Zhao Xiaohui, Su Xiaobo, Cao Lu, Xie Tian, Chen Quan, Li Jing, Xu Rui, Jiang Chao
GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China.
Juancheng People's Hospital, Heze City, Shandong Province 274600, People's Republic of China.
Cancer Manag Res. 2020 Feb 28;12:1503-1512. doi: 10.2147/CMAR.S233028. eCollection 2020.
Deubiquitinase OTU domain containing 4 (OTUD4) is initially identified as a K48-specific deubiquitinase and plays an important role in DNA damage repair signaling transduction. However, the expression level, prognostic role, biological function and mechanism of OTUD4 in multiple human cancers are unclear.
GEPIA online (http://gepia.cancer-pku.cn/; The Cancer Genome Atlas (TCGA) database) was used to analyze the mRNA expression of OTUD4 in multiple human cancers. Kaplan-Meier plotter (KM plotter) database and TCGA database were used to evaluate the prognostic value of OTUD4 expression in multiple human cancers. MTT, Transwell and 3D culture assays were used to detect the role of OTUD4 in breast, liver and lung cancer cells. The correlation between OTUD4 and apoptosis signaling pathway and AKT signaling pathway was analyzed by Gene set enrichment analysis (GSEA).
OTUD4 mRNA expression is significantly downregulated in multiple human cancer tissues. Survival analysis establishes that the downregulation of OTUD4 predicts poor prognosis in many solid tumors, including breast invasive carcinoma (BRCA), esophageal carcinoma (ESCA), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and ovarian serous cystadenocarcinoma (OV). Furthermore, overexpression of OTUD4 could inhibit tumor cell proliferation, migration and invasion of breast, liver and lung cancer cells through inhibiting the AKT signaling pathway.
This study found that OTUD4 may be a potential predictive factor for several human cancers and a tumor suppressor for breast, liver and lung cancer. The overexpression of OTUD4 restrained proliferation, migration and invasion of human breast, liver and lung cancer cells through promoting cancer cells apoptosis and inhibiting AKT signaling pathway. Notably, our results indicated that OTUD4 could be a useful biomarker for the prognosis of human cancers and a potential molecular target for diagnosis and treatment of breast, liver and lung cancer.
去泛素化酶含OTU结构域4（OTUD4）最初被鉴定为一种K48特异性去泛素化酶，在DNA损伤修复信号转导中起重要作用。然而，OTUD4在多种人类癌症中的表达水平、预后作用、生物学功能及机制尚不清楚。
利用GEPIA在线工具（http://gepia.cancer-pku.cn/；癌症基因组图谱（TCGA）数据库）分析OTUD4在多种人类癌症中的mRNA表达。使用Kaplan-Meier plotter数据库和TCGA数据库评估OTUD4表达在多种人类癌症中的预后价值。采用MTT、Transwell和3D培养试验检测OTUD4在乳腺癌、肝癌和肺癌细胞中的作用。通过基因集富集分析（GSEA）分析OTUD4与凋亡信号通路和AKT信号通路之间的相关性。
OTUD4 mRNA表达在多种人类癌组织中显著下调。生存分析表明，OTUD4的下调预示着许多实体瘤预后不良，包括乳腺浸润性癌（BRCA）、食管癌（ESCA）、肝细胞癌（LIHC）、肺腺癌（LUAD）和卵巢浆液性囊腺癌（OV）。此外，OTUD4的过表达可通过抑制AKT信号通路抑制乳腺癌、肝癌和肺癌细胞的增殖、迁移和侵袭。
本研究发现OTUD4可能是几种人类癌症的潜在预测因子，以及乳腺癌、肝癌和肺癌的肿瘤抑制因子。OTUD4的过表达通过促进癌细胞凋亡和抑制AKT信号通路抑制人乳腺癌、肝癌和肺癌细胞的增殖、迁移和侵袭。值得注意的是，我们的结果表明OTUD4可能是人类癌症预后的有用生物标志物，以及乳腺癌、肝癌和肺癌诊断和治疗的潜在分子靶点。
