Zhao Jie, Guo Jinhui, Wang Yanan, Ma Qiancheng, Shi Yu, Cheng Feng, Lu Qiliang, Fu Wen, Ouyang Guangxiong, Zhang Ji, Xu Qiuran, Hu Xiaoge
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
Front Oncol. 2022 Jun 27;12:920287. doi: 10.3389/fonc.2022.920287. eCollection 2022.
According to GLOBOCAN 2021 cancer incidence and mortality statistics compiled by the International Agency for Research on Cancer, hepatocellular carcinoma (HCC) is the most common malignancy in the human liver and one of the leading causes of cancer death worldwide. Although there have been great advances in the treatment of HCC, such as regofenib, sorafenib, and lomvatinib, which have been developed and approved for the clinical treatment of advanced or metastatic HCC. However, they only prolong survival by a few months, and patients with advanced liver cancer are susceptible to tumor invasion metastasis and drug resistance. Ubiquitination modification is a type of post-translational modification of proteins. It can affect the physiological activity of cells by regulating the localization, stability and activity of proteins, such as: gene transcription, DNA damage signaling and other pathways. The reversible process of ubiquitination is called de-ubiquitination: it is the process of re-releasing ubiquitinated substrates with the participation of de-ubiquitinases (DUBs) and other active substances. There is growing evidence that many dysregulations of DUBs are associated with tumorigenesis. Although dysregulation of deuquitinase function is often found in HCC and other cancers, The mechanisms of action of many DUBs in HCC have not been elucidated. In this review, we focused on several deubiquitinases (DUBs) associated with hepatocellular carcinoma, including their structure, function, and relationship to hepatocellular carcinoma. hepatocellular carcinoma was highlighted, as well as the latest research reports. Among them, we focus on the USP family and OTU family which are more studied in the HCC. In addition, we discussed the prospects and significance of targeting DUBs as a new strategy for the treatment of hepatocellular carcinoma. It also briefly summarizes the research progress of some DUB-related small molecule inhibitors and their clinical application significance as a treatment for HCC in the future.
根据国际癌症研究机构汇编的2021年全球癌症发病率和死亡率统计数据，肝细胞癌（HCC）是人类肝脏中最常见的恶性肿瘤，也是全球癌症死亡的主要原因之一。尽管HCC的治疗取得了很大进展，如瑞戈非尼、索拉非尼和仑伐替尼等已被开发并批准用于晚期或转移性HCC的临床治疗。然而，它们仅能将生存期延长几个月，晚期肝癌患者易发生肿瘤侵袭转移和耐药。泛素化修饰是蛋白质的一种翻译后修饰。它可以通过调节蛋白质的定位、稳定性和活性来影响细胞的生理活性，如：基因转录、DNA损伤信号传导等途径。泛素化的可逆过程称为去泛素化：它是在去泛素化酶（DUBs）和其他活性物质参与下重新释放泛素化底物的过程。越来越多的证据表明，许多DUBs的失调与肿瘤发生有关。尽管在HCC和其他癌症中经常发现去泛素化酶功能失调，但许多DUBs在HCC中的作用机制尚未阐明。在本综述中，我们聚焦于几种与肝细胞癌相关的去泛素化酶（DUBs），包括它们的结构、功能以及与肝细胞癌的关系。突出了肝细胞癌以及最新的研究报告。其中，我们重点关注在HCC中研究较多的USP家族和OTU家族。此外，我们讨论了将DUBs作为肝细胞癌治疗新策略的前景和意义。还简要总结了一些与DUB相关的小分子抑制剂的研究进展及其作为未来HCC治疗的临床应用意义。
