探究ETV4与结直肠癌的关系

doi:10.3969/j.issn.1009-976X.2025.05.002

摘要/Abstract

摘要： 目的探究ETS转录因子4（ETV4）与结直肠癌的关系。方法收集40例结直肠癌患者的癌组织及癌旁组织,采用RT-qPCR及免疫组化法检测癌组织和癌旁组织中ETV4的表达水平。通过生物信息学方法,使用cBioPortal数据库分析ETV4的突变情况;通过String数据库提取ETV4相关蛋白质相互作用网络;通过UALCAN数据库分析ETV4的表达与结直肠癌分期、淋巴结转移情况、年龄、性别等临床数据之间的关系;通过Kaplan-Meier Plotter数据库分析ETV4的表达与患者预后的关系。结果 RT-qPCR及免疫组化显示,与癌旁组织相比,ETV4在结直肠癌患者癌组织中的表达水平显著升高（P<0.01）;cBioPortal数据库显示ETV4在结直肠癌中的突变类型主要包括错义突变和剪切突变;UALCAN数据库分析得出ETV4的表达与结直肠癌的TNM分期、组织学亚型、是否合并TP53突变均有相关性（P<0.05）,该基因的表达与患者年龄、性别、种族、体重无相关性（P>0.05）;Kaplan-Meier Plotter分析生存曲线显示,与ETV4低表达的结直肠癌患者相比,高表达患者的总生存期（OS）显著延长（Logrank P=0.031,HR=0.8,95%CI：0.66~0.98）;肿瘤进展后生存期（PPS）显著改善（Logrank P=0.005,HR=0.64,95%CI：0.47~0.88）。结论 ETV4在结直肠癌组织中表达上调,其高表达与预后良好相关。这表明ETV4有望成为预测患者预后情况的重要指标,同时也为未来临床治疗提供了新的靶点方向。

关键词: 结直肠癌, ETV4, 生物信息学

Abstract: Objective To explore the relationship between ETS transcription factor 4 （ETV4） and colorectal cancer. Methods Colorectalcancer tissues and adjacent tissues from 40 cancer patients were collected. RT-qPCR and immunohistochemistry were used to detect ETV4 expression levels. Bioinformatics methods were applied： cBioPortal for ETV4 mutation analysis, String to extract its protein-protein interaction network, UALCAN to analyze the correlation between ETV4 expression and clinical data like cancer stage, lymph node metastasis, age, and gender, and Kaplan-Meier Plotter to analyze the relationship between ETV4 expression and patient prognosis. Results RT-qPCR and immunohistochemistry showed that ETV4 expression was significantly higher in cancer tissues than in adjacent tissues （P<0.01）. cBioPortal showed that ETV4 mutations in colorectal cancer mainly included missense and splice mutations. UALCAN analysis indicated that ETV4 expression was correlated with TNM stage, histological subtype, and TP53 mutation status （P<0.05）, but not with age, gender, race, or weight （P>0.05）. Kaplan-Meier analysis demonstrated that high ETV4 expression was associated with significantly improved overall survival （OS; Logrank P=0.031, HR=0.8, 95%CI： 0.66~0.98） and post-progression survival （PPS; Logrank P=0.05, HR=0.64, 95%CI： 0.47~0.88） in colorectal cancer patients. Conclusion The upregulation of ETV4 in colorectal cancer tissues correlates with a better prognosis, indicating its potential as a promising prognostic biomarker and a novel therapeutic target.

Key words: colorectal cancer, ETV4, bioinformatics

中图分类号:

刘锦裕, 国强, 马兴越, 陈会文, 徐鸿超. 探究ETV4与结直肠癌的关系[J]. 岭南现代临床外科, 2025, 25(05): 288-296.

LIU Jin-yu, GUO Qiang, MA Xing-yue, CHEN Hui-wen, XU Hong-chao. Exploring the relationship between ETV4 and colorectal cancer[J]. Lingnan Modern Clinics In Surgery, 2025, 25(05): 288-296.

