State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Cell Death Dis. 2022 Aug 4;13(8):676. doi: 10.1038/s41419-022-05135-7.
The poor prognosis of hepatocellular carcinoma (HCC) could be attributed to its high metastasis rate. Here, we report the role of nucleoredoxin (NXN), a multifunctional redox-active protein, in HCC metastasis. The expression of NXN in HCC tissues was measured by immunohistochemistry. The role of NXN on HCC proliferation was determined by CCK-8, EdU and colony formation assays in vitro and subcutaneous tumor formation model in vivo. Transwell and wound healing assays and tail vein injection model were performed to assess the function of NXN on HCC metastasis. Co-immunoprecipitation assay was performed to examine the interaction among NXN, Snail and DUB3. Our results showed that NXN was downregulated in HCC tissues compared to adjacent liver tissues. Patients with low NXN expression had shorter overall survival (OS) time (P < 0.001) than those with high NXN expression. Biologically, ectopic expression of NXN significantly inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo by suppressing epithelial-mesenchymal transition (EMT). Mechanistically, NXN promoted the ubiquitin-proteasome-mediated degradation of Snail through interaction with DUB3. Further, depletion of Snail abolished NXN-inhibited cell proliferation and metastasis. In summary, NXN suppressed the proliferation and metastasis of HCC by inhibiting DUB3-mediated deubiquitylation of Snail protein. Our study demonstrates that NXN, DUB3 and Snail complex functioned as an important regulatory mechanism of HCC progression and indicates a potential therapeutic approach for the treatment of HCC metastasis.
肝细胞癌（HCC）预后较差的原因可能与其高转移率有关。在这里，我们报告了多功能氧化还原活性蛋白核仁素（NXN）在 HCC 转移中的作用。通过免疫组织化学测定 HCC 组织中 NXN 的表达。通过体外 CCK-8、EdU 和集落形成测定以及体内皮下肿瘤形成模型测定 NXN 对 HCC 增殖的作用。通过 Transwell 和划痕愈合测定以及尾静脉注射模型评估 NXN 对 HCC 转移的功能。通过共免疫沉淀测定来检查 NXN、Snail 和 DUB3 之间的相互作用。我们的结果表明，与相邻肝组织相比，NXN 在 HCC 组织中表达下调。NXN 低表达的患者总生存期（OS）时间短于 NXN 高表达的患者（P<0.001）。在生物学上，通过抑制上皮间质转化（EMT），NXN 的异位表达显著抑制了 HCC 细胞的体外和体内增殖和转移。从机制上讲，NXN 通过与 DUB3 相互作用促进了 Snail 的泛素蛋白酶体介导的降解。此外，Snail 的耗竭消除了 NXN 抑制的细胞增殖和转移。总之，NXN 通过抑制 DUB3 介导的 Snail 蛋白去泛素化来抑制 HCC 的增殖和转移。我们的研究表明，NXN、DUB3 和 Snail 复合物作为 HCC 进展的重要调节机制发挥作用，并表明了治疗 HCC 转移的潜在治疗方法。
