SOX4在幽门螺杆菌介导的胃黏膜上皮异型增生中的作用及机制研究

doi:10.3969/j.issn.1006-7795.2025.04.010

首都医科大学学报 ›› 2025, Vol. 46 ›› Issue (4): 644-653.doi: 10.3969/j.issn.1006-7795.2025.04.010

SOX4在幽门螺杆菌介导的胃黏膜上皮异型增生中的作用及机制研究

杜风¹,徐瑞²,赵梦冉¹,冀旭¹,苏珈仪¹,邱煜婷¹,朱圣韬¹,吴静¹,李鹏^1*, 张澍田¹

1.首都医科大学附属北京友谊医院消化科消化健康全国重点实验室国家消化系统疾病临床医学研究中心胃肠早癌药械研发北京市重点实验室，北京 100050；2.首都医科大学附属北京友谊医院病理科，北京 100050

收稿日期:2025-04-01 出版日期:2025-08-21 发布日期:2025-08-29
通讯作者: 李鹏 E-mail:lipeng@ccmu.edu.cn
基金资助:
国家自然科学基金面上项目（82270591，82203700，82473041）,国家重点研发计划项目（2023YFC2507400，2024ZD0520904）,北京市医院管理中心“登峰”人才计划项目（DFL20220101），北京友谊医院种子计划项目(YYZZ202216),青才计划项目（YYQCJH20223）。

The role and mechanism of SOX4 in Helicobacter pylori-mediated gastric mucosal epithelial dysplasia

Du Feng¹, Xu Rui², Zhao Mengran¹, Ji Xu¹, Su Jiayi¹, Qiu Yuting¹, Zhu Shengtao¹, Wu Jing¹, Li Peng^1*, Zhang Shutian¹

1. Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University; State Key Laboratory of Digestive Health; National Clinical Research Center for Digestive Diseases; Beijing Key Laboratory of Early Gastrointestinal Cancer Medicine and Medical Devices, Beijing 100050，China；2.Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050，China

Received:2025-04-01 Online:2025-08-21 Published:2025-08-29
Supported by:
This study was supported by National Natural Science Foundation of China（82270591，82203700，82473041），National Key Research and Development Program of China（2023YFC2507400，2024ZD0520904），Beijing Hospitals Authority “Dengfeng” Talent Training Plan （DFL20220101），Seed Program of Beijing Friendship Hospital(YYZZ202216)，Youth Talent Program（YYQCJH20223）.

摘要/Abstract

摘要： 目的探讨SOX4在幽门螺杆菌（Helicobacter pylori，H.pylori）介导的胃黏膜上皮细胞异型增生中的作用及分子机制。方法反转录聚合酶链反应（reverse transcription-polymerase chain reaction，RT-PCR）、蛋白免疫印迹和免疫组织化学染色分析SOX4在胃组织和细胞中的表达，CCK-8和平板克隆实验明确SOX4对胃上皮细胞增殖和克隆形成能力的影响，PCR array表达芯片筛选SOX4介导H.pylori感染胃上皮细胞后异型增生的下游靶基因；萤光素酶报告实验、启动子截短实验和染色质免疫沉淀技术阐明SOX4对靶基因MLH3的转录调控作用和结合位点。结果 SOX4在H.pylori感染的胃组织中表达显著升高（P<0.05）；SOX4过表达显著增强胃正常上皮细胞的增殖和克隆形成能力（P<0.05）；SOX4升高导致H.pylori感染胃上皮细胞后MLH3等DNA损伤修复相关分子表达失调（|logFC|>1，P<0.05）；H.pylori通过SOX4促进胃上皮细胞MLH3表达；SOX4可直接结合MLH3启动子第5位点转录激活其表达，SOX4和MLH3表达升高与胃癌患者不良预后相关。结论 SOX4与H.pylori感染后胃上皮细胞异型增生密切相关，SOX4升高通过转录激活MLH3调控胃上皮细胞增殖和克隆形成失衡促进H.pylori相关异型增生。

关键词: 胃癌, 胃癌前病变, 幽门螺杆菌, SOX4, MLH3, 转录调控

Abstract: Objective To investigate the role and molecular mechanism of SOX4 in Helicobacter pylori (H. pylori)-mediated gastric mucosal epithelial dysplasia.Methods The expression of SOX4 in gastric tissues and cells was analyzed with reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining. The effects of SOX4 on gastric epithelial cell proliferation and colony formation were determined with CCK-8 and colony formation assays. A PCR array was used to screen downstream target genes involved in H. pylori-induced dysplasia mediated by SOX4. The transcriptional regulation and binding sites of the target gene MLH3 by SOX4 were elucidated with luciferase reporter assay, promoter truncation assay, and chromatin immunoprecipitation (ChIP).Results SOX4 expression was significantly increased in H. pylori-infected gastric tissues (P<0.05). Overexpression of SOX4 markedly enhanced the proliferation and colony formation abilities of normal gastric epithelial cells (P<0.05). Elevated SOX4 led to the dysregulation of MLH3 and other DNA damage repair-related molecules after H. pylori infection in gastric epithelial cells (|logFC|>1, P<0.05). H. pylori promoted MLH3 expression in gastric epithelial cells through SOX4. SOX4 transcriptionally activated MLH3 expression by binding to the 5th site of the MLH3 promoter. The increased expression of SOX4 and MLH3 is associated with poor prognosis of gastric cancer patients.Conclusion SOX4 is closely associated with H. pylori-induced dysplasia in gastric epithelial cells. Upregulation of SOX4 promotes H. pylori-related dysplasia by transcriptionally activating MLH3, leading to the imbalance of proliferation and colony formation in gastric epithelial cells.