参考文献

[1] Morgan E, Arnold M, Gini A, et al.Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN[J]. Gut, 2023, 72(2): 338-344.
[2] Yao Y, Lu Q, Hu Z, et al.A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure[J]. Nat Commun, 2017, 8(1): 133.
[3] Chang Y, Tseng H, Leung C, et al.Targeted Next-Generation Sequencing-Based Multiple Gene Mutation Profiling of Patients with Rectal Adenocarcinoma Receiving or Not Receiving Neoadjuvant Chemoradiotherapy[J]. Int J Mol Sci, 2022, 23(18): 10353.
[4] Graves BJ, Petersen JM.Specificity within the ets family of transcription factors[J]. Adv Cancer Res, 1998, 75: 1-55.
[5] Xin JH, Cowie A, Lachance P, et al.Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells[J]. Genes Dev, 1992, 6(3): 481-496.
[6] 兰宏伟, 马微, 程龙. ETV4转录因子在结直肠癌中的研究进展[J]. 牡丹江医学院学报, 2020, 41(3): 145-147.
[7] 杨健, 蔡浩洋. 肿瘤生物信息学数据库[J]. 生物技术通报, 2015, 31(11): 89-101.
[8] King L, Flaus A, Coughlan S, et al.GNOSIS: an R Shiny app supporting cancer genomics survival analysis with cBioPortal[J]. HRB Open Res, 2022, 5: 8.
[9] Szklarczyk D, Nastou K, Koutrouli M, et al.The STRING database in 2025: protein networks with directionality of regulation[J]. Nucleic Acids Res, 2025, 53(D1): D730-D737.
[10] Chandrashekar DS, Bashel B, Balasubramanya SAH, et al.UALCAN: A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses[J]. Neoplasia, 2017, 19(8): 649-658.
[11] Győrffy B, Surowiak P, Budczies J, et al.Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer[J]. PLoS One, 2013, 8(12): e82241.
[12] 中国抗癌协会, 中国抗癌协会结直肠肿瘤专业委员会. 中国恶性肿瘤整合诊治指南-结肠癌部分[J]. 中华结直肠疾病电子杂志, 2022, 11(1): 1-16.
[13] Li Y, Liang J, Dang H, et al.NCOA3 is a critical oncogene in thyroid cancer via the modulation of major signaling pathways[J]. Endocrine, 2022, 75(1): 149-158.
[14] 李赛赛, 王潇雨, 高擎, 等. GDNF 重塑 BV2 细胞对胶质瘤相关因子的分泌能力[J]. 徐州医科大学学报, 2020, 40(10): 735-740.
[15] 王小娟, 李小丽, 金正旭, 等. GDNF 与消化系统肿瘤关系研究进展[J]. 基础医学与临床, 2020, 40(7): 986-989.
[16] Zhou J, Li X, Wu M, et al.Knockdown of Long Noncoding RNA GHET1 Inhibits Cell Proliferation and Invasion of Colorectal Cancer[J]. Oncol Res, 2016, 23(6): 303-309.
[17] Gandal MJ, Haney JR, Wamsley B, et al.Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD[J]. Nature, 2022, 611(7936): 532-539.
[18] Wei H, Ma Y, Chen S, et al.Multi-omics analysis identifies PTTG1 as a prognostic biomarker associated with immunotherapy and chemotherapy resistance[J]. BMC Cancer, 2024, 24(1): 1315.
[19] Sun T, Zhang J.ETV4 mediates the Wnt/β-catenin pathway through transcriptional activation of ANXA2 to promote hepatitis B virus-associated liver hepatocellular carcinoma progression[J]. J Biochem, 2021, 170(5): 663-673.
[20] 郗雪艳, 邓婷, 杜伯雨. 结直肠成纤维细胞通过激活 ERK 信号通路促进结直肠癌细胞的恶性生物学行为[J]. 南方医科大学学报, 2024, 44(10): 1866.
[21] Wang H, Dai Y, Wang F.ETV4? mediated transcriptional activation of SLC12A5 exacerbates ferroptosis resistance and glucose metabolism reprogramming in breast cancer cells[J]. Mol Med Rep, 2024, 30(6): 217.
[22] Park P, Jo SJ, Kim MJ, et al.Role of LOXL2 in the epithelial-mesenchymal transition and colorectal cancer metastasis[J]. Oncotarget, 2017, 8(46): 80325-80335.
[23] Yang S, Golkaram M, Oh S, et al.ETV4 is a mechanical transducer linking cell crowding dynamics to lineage specification[J]. Nat Cell Biol, 2024, 26(6): 903-916.
[24] Herbert RP, Harris J, Chong KP, et al.Cytokines and olfactory bulb microglia in response to bacterial challenge in the compromised primary olfactory pathway[J]. J Neuroinflammation, 2012, 9: 109.
[25] Atzeni F, Turiel M, Capsoni F, et al.Autoimmunity and anti‐TNF‐α agents[J]. Annals of the New York Acad Sci, 2005, 1051(1): 559-569.
[26] Gadiraju B, Magisetty J, Kondreddy V.Transcription factor ETV4 plays a critical role in the development of non-alcoholic fatty liver disease[J]. Int J Biol Macromol, 2024, 282(Pt 5): 137235.