多组学分析 TRPV 通道家族在透明细胞肾细胞癌中的预后和生物学功能。

BACKGROUND: The transient receptor potential vanilloid (TRPV) channels family, TRPV1-6, has been identified to profoundly affect a wide spectrum of pathological processes in various cancers. However, the biological function and prognostic value of TRPVs in clear cell renal cell carcinoma (ccRCC) are still largely unknown. METHODS: We obtained the gene expression data and clinical information of 539 ccRCC patients from The Cancer Genome Atlas (TCGA) database. A series of databases were used for data processing and visualization, including GEPIA, GeneMANIA, MethSurv, GSCA, TIMER, and starBase databases. RESULTS: The mRNA expression of TRPV2/3 was upregulated while the expression of TRPV5/6 was downregulated in ccRCC tumor tissues. TRPV family members in ccRCC were rarely mutated (nearly 7 frequencies). The ROC curve showed that TRPV2/5/6 had a high diagnostic ability in discriminating ccRCC from the control samples (AUC>0.9). Higher levels of TRPV3 expression were associated with poor prognosis of ccRCC patients, while higher expression of TRPV4 was associated with favorable prognosis. The expression of TRPV3 in normal and ccRCC tissues was validated by Immunohistochemistry, and its expression was remarkably related to high histologic grade and advanced stage. Besides, TRPV3 exhibit a reduction of DNA methylation level with tumor progression, and 12 CpGs of TRPV3 were associated with a significant prognosis. In addition, TRPV3 expression was significantly associated with the accumulation of several tumor-infiltrating immune cells, especially regulatory T cells. Furthermore, high levels of TRPV3 induced the expression of immune checkpoints such as LAG3, CTLA4, PDCD1, and TIGIT. Finally, we predicted a key SNHG3/AL513497.1-miR-10b-5p-TRPV3 axis linking to carcinogenesis and progression of ccRCC. CONCLUSION: Our study may uncover TRPV channels-associated molecular mechanisms involved in the tumorigenesis and progression of ccRCC. TRPV family members might be diagnosed and prognostic markers and potential therapeutic targets for ccRCC patients.

背景：瞬时受体电位香草酸（TRPV）通道家族 TRPV1-6 已被确定对各种癌症的广泛病理过程产生深远影响。然而，TRPV 在透明细胞肾细胞癌（ccRCC）中的生物学功能和预后价值在很大程度上仍然未知。

方法：我们从癌症基因组图谱（TCGA）数据库中获得了 539 例 ccRCC 患者的基因表达数据和临床信息。使用一系列数据库进行数据处理和可视化，包括 GEPIA、GeneMANIA、MethSurv、GSCA、TIMER 和 starBase 数据库。

结果：ccRCC 肿瘤组织中 TRPV2/3 的 mRNA 表达上调，而 TRPV5/6 的表达下调。ccRCC 中 TRPV 家族成员很少发生突变（近 7 个频率）。ROC 曲线显示 TRPV2/5/6 在区分 ccRCC 与对照样本方面具有较高的诊断能力（AUC>0.9）。TRPV3 表达水平较高与 ccRCC 患者的预后不良相关，而 TRPV4 表达水平较高与预后良好相关。免疫组织化学验证了 TRPV3 在正常和 ccRCC 组织中的表达，其表达与高组织学分级和晚期显著相关。此外，TRPV3 的 DNA 甲基化水平随肿瘤进展而降低，TRPV3 的 12 个 CpG 与显著的预后相关。此外，TRPV3 的表达与多种肿瘤浸润免疫细胞的积累显著相关，尤其是调节性 T 细胞。此外，高水平的 TRPV3 诱导免疫检查点如 LAG3、CTLA4、PDCD1 和 TIGIT 的表达。最后，我们预测了一个关键的 SNHG3/AL513497.1-miR-10b-5p-TRPV3 轴，该轴与 ccRCC 的发生和进展有关。

结论：本研究可能揭示了 TRPV 通道相关的分子机制，参与了 ccRCC 的发生和发展。TRPV 家族成员可能是 ccRCC 患者的诊断和预后标志物，以及潜在的治疗靶点。