Key words: gastric cancer, precancerous gastric lesions, Helicobacter pylori, SOX4, MLH3, transcriptional regulation

中图分类号:

R735.2

杜风, 徐瑞, 赵梦冉, 冀旭, 苏珈仪, 邱煜婷, 朱圣韬, 吴静, 李鹏, 张澍田. SOX4在幽门螺杆菌介导的胃黏膜上皮异型增生中的作用及机制研究[J]. 首都医科大学学报, 2025, 46(4): 644-653.

Du Feng, Xu Rui, Zhao Mengran, Ji Xu, Su Jiayi, Qiu Yuting, Zhu Shengtao, Wu Jing, Li Peng, Zhang Shutian. The role and mechanism of SOX4 in Helicobacter pylori-mediated gastric mucosal epithelial dysplasia[J]. Journal of Capital Medical University, 2025, 46(4): 644-653.

参考文献

［1］Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries［J］. CA Cancer J Clin, 2024, 74(3): 229－263.
［2］Lee Y C, Chiang T H, Chiu H M, et al. Screening for Helicobacter pylori to prevent gastric cancer: a pragmatic randomized clinical trial［J］. JAMA, 2024, 332(19): 1642－1651.
［3］Qiu M Z, Oh D Y, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma:RATIONALE-305 randomised,double blind,phase 3 trial［J］. BMJ, 2024, 385: e078876.
［4］Chen Y C, Malfertheiner P, Yu H T, et al. Global prevalence of Helicobacter pylori infection and incidence of gastric cancer between 1980 and 2022［J］. Gastroenterology, 2024, 166(4): 605－619.
［5］Wizenty J, Sigal M. Helicobacter pylori, microbiota and gastric cancer-principles of microorganism-driven carcinogenesis［J］. Nat Rev Gastroenterol Hepatol, 2025: 22(5): 296－313.
［6］Gao Y, Tan D S, Girbig M, et al. The emergence of Sox and POU transcription factors predates the origins of animal stem cells［J］. Nat Commun, 2024, 15(1): 9868.
［7］Angelozzi M, Karvande A, Lefebvre V. SOXC are critical regulators of adult bone mass［J］. Nat Commun, 2024, 15(1): 2956.
［8］Wang S H, Zhu X, Hao Y, et al. ALKBH5-mediated m6A modification of circFOXP1 promotes gastric cancer progression by regulating SOX4 expression and sponging miR-338-3p［J］. Commun Biol, 2024, 7(1): 565.
［9］Mülder D T, Hahn A I, Huang R J, et al. Prevalence of gastric precursor lesions in countries with differential gastric cancer burden: a systematic review and meta-analysis［J］. Clin Gastroenterol Hepatol, 2024, 22(8): 1605－1617, e46.
［10］Zeng R J, Gou H Y, Lau H C H, et al. Stomach microbiota in gastric cancer development and clinical implications［J］. Gut, 2024, 73(12): 2062－2073.
［11］Baldan J, Camacho-Roda J, Ballester M, et al. Resolution of acinar dedifferentiation regulates tissue remodeling in pancreatic injury and cancer initiation［J］. Gastroenterology, 2024, 167(4): 718－732, e18.
［12］Anon. Shaping a nature reviews cancer article［J］. Nat Rev Cancer, 2019, 19(3): 121.
［13］Aryal S, Lu R. HOXA9 regulome and pharmacological interventions in leukemia［J］. Adv Exp Med Biol, 2024, 1459: 405－430.
［14］Wang X W, Wu Y, Wang D, et al. MicroRNA network analysis identifies key microRNAs and genes associated with precancerous lesions of gastric cancer［J］. Genet Mol Res, 2014, 13(4): 8695－8703.
［15］Ai C, Huang Z H, Rong T H, et al. The impact of SOX4-activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma［J］. Electrophoresis, 2024, 45(15/16): 1408－1417.
［16］Pan X, Zhao J, Zhang W N, et al. Induction of SOX4 by DNA damage is critical for p53 stabilization and function［J］. Proc Natl Acad Sci U S A, 2009, 106(10): 3788－3793.
［17］Drflinger B, Badr M T, Haimovici A, et al. Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H.pylori infection［J］. Cell Death Differ, 2022, 29(11): 2218－2232.
［18］He J Z, Nascakova Z, Leary P, et al. Inactivation of the tumor suppressor gene Apc synergizes with H.pylori to induce DNA damage in murine gastric stem and progenitor cells［J］. Sci Adv, 2023, 9(46): eadh0322.
［19］Ha Thi H T, Kim H Y, Kim Y M, et al. MicroRNA-130a modulates a radiosensitivity of rectal cancer by targeting SOX4［J］. Neoplasia, 2019, 21(9): 882－892.

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SOX4在幽门螺杆菌介导的胃黏膜上皮异型增生中的作用及机制研究

The role and mechanism of SOX4 in Helicobacter pylori-mediated gastric mucosal epithelial dysplasia

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