YTH基因家族在肝癌中的表达和预后价值
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1.中南大学湘雅医院,肝脏外科,湖南 长沙 410008;2.中南大学湘雅医院,病理科,湖南 长沙 410008

作者简介:

胡宽,中南大学湘雅医院主治医师,主要从事消化系统肿瘤侵袭与耐药方面的研究。

基金项目:

湘雅医院青年科学基金资助项目(2020Q07)。


Expressions of YTH family members in hepatocellular carcinoma and their prognostic values
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1.Department of Hepatobiliary Surgery, Xiangya Hospital, Central South University, Changsha 410008, China;2.Department of Pathology, Xiangya Hospital, Central South University, Changsha 410008, China

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    摘要:

    背景与目的 YTH基因家族的所有成员都属于m6A阅读蛋白,负责参与肿瘤发生发展过程中的甲基化调控。然而,YTH基因家族在肝癌中的表达情况和具体作用仍有待进一步阐明。本文旨在通过生物信息学方法探究YTH家族成员在肝癌中的表达与预后价值,及其与免疫浸润及相关功能的关系。方法 用UALCAN数据库分析YTH基因家族在肝癌及其亚组中的表达差异。采用Kaplan-Meier plotter数据库分析YTH基因家族在肝癌中的预后价值。使用cBioPortal数据库进行YTH基因家族的共表达谱和遗传学变异分析。通过WebGestalt数据库进行YTH基因家族的功能和通路富集分析。YTH基因家族与肝癌中的免疫细胞浸润的相关性分析采用TIMER 2.0数据库完成。结果 肝癌中YTHDC1、YTHDC2、YTHDF1、YTHDF2、YTHDF3的mRNA表达均较正常肝组织明显升高,并与临床TNM分期及肿瘤分级密切相关,其在1、2、3期/级中表达逐级升高,而在4期/级中表达水平下降。预后分析显示,YTHDF1和YTHDF2的高表达均与患者更短的总生存期(OS)和无复发生存期(RFS)明显相关。TCGA数据库和cBioPortal工具分析显示,YTHDF3基因变异率为25%,是YTH家族中最高的。GO功能富集分析显示YTH基因家族的主要癌症相关功能指向代谢及生物合成分解方向,尤其是激素代谢、固醇类代谢、脂代谢、药物分解代谢等。通过TIMER 2.0数据库分析多数YTH家族成员的表达与CD4+ T细胞、CD8+ T细胞、B细胞、中性粒细胞以及树突细胞的浸润呈正相关,与巨噬细胞浸润呈负相关。结论 YTH基因家族在肝癌中存在分子和表达谱的失调。YTH基因家族成员(尤其是YTHDF1和YTHDF2)是肝癌潜在的预后标志物和新的治疗靶点,这些发现可为肝癌机制与靶向治疗的研究提供新的途径。

    Abstract:

    Background and Aims All the YTH family members belong to the m6A reading protein, and are involved in the regulation of methylation in tumor development. However, the expression and specific role of the YTH family in hepatocellular carcinoma (HCC) remains to be further elucidated. Therefore, this study was conducted to explore the expression profiles and prognostic value of YTH family members and their relations with immune infiltration and relevant functions based on bioinformatics approaches.Methods The expression profiles of YTH family members in HCC and its subgroups were analyzed using UALCAN database, and their prognostic value in HCC were evaluated using Kaplan-Meier plotter. The co-expression profiles and genetic alterations of YTH family members were analyzed using the cBioPortal. The function and pathway enrichment analysis of YTH family were performed using WebGestalt database. The correlation analysis of YTH family and immune cell infiltration in HCC was conducted using TIMER 2.0 database.Results The mRNA expression levels of YTHDC1, YTHDC2, YTHDF1, YTHDF2 and YTHDF3 in HCC were significantly increased compared with those in normal liver tissues, and were closely related to clinical TNM stage and tumor grade, and their mRNA expression levels were progressively increased in 1, 2 and 3 stage/grade, while decreased in 4 stage/grade. Prognostic analysis showed that high expressions of both YTHDF1 and YTHDF2 were significantly associated with shorter overall survival (OS) and relapse-free survival (RFS). Analysis of the TCGA database and cBioPortal showed that the genetic alteration rate of YTHDF3 was 25%, which was the highest among YTH family members. GO function enrichment analysis showed that the main functions of YTH family were oriented toward metabolism and biosynthesis decomposition, especially hormone metabolism, sterol metabolism, lipid metabolism, drug catabolism, etc. The TIMER 2.0 database analysis showed that the expressions of most YTH family members were significantly positively correlated with the infiltration of CD4+ T cells, CD8+ T cells, B cells, neutrophils and dendritic cells, and negatively correlated with the infiltration of macrophages.Conclusion The molecular and expression profiles of YTH members were dysregulated in HCC. YTH family members (especially YTHDF1 and YTHDF2) are potential prognostic markers and new therapeutic targets. These findings may provide a new avenue for studying the mechanism and targeted therapy of HCC.

