Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
Cell Death Dis. 2023 Feb 10;14(2):100. doi: 10.1038/s41419-023-05636-z.
Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.
卵巢癌（OvCa）细胞的扩散可导致肠道和网膜出现无法手术的转移性病变，尽管有手术和化疗选择，但这些病变预后较差。迫切需要更好地了解转移的机制。在这项研究中，生物信息学分析显示，UBE2E2，一种研究较少的泛素（Ub）连接酶（E2），在 OvCa 中上调，与预后不良相关。随后，我们使用 88 例 OvCa 和 26 例正常卵巢组织样本进行了 Western blot 分析和 IHC 染色，进一步证实 UBE2E2 蛋白在 OvCa 组织中高表达，而在正常组织中弱表达。此外，UBE2E2 的沉默在体外阻断了 OvCa 细胞的迁移、上皮-间充质转化（EMT）和转移，而 UBE2E2 的过表达则产生相反的效果。在机制上，UBE2E2 促进了 p62 的积累，并增加了 Nrf2-抗氧化反应元件（ARE）系统的活性，最终通过抑制 Snail 的泛素介导降解来激活 Snail 信号通路。此外，共免疫沉淀和免疫荧光表明 UBE2E2 和 Nrf2 之间存在直接相互作用，UBE2E2 的 N 端（残基 1-52）是与 Nrf2 蛋白相互作用所必需和充分的。活性位点半胱氨酸（Cys139）的突变损害了 UBE2E2 的功能和细胞分布。更重要的是，UBE2E2 的缺失减少了异种移植 OvCa 小鼠模型中的致瘤性和转移。总之，我们的研究结果揭示了 UBE2E2-Nrf2-p62-Snail 信号轴在 OvCa 中的作用，从而为预防 OvCa 转移提供了新的治疗靶点。
