目的: 利用生物信息学和免疫组化方法分析YTHDF1和YTHDF2在肺鳞癌(lung squamous cell carcinoma, LUSC)组织中的表达水平及临床意义。方法: 利用TCGA数据库对LUSC中YTHDF1和YTHDF2的表达和相关性进行分析。通过基因集富集分析(gene set enrichment analysis, GSEA)揭示YTHDF1和YTHDF2可能涉及的生物学功能和信号通路。最后采用免疫组化方法证实YTHDF1和YTHDF2在LUSC组织样本中的表达,探讨YTHDF1和YTHDF2表达水平与病理特征的关系,并用统计学方法分析其与PD-L1的相关性。结果: (1)YTHDF1和YTHDF2在LUSC组织中均高于癌旁组织(P＜0.05);(2)YTHDF1与T分期、肿瘤分期存在相关性(P＜0.05);(3)年龄是影响LUSC患者总生存期(over all survival, OS)的独立危险因素,YTHDF1表达量与T分期是影响疾病特异生存期(disease specific survival, DSS)的独立危险因素;(4)YTHDF1和YTHDF2高表达LUSC患者的基因富集主要在治疗靶点上通路上;在低表达YTHDF1和YTHDF2组中,基因富集在免疫活性相关方面。(5)YTHDF2与PD-L1表达呈正相关(P＜0.05)。结论: YTHDF1和YTHDF2的表达水平可能影响LUSC免疫微环境,同时也提示了其可能是LUSC免疫治疗的潜在靶点和生物标志物。
Objective: The expression levels and clinical significance of YTHDF1 and YTHDF2 in lung squamous cell carcinoma (LUSC) tissues were analyzed using bioinformatics and immunohistochemical methods. Methods: TCGA database was used to analyze the expression and correlation of MYC and FTO in colorectal cancer.Gene set enrichment analysis (GSEA) revealed the biological functions and signaling pathways associated with YTHDF1 and YTHDF2.Finally,the expression of YTHDF1 and YTHDF2 in LUSC tissues was validated through immunohistochemical experiments,and the correlation between expression levels of YTHDF1 and YTHDF2 and clinical features was analyzed.In addition,we investigated the relation between expression levels of YTHDF1 and YTHDF2 and PD-L1 by statistical methods. Results: (1) YTHDF1 and YTHDF2 were higher in tumors than in adjacent tissues(P＜0.05);(2) YTHDF1 was correlated with T stage and tumor clinical stage(P＜0.05);(3) Age was an independent risk factor for overall survival (OS) of LUSC patients, and YTHDF1 expression and T stage were independent risk factors for disease specific survival (DSS);(4)Genes in the groups with high expression of YTHDF1 and YTHDF2 were mainly enriched in therapeutic targets.Low expression groups of YTHDF1 and YTHDF2 were related to immune activity.(5)YTHDF2 were positively correlated with the expression of PD-L1(P＜0.05). Conclusion: The expression levels of YTHDF1 and YTHDF2 may affect the immune microenvironment of LUSC, revealing its potential as targets and biological markers for immunotherapy.
[1] Braf F, Laversane 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] 赵文静, 尹周一, 王裕新, 等.2024美国癌症统计报告解读及中美癌症流行情况对比[J].肿瘤防治研究, 2024, 51(8): 630-641.
[3] Liang Y, Wang N, Zhang Y, et al.Self-restricted circular RNA circSOX2 suppressed the malignant progression in SOX2-amplified LUSC[J].Cell Death Dis, 2022, 13(10): 873.
[4] Bonomi PD, Gandara D, Hirsch FR, et al.Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer[J].Ann Oncol, 2018, 29(8): 1701-1709.
[5] Liu ZX, Li LM, Sun HL,et al.Link Between m6A Modification and Cancers[J].Front Bioeng Biotechnol, 2018, 6: 89.
[6] Bao Y, Zhai J, Chen H, et al.Targeting m6A reader YTHDF1 augments antitumour immunity and boosts anti-PD-1 efficacy in colorectal cancer[J].Gut, 2023, 72(8): 1497-1509.
[7] Ren W, Yuan Y, Li Y, et al.The function and clinical implication of YTHDF1 in the human system development and cancer[J].Biomark Res, 2023, 11(1): 5.
[8] Liu T, Wei Q, Jin J, et al.The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation[J].Nucleic Acids Res, 2020, 48(7): 3816-3831.
[9] Li W, Chen G, Feng Z, et al.YTHDF1 promotes the proliferation, migration, and invasion of prostate cancer cells by regulating TRIM44[J].Genes Genomics, 2021, 43(12): 1413-1421.
[10] Chen X, Zhou X, Wang X.m(6)A binding protein YTHDF2 in cancer[J].Exp Hematol Oncol, 2022, 11(1): 21.
[11] Yang J, Chen Y, He Y, et al.YTHDF2 promotes gastric cancer progression and enhances chemoradiotherapy resistance[J].Drug Dev Res, 2024, 85(2): e22179.
[12] Jiang X, Chen X, Huang X, et al.DNA methylation-regulated YTHDF2 correlates with cell migration and immune cell infiltration in glioma[J].Aging, 2022, 14(19): 7774-7793.
[13] Tsuchyia K, Yoshimura K, Inoue Y, et al.YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer[J].Oncoimmunology, 2021, 10(1): 1962656.
[14] Liu X, Liu L, Dong Z, et al.Expression patterns and prognostic value of m(6)A-related genes in colorectal cancer[J].Am J Transl Res, 2019, 11(7): 3972-3991.
[15] Xu P, Hu K, Zhang P, et al.Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis[J].Cancer Cell Int, 2022, 22(1): 13.
[16] Wu T, Dai Y.Tumor microenvironment and therapeutic response[J].Cancer Lett, 2017, 387: 61-68.
[17] Bai X, Wong CC, Pan Y, et al.Loss of YTHDF1 in gastric tumors restores sensitivity to antitumor immunity by recruiting mature dendritic cells[J].J Immunother Cancer, 2022, 10(2): e003663.
[18] Zhang L, Dou X, Zheng Z, et al.YTHDF2/m(6) A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs[J].EMBO J, 2023, 42(15): e113126.
[19] Ma S, Yan J, Barr T, et al.The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity[J].J Exp Med, 2021, 218(8): e20210279.
