NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3
Abstract 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 ro...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05135-7 |
| _version_ | 1811342772438827008 |
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| author | Yuanping Zhang Dinglan Zuo Jiliang Qiu Kai Li Yi Niu Yichuan Yuan Yuxiong Qiu Liang Qiao Wei He Chenwei Wang Yunfei Yuan Binkui Li |
| author_facet | Yuanping Zhang Dinglan Zuo Jiliang Qiu Kai Li Yi Niu Yichuan Yuan Yuxiong Qiu Liang Qiao Wei He Chenwei Wang Yunfei Yuan Binkui Li |
| author_sort | Yuanping Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T19:16:49Z |
| format | Article |
| id | doaj.art-6fefaeace3bb4aac970fa686c3df9cde |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T19:16:49Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-6fefaeace3bb4aac970fa686c3df9cde2022-12-22T02:33:39ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811110.1038/s41419-022-05135-7NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3Yuanping Zhang0Dinglan Zuo1Jiliang Qiu2Kai Li3Yi Niu4Yichuan Yuan5Yuxiong Qiu6Liang Qiao7Wei He8Chenwei Wang9Yunfei Yuan10Binkui Li11State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterDepartment of Liver Surgery, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterState Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer CenterAbstract 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.https://doi.org/10.1038/s41419-022-05135-7 |
| spellingShingle | Yuanping Zhang Dinglan Zuo Jiliang Qiu Kai Li Yi Niu Yichuan Yuan Yuxiong Qiu Liang Qiao Wei He Chenwei Wang Yunfei Yuan Binkui Li NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 Cell Death and Disease |
| title | NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 |
| title_full | NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 |
| title_fullStr | NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 |
| title_full_unstemmed | NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 |
| title_short | NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3 |
| title_sort | nxn suppresses metastasis of hepatocellular carcinoma by promoting degradation of snail through binding to dub3 |
| url | https://doi.org/10.1038/s41419-022-05135-7 |
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