Zhang Qian, Liu Yuan-Jie, Li Jie-Pin, Zeng Shu-Hong, Shen Hui, Han Mei, Guo Shun, Liu Shen-Lin, Zou Xi
Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People's Republic of China.
No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People's Republic of China.
J Inflamm Res. 2022 May 24;15:3065-3082. doi: 10.2147/JIR.S362619. eCollection 2022.
As one of the most immunogenic malignancies, skin cutaneous melanoma (SKCM) is mainly characterized by a high prevalence in immune-compromised patients and a brisk lymphocyte infiltration in the tumor microenvironment (TME). However, to date, studies on deubiquitination in SKCM are still very limited.
Public data with regard to this study in SKCM patients were acquired from The Cancer Genome Atlas (TCGA) and the Gene-Expression Omnibus (GEO) databases. We stratified TCGA-SKCM cases using consensus clustering and identified independent prognostic factors in deubiquitinating enzymes encoding genes (DECGs) by LASSO-Cox analysis. transcriptome level was examined using public data and validated by Immunohistochemical (IHC) staining at the protein level. Enrichment analysis was used to explore the potential functions of , and the TISCH database, providing further evidence at the single-cell level. The CIBERSORT algorithm was used to assess the relationship between and the immune microenvironment, and IHC was used to further evaluate the relationship between USP35 and immunotherapy response. Finally, we used the cBioPortal and the Methsurv database to analyze the significance of genomic alterations of in melanoma.
Our results showed that DECGs can be effectively used to stratify SKCM patients, suggesting their potential significance in the development of SKCM. Furthermore, overexpression was significantly associated with an unfavorable prognosis. We further revealed that may be involved in the activation of TORC1 signaling. Most importantly, was found to be significantly associated with an immunosuppressive TME, both in terms of negative correlation with the abundance of infiltrating CD8+ T cells and in terms of the fact that patients with high expression may benefit less from immunotherapy than those with low expression.
Deubiquitinating enzymes are of great importance in the diagnosis and treatment of SKCM, and is an extremely promising target for immunotherapy.
皮肤黑色素瘤（SKCM）作为免疫原性最强的恶性肿瘤之一，主要特征是在免疫功能低下患者中高发，且肿瘤微环境（TME）中有活跃的淋巴细胞浸润。然而，迄今为止，关于SKCM中去泛素化的研究仍然非常有限。
本研究中关于SKCM患者的公共数据来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）。我们使用一致性聚类对TCGA-SKCM病例进行分层，并通过LASSO-Cox分析确定去泛素化酶编码基因（DECGs）中的独立预后因素。利用公共数据在转录组水平进行检测，并通过蛋白质水平的免疫组织化学（IHC）染色进行验证。富集分析用于探索其潜在功能，TISCH数据库在单细胞水平提供了进一步的证据。使用CIBERSORT算法评估其与免疫微环境的关系，并通过IHC进一步评估USP35与免疫治疗反应的关系。最后，我们使用cBioPortal和Methsurv数据库分析其在黑色素瘤中基因组改变的意义。
我们的结果表明，DECGs可有效用于对SKCM患者进行分层，提示其在SKCM发生发展中的潜在意义。此外，其过表达与不良预后显著相关。我们进一步揭示其可能参与TORC1信号的激活。最重要的是，发现其与免疫抑制性TME显著相关，一方面与浸润性CD8 + T细胞丰度呈负相关，另一方面高表达患者可能比低表达患者从免疫治疗中获益更少。
去泛素化酶在SKCM的诊断和治疗中具有重要意义，且是免疫治疗极具前景的靶点。
