TIMELESS高表达预示预后不良：皮肤黑色素瘤的潜在治疗靶点
High Expression of TIMELESS Predicts Poor Prognosis: A Potential Therapeutic Target for Skin Cutaneous Melanoma.
作者信息
Zhao Shixin, Wen Shifeng, Liu Hengdeng, Zhou Ziheng, Liu Yiling, Zhong Jinbao, Xie Julin
机构信息
Department of Burn Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Department of Orthopedics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
出版信息
Front Surg. 2022 May 19;9:917776. doi: 10.3389/fsurg.2022.917776. eCollection 2022.
BACKGROUND
Skin cutaneous melanoma (SKCM) is the most lethal skin cancer with an increasing incidence worldwide. The poor prognosis of SKCM urgently requires us to discover prognostic biomarkers for accurate therapy. As a regulator of DNA replication, TIMELESS (TIM) has been found to be highly expressed in various malignancies but rarely reported in SKCM. The objective of this study was to evaluate the relationship between TIM and SKCM tumorigenesis and prognosis.
METHODS
We obtained RNA sequencing data from TCGA and GTEx to analyze TIM expression and differentially expressed genes (DEGs). Subsequently, GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network were used to perform the functional enrichment analysis of TIM-related DEGs. Moreover, the receiver operating characteristic (ROC) curves, Cox regression analysis, Kaplan-Meier (K-M) analysis, and nomograms were applied to figure out the clinical significance of TIM in SKCM. In addition, we investigated the relationship between TIM promoter methylation and SKCM prognosis through the UALCAN database. Finally, the immunohistochemical (IHC) results of normal skin and SKCM were analyzed to determine expression differences.
RESULTS
TIM was significantly elevated in various malignancies, including SKCM, and high expression of TIM was associated with poor prognosis. Moreover, a total of 402 DEGs were identified between the two distinct TIM expression groups, and functional annotation showed enrichment with positive regulation of cell cycle and classic oncogenic pathways in the high TIM expression phenotype, while keratinization pathways were negatively regulated and enriched. Further analysis showed that TIM was correlated with infiltration of multiple immune cells. Finally, IHC validated the differential expression of TIM in SKCM.
CONCLUSION
TIM might play a pivotal role in tumorigenesis of SKCM and is closely related to its prognosis.
背景
皮肤黑色素瘤（SKCM）是最致命的皮肤癌，在全球范围内发病率不断上升。SKCM的预后较差，迫切需要我们发现预后生物标志物以进行精准治疗。作为DNA复制的调节因子，永恒蛋白（TIM）已被发现在各种恶性肿瘤中高表达，但在SKCM中的报道很少。本研究的目的是评估TIM与SKCM肿瘤发生及预后之间的关系。
方法
我们从TCGA和GTEx获得RNA测序数据，以分析TIM表达和差异表达基因（DEG）。随后，使用GO/KEGG、GSEA、免疫细胞浸润分析和蛋白质-蛋白质相互作用（PPI）网络对TIM相关的DEG进行功能富集分析。此外，应用受试者工作特征（ROC）曲线、Cox回归分析、Kaplan-Meier（K-M）分析和列线图来确定TIM在SKCM中的临床意义。另外，我们通过UALCAN数据库研究TIM启动子甲基化与SKCM预后之间的关系。最后，分析正常皮肤和SKCM的免疫组织化学（IHC）结果以确定表达差异。
结果
TIM在包括SKCM在内的各种恶性肿瘤中显著升高，TIM高表达与预后不良相关。此外，在两个不同的TIM表达组之间共鉴定出402个DEG，功能注释显示在高TIM表达表型中细胞周期的正调控和经典致癌途径富集，而角质化途径则受到负调控和富集。进一步分析表明，TIM与多种免疫细胞的浸润相关。最后，IHC验证了TIM在SKCM中的差异表达。
结论
TIM可能在SKCM的肿瘤发生中起关键作用，并且与其预后密切相关。
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