Pan-cancer analysis identifies YTHDF2 as an immunotherapeutic and prognostic biomarker.
Pan-cancer analysis identifies YTHDF2 as an immunotherapeutic and prognostic biomarker.
复制标题
DOI：
10.3389/fcell.2022.954214
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
背景：N6-甲基腺苷(M6A)修饰是一种广泛存在于真核细胞中的动态、可逆的转录后RNA修饰。YT521-B同源结构域家族2(YTHDF2)已被鉴定为m6A阅读器蛋白的成员，参与许多重要的生物学过程，但其在癌症中的作用和作用机制尚不清楚。方法：在GTEx、TCGA、GEO和cBioPortal4个数据库上进行生物信息学分析，探讨YTHDF2的表达与其基因组变化(包括肿瘤突变负荷、微卫星不稳定性和错配修复)之间的关系。我们还研究了YTHDF2的表达与预后、免疫浸润、肿瘤微环境、免疫检查点和趋化因子的关系。此外，还研究了YTHDF2在肿瘤组织和正常组织中的表达与拷贝数变异和启动子甲基化的关系。最后，我们对YTHDF2的蛋白质-蛋白质相互作用网络和相关基因进行了分析，以丰富其在肿瘤发生发展中的潜在作用机制。采用实时荧光定量聚合酶链式反应检测YTHDF2相关基因在结直肠癌细胞中的表达，免疫组织化学染色检测51例肝细胞癌组织切片中的免疫细胞浸润情况。结果：YTHDF2在大多数肿瘤类型中过表达，并与总体生存期、无进展间期和疾病特异性生存期差有关。YTHDF2的表达与肿瘤的突变负荷、微卫星不稳定性和错配修复有关。此外，YTHDF2可能通过影响免疫检查点基因的表达和免疫细胞在肿瘤微环境中的渗透而参与免疫调节。值得注意的是，YTHDF2的表达与CD8+T细胞和巨噬细胞在许多肿瘤中的浸润呈正相关，并在51例临床肝细胞癌组织中得到验证。此外，YTHDF2参与“剪接体”和“RNA降解”是其影响肿瘤进展的两个潜在的作用机制。YTHDF2对预测基因的调控已在结直肠癌细胞中得到验证。结论：YTHDF2可能是一种新的治疗靶点和潜在的肿瘤免疫逃逸和预后不良的生物标志物。
Background: N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional RNA modification prevalent in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) has been identified as a member of m6A reader protein involving in many vital biological processes, whereas its role and functional mechanisms in cancers remain unclear. Methods: Bioinformatics analyses were performed on multiple databases including GTEx, TCGA, GEO and Cbioportal to explore the connection between YTHDF2 expression and its genomic changes including tumor mutation burden, microsatellite instability and mismatch repair in 33 different cancer types. We also investigated the association of YTHDF2 expression with prognosis, immune infiltration, tumor microenvironment, immune checkpoints and chemokines. Besides, the correlation of YTHDF2 expression with copy number variation and promoter methylation was also studied in tumors compared with normal tissues. At last, we analyzed the protein-protein interacting network and related genes of YTHDF2 to enrich its potential functional mechanism in tumor development and progression. Real-time qPCR was used to verify the expression of YTHDF2-related genes in colorectal cancer cells, and immunohistochemical staining was adopted to verify immune infiltration in tissue sections from 51 hepatocellular carcinoma patients. Results: YTHDF2 was overexpressed in a majority of tumor types and associated with their poor overall survival, progression-free interval, and disease-specific survival. The correlation of YTHDF2 expression with tumor mutation burden, microsatellite instability and mismatch repair was also detected in most of the tumor types. Moreover, YTHDF2 might participate in the immune regulation through influencing the expression of immune checkpoint genes and the infiltration of immunocytes in tumor microenvironment. Notably, we demonstrated a positive correlation between YTHDF2 expression and the infiltration of CD8+ T cells and macrophages in many tumors, and it was verified in 51 clinic hepatocellular carcinoma tissues. In addition, the involvement of YTHDF2 in “Spliceosome” and “RNA degradation” were two potential functional mechanisms underlying its influence on tumor progression. The regulation of YTHDF2 on predicted genes has been verified in CRC cells. Conclusion: YTHDF2 might be a new therapeutic target and a potential biomarker of cancer immune evasion and poor prognosis.