Yu Jian, Huang Wei-Long, Xu Qing-Guo, Zhang Ling, Sun Shu-Han, Zhou Wei-Ping, Yang Fu
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, China.
Cancer Med. 2018 Jul;7(7):3363-3372. doi: 10.1002/cam4.1578. Epub 2018 May 30.
Dysregulation of the neddylation pathway is related to various cancers. However, the specific role of the neddylation pathway in human hepatocellular carcinoma (HCC) remains largely unclear. In this study, the neddylation pathway in HCC and adjacent noncancerous liver (ANL) tissues was evaluated by immunohistochemistry (IHC), Western blotting, and qRT-PCR (quantitative real-time polymerase chain reaction). The results showed that the entire neddylation pathway, including NEDD8 (the IHC staining of NEDD8 represents the global-protein neddylation), E1 NEDD8-activating enzymes (NAE1 and UBA3), E2 NEDD8-conjugating enzymes (UBE2F and UBE2M), E3 NEDD8-ligases (MDM2, RBX1 and RNF7), and deneddylation enzymes (COPS5, UCHL1 and USP21), was overactivated in HCC. Furthermore, the upregulation of NEDD8 in HCC was correlated with aggressive characteristics and was an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in patients with HCC after hepatectomy. The upregulation of NAE1, UBE2M, and UCHL1 in HCC was associated with aggressive characteristics and poor OS and RFS in patients with HCC after hepatectomy. In conclusion, our research reveals that the entire neddylation pathway is overactivated in HCC and associated with clinical characteristics and prognosis of patients with HCC.
NEDD8化途径的失调与多种癌症相关。然而，NEDD8化途径在人类肝细胞癌（HCC）中的具体作用仍不清楚。在本研究中，通过免疫组织化学（IHC）、蛋白质印迹法和qRT-PCR（定量实时聚合酶链反应）对HCC及癌旁非癌肝组织（ANL）中的NEDD8化途径进行了评估。结果显示，整个NEDD8化途径，包括NEDD8（NEDD8的IHC染色代表全局蛋白质NEDD8化）、E1 NEDD8激活酶（NAE1和UBA3）、E2 NEDD8缀合酶（UBE2F和UBE2M）、E3 NEDD8连接酶（MDM2、RBX1和RNF7）以及去NEDD8化酶（COPS5、UCHL1和USP21）在HCC中均被过度激活。此外，HCC中NEDD8的上调与侵袭性特征相关，并且是肝切除术后HCC患者总生存期（OS）和无复发生存期（RFS）的独立危险因素。HCC中NAE1、UBE2M和UCHL1的上调与侵袭性特征相关，并且与肝切除术后HCC患者较差的OS和RFS相关。总之，我们的研究表明，整个NEDD8化途径在HCC中被过度激活，并与HCC患者的临床特征和预后相关。
