甲状腺癌(THCA)是最常见的内分泌肿瘤。磷酸二酯酶(PDE)4酶家族,作为环磷酸腺苷的特异性调节剂,可能在THCA中起重要作用。然而,关于THCA中PDE4酶家族的研究很少。因此,本研究旨在系统分析PDE4酶家族在THCA中的变化,寻找THCA治疗的潜在靶点。我们系统地分析了表达差异,预后价值,遗传改变,甲基化修饰,利用多个公共数据库研究THCA中PDE4家族与肿瘤免疫微环境的相关性,包括TCGA,GEO,GSCA,TNMplot,cBioPortal,DiseaseMeth和TIMER。此外,使用Metascape和STRING数据库研究了PDE4家族的功能富集分析和蛋白质-蛋白质相互作用(PPI)网络。PDE4A的表达水平,PDE4B和PDE4D在不同癌症分期的THCA患者中下调,而PDE4C的表达水平显著上调。此外,与PDE4C表达较低的患者相比,PDE4C表达较高的THCA患者的无进展生存期较短。在THCA患者中发现PDE4家族的低基因组改变频率和轻度增加的甲基化水平。除了PDE4A,PDE4B的表达水平,PDE4C和PDE4D可在THCA进展期间影响许多免疫细胞浸润。四种PDE4亚型均富集于cAMP分解代谢进程中。然而,PDE4C在cAMP结合信号通路中没有富集,和PDE4B在Gα信号转导事件中没有富集。值得注意的是,PDE4C通过调节腺苷酸环化酶(ADCYs)参与cAMP代谢过程,其中涉及ADCY1、ADCY5、ADCY6、ADCY8和ADCY9。本研究结果为PDE4家族在THCA发生发展中的作用提供了部分依据。此外,这项研究还表明PDE4C可能是THCA的潜在预后标志物,为今后的基础和临床研究提供参考。
Thyroid carcinoma (THCA) is the most common endocrine cancer. Phosphodiesterase (PDE) 4 enzyme family, as specific regulator of cyclic adenosine monophosphate, may play a important role in THCA. However, few studies on PDE4 enzyme family in THCA have been reported yet. Therefore, this study aimed to systematically analyze the changes of PDE4 enzyme family in THCA, and look for potential target for THCA therapy. We systematically analyzed the expression differences, prognostic value, genetic alteration, methylation modification, and the correlation with tumor immune microenvironment of PDE4 family in THCA using several public databases, including TCGA, GEO, GSCA, TNMplot, cBioPortal, DiseaseMeth and TIMER. Besides, functional enrichment analysis and protein-protein interaction (PPI) network of PDE4 family was investigated using Metascape and STRING databases. The expression levels of PDE4A, PDE4B and PDE4D were down-regulated in THCA patients at different cancer stages, while the expression level of PDE4C was significantly up-regulated. Moreover, THCA patients with higher PDE4C expression had shorter progress free survival compared with those with lower PDE4C expression. The low genomic alteration frequencies and mildly increased methylation levels of PDE4 family were found in THCA patients. Except for PDE4A, the expression levels of PDE4B, PDE4C and PDE4D could affect many immune cells infiltration during THCA progression. Four PDE4 subtypes were all enriched in cAMP catabolic process. Nevertheless, PDE4C was not enriched in the cAMP binding signal pathway, and PDE4B was not enriched in the G alphas signaling events. Notably, PDE4C participated in cAMP metabolic process by regulating adenylate cyclases (ADCYs), which involved ADCY1, ADCY5, ADCY6, ADCY8 and ADCY9. The findings of this study provide a partial basis for the role of PDE4 family in the occurrence and development of THCA. In addition, this study also suggested that PDE4C might be a potential prognostic marker of THCA, which could serve as a reference for future basic and clinical research.