    Fig.
    图1 YTH基因家族表达分析 A:YTH家族各成员在肝癌及正常肝组织中的mRNA表达差异(ULCAN);B:肝癌中YTH家族各成员的相对表达水平(GEPIA2)Fig.1 Analysis of the mRNA expression profiles of YTH family A: Differences in mRNA expression profiles between HCC and normal liver tissue (ULCAN); B: The relative expression levels of individual YTH members in HCC (GEPIA2)
    图2 YTH基因家族的表达与肝癌患者临床TNM分期及肿瘤分级的相关性(ULCAN) A:YTH家族各成员的表达与TNM分期的相关性分析;B:YTH家族各成员的表达与肿瘤分级的相关性分析Fig.2 The relationship between the mRNA expression of YTH family and clinical stage and tumor grade in HCC (ULCAN) A: Association of the mRNA expression of YTH family with clinical stage; B: Association of the mRNA expression of YTH family with tumor grade
    图3 YTH基因家族与肝癌患者预后的关系(Kaplan-Meier plotter) A:YTH基因家族在肝癌患者中的OS曲线;B:YTH基因家族在肝癌患者中的RFS曲线Fig.3 The relationship between mRNA expression of YTH family and prognosis of HCC patients (Kaplan-Meier Plotter) A: The OS curves of YTH family in HCC patients; B: The RFS curves of YTH family in HCC patients
    图4 YTH基因家族在肝癌中的遗传学改变及家族成员之间相关性分析 A:肝癌中各YTH家族成员的基因改变频率(cBioPortal);B:YTH家族各成员互相之间的相关性(GEPIA2)Fig.4 Genetic alterations and correlation analysis of YTH family in HCC A: Summary of alteration rates for YTH family in HCC (cBioPortal); B: Correlation between each YTH member in HCC (GEPIA2)
    图5 YTH基因家族相关分子的功能及通路富集分析 A:肝癌中155个YTH基因家族相关分子的蛋白相互作用网络图(cBioPortal,Cytoscape);B:GO功能富集分析预测与YTH家族相关的生物过程、细胞成分、分子功能(WebGestalt);C:KEGG通路富集分析预测与YTH家族相关的信号通路(WebGestalt)Fig.5 Predicted functions and pathways of the relevant molecules of YTH family A: Protein-protein interaction (PPI) of the 55 co-expressed genes of YTH family in HCC (cBioPortal and Cytoscape); B: GO functional enrichment analysis of the relevant biological process, cellular components and molecular functions of YTH family (WebGestalt); C: KEGG pathway analysis of the relevant signal pathways of YTH family (WebGestalt)
    图6 TIMER 2.0数据库分析YTH基因家族与肿瘤免疫细胞浸润的相关性Fig.6 The correlation analysis between YTH family expression and immune cell infiltrations using TIMER2.0
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胡宽,姚磊,李娟妮. YTH基因家族在肝癌中的表达和预后价值[J].中国普通外科杂志,2021,30(7):836-846.
DOI:10.7659/j. issn.1005-6947.2021.07.010

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  • 收稿日期:2021-05-05
  • 最后修改日期:2021-06-26
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  • 在线发布日期: 2021-08-25