 或联合沉默 SOX21 的 GC 细胞中进行挽救实验。

结果

SOX21 在 GC 组织和细胞中表达下调。SOX21 的异位表达抑制 GC 细胞的生长、侵袭和迁移，并诱导其凋亡。CKS2 是 SOX21 的一个靶标，CKS2 的过表达促进了过表达 SOX21 的 GC 细胞的活力和迁移能力。SOX21 的下调与 DNMT1 催化的 DNA 高甲基化有关。相比之下，SOX21 的沉默在体外和体内均逆转了 sh-DNMT1 的抗肿瘤作用。