SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin
Abstract Background Cervical cancer (CC) is a prevalent gynecological malignancy, with lymph node metastasis (LNM) serving as a critical factor influencing patient prognosis. SORBS3, an adaptor protein with two known isoforms (α and β), has been implicated in tumor suppression, but the specific role...
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| Language: | English |
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BMC
2025-04-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06409-2 |
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| author | Huating Sun Yinghui Zhang Fang Wang Zizhao Wang Yuhong Zhang Youguo Chen Li Wang Jinhua Zhou |
| author_facet | Huating Sun Yinghui Zhang Fang Wang Zizhao Wang Yuhong Zhang Youguo Chen Li Wang Jinhua Zhou |
| author_sort | Huating Sun |
| collection | DOAJ |
| description | Abstract Background Cervical cancer (CC) is a prevalent gynecological malignancy, with lymph node metastasis (LNM) serving as a critical factor influencing patient prognosis. SORBS3, an adaptor protein with two known isoforms (α and β), has been implicated in tumor suppression, but the specific roles of its isoforms in CC metastasis remains unexplored. This study aimed to identify the functional isoform of SORBS3 driving LNM suppression and elucidate its mechanisms. Methods Proteomic analysis of clinical CC tissues and metastatic lymph nodes revealed progressive downregulation of SORBS3. The mRNA and protein levels of SORBS3-α and SORBS3-β were subsequently examined in normal cervical epithelial and CC cell lines. Functional studies, including siRNA-mediated knockdown of SORBS3-α, lentiviral-mediated overexpression and knockdown of SORBS3-β, Transwell migration, lymphangiogenesis assays, and in vivo footpad xenograft models, were conducted to evaluate the role of SORBS3 isoforms in LNM. SORBS3 DNA methylation mechanisms were analyzed by MSP and Targeted Bisulfite sequencing. Mechanistic insights were derived from Co-IP, ubiquitination assays, RNA-seq, and LC–MS/MS. Results Knockdown of SORBS3-α had no effect on CC cell migration, invasion, or lymphangiogenesis. In contrast, SORBS3-β overexpression markedly suppressed CC cell invasion, lymphangiogenesis, and adhesion to lymphatic endothelial cells, whereas its knockdown significantly promoted these phenotypes. Promoter hypermethylation driven by DNMT-1 inhibited SORBS3 expression in CC. SORBS3- β directly binds to β-catenin and recruits UBA1 to enhance its ubiquitination and degradation, thereby inhibiting Wnt/β-catenin signaling. This inhibition reduced accumulation of β-catenin and downregulated the pro-lymphangiogenic gene VEGFC, ultimately suppressing lymphangiogenesis and LNM. In vivo, SORBS3-β overexpression attenuated lymphatic metastasis in nude mice, whereas its knockdown promoted metastasis. Conclusion SORBS3-β is the major isoform of SORBS3 that inhibits lymphatic metastasis of cervical cancer by degrading β-catenin through UBA1-mediated ubiquitination, blocking Wnt/β-catenin signaling and downstream lymphangiogenesis pathways, thereby inhibiting lymphatic metastasis. Our findings elucidate key molecular mechanisms underlying cervical cancer lymph node metastasis, offering potential therapeutic targets.metastasis. |
| format | Article |
| id | doaj-art-af2c95ac78cf4b40851498ae171fcdf6 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-af2c95ac78cf4b40851498ae171fcdf62025-08-20T03:10:10ZengBMCJournal of Translational Medicine1479-58762025-04-0123111810.1186/s12967-025-06409-2SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-cateninHuating Sun0Yinghui Zhang1Fang Wang2Zizhao Wang3Yuhong Zhang4Youguo Chen5Li Wang6Jinhua Zhou7Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityDepartment of Obstetrics and Gynecology, the Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Suzhou Municipal Hospital, Nanjing Medical UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityChangzhou Maternal and Child Health Care HospitalDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow UniversityAbstract Background Cervical cancer (CC) is a prevalent gynecological malignancy, with lymph node metastasis (LNM) serving as a critical factor influencing patient prognosis. SORBS3, an adaptor protein with two known isoforms (α and β), has been implicated in tumor suppression, but the specific roles of its isoforms in CC metastasis remains unexplored. This study aimed to identify the functional isoform of SORBS3 driving LNM suppression and elucidate its mechanisms. Methods Proteomic analysis of clinical CC tissues and metastatic lymph nodes revealed progressive downregulation of SORBS3. The mRNA and protein levels of SORBS3-α and SORBS3-β were subsequently examined in normal cervical epithelial and CC cell lines. Functional studies, including siRNA-mediated knockdown of SORBS3-α, lentiviral-mediated overexpression and knockdown of SORBS3-β, Transwell migration, lymphangiogenesis assays, and in vivo footpad xenograft models, were conducted to evaluate the role of SORBS3 isoforms in LNM. SORBS3 DNA methylation mechanisms were analyzed by MSP and Targeted Bisulfite sequencing. Mechanistic insights were derived from Co-IP, ubiquitination assays, RNA-seq, and LC–MS/MS. Results Knockdown of SORBS3-α had no effect on CC cell migration, invasion, or lymphangiogenesis. In contrast, SORBS3-β overexpression markedly suppressed CC cell invasion, lymphangiogenesis, and adhesion to lymphatic endothelial cells, whereas its knockdown significantly promoted these phenotypes. Promoter hypermethylation driven by DNMT-1 inhibited SORBS3 expression in CC. SORBS3- β directly binds to β-catenin and recruits UBA1 to enhance its ubiquitination and degradation, thereby inhibiting Wnt/β-catenin signaling. This inhibition reduced accumulation of β-catenin and downregulated the pro-lymphangiogenic gene VEGFC, ultimately suppressing lymphangiogenesis and LNM. In vivo, SORBS3-β overexpression attenuated lymphatic metastasis in nude mice, whereas its knockdown promoted metastasis. Conclusion SORBS3-β is the major isoform of SORBS3 that inhibits lymphatic metastasis of cervical cancer by degrading β-catenin through UBA1-mediated ubiquitination, blocking Wnt/β-catenin signaling and downstream lymphangiogenesis pathways, thereby inhibiting lymphatic metastasis. Our findings elucidate key molecular mechanisms underlying cervical cancer lymph node metastasis, offering potential therapeutic targets.metastasis.https://doi.org/10.1186/s12967-025-06409-2Cervical cancerSORBS3-βWnt/β-cateninLymph node metastasis |
| spellingShingle | Huating Sun Yinghui Zhang Fang Wang Zizhao Wang Yuhong Zhang Youguo Chen Li Wang Jinhua Zhou SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin Journal of Translational Medicine Cervical cancer SORBS3-β Wnt/β-catenin Lymph node metastasis |
| title | SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin |
| title_full | SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin |
| title_fullStr | SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin |
| title_full_unstemmed | SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin |
| title_short | SORBS3-β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β-catenin |
| title_sort | sorbs3 β suppresses lymph node metastasis in cervical cancer by promoting the ubiquitination of β catenin |
| topic | Cervical cancer SORBS3-β Wnt/β-catenin Lymph node metastasis |
| url | https://doi.org/10.1186/s12967-025-06409-2 |
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