The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2
Abstract Ovarian cancer is an aggressive gynecological tumor usually diagnosed with widespread metastases. Extracellular vesicles (EVs), though recognized as important mediators of tumor metastasis, have received limited attention into their specific functions via the mRNA profiling. Here it is repo...
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| Format: | Article |
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202500912 |
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| author | Lingkai Gu Zhangjin Shen Shizhen Shen Conghui Wang Yuwan Liu Xinyi Wei Mengxia Zheng Jiaxin Gu Xiaojing Chen Yi Sun Junfen Xu Yan Lu Weiguo Lu |
| author_facet | Lingkai Gu Zhangjin Shen Shizhen Shen Conghui Wang Yuwan Liu Xinyi Wei Mengxia Zheng Jiaxin Gu Xiaojing Chen Yi Sun Junfen Xu Yan Lu Weiguo Lu |
| author_sort | Lingkai Gu |
| collection | DOAJ |
| description | Abstract Ovarian cancer is an aggressive gynecological tumor usually diagnosed with widespread metastases. Extracellular vesicles (EVs), though recognized as important mediators of tumor metastasis, have received limited attention into their specific functions via the mRNA profiling. Here it is reported elevated expression and selective enrichment of INAVA mRNA in both plasma‐ and tissue‐derived EVs from ovarian cancer patients, which is positively correlated with distant metastasis and poor prognosis. Functionally, INAVA mRNA, upon uptake and translation, activates normal ovarian fibroblasts (NOFs) and drives extensive peritoneum metastasis in the orthotopic xenograft mouse model. Mechanistically, INAVA competitively binds with high mobility group protein A2 (HMGA2) and consequently inhibit its interaction with vaccinia‐related kinase 1 (VRK1), leading to reduced HMGA2 phosphorylation on Ser105. Interestingly, this inhibitory phosphorylation stabilizes HMGA2 via blocking tripartite motif‐containing 21 (TRIM21) ‐mediated K48‐linked ubiquitylation, and ultimately enhances the transcription of STAT3 to activate NOFs. Lastly, a cell‐permeable peptide that disrupts the INAVA–HMGA2 interaction leads to attenuated NOF activation and provides a promising strategy for ovarian cancer therapy. |
| format | Article |
| id | doaj-art-e482f754824d478ea5df6d0d99831770 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e482f754824d478ea5df6d0d998317702025-08-20T03:28:58ZengWileyAdvanced Science2198-38442025-07-011225n/an/a10.1002/advs.202500912The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2Lingkai Gu0Zhangjin Shen1Shizhen Shen2Conghui Wang3Yuwan Liu4Xinyi Wei5Mengxia Zheng6Jiaxin Gu7Xiaojing Chen8Yi Sun9Junfen Xu10Yan Lu11Weiguo Lu12Zhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaDepartment of Obstetrics and Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaZhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaZhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaZhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaInstitute of Translational Medicine Zhejiang University School of Medicine Hangzhou 310029 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaDepartment of Gynecologic Oncology Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaZhejiang Key Laboratory of Maternal and Infant Health Women's Hospital Zhejiang University School of Medicine Hangzhou 310006 ChinaAbstract Ovarian cancer is an aggressive gynecological tumor usually diagnosed with widespread metastases. Extracellular vesicles (EVs), though recognized as important mediators of tumor metastasis, have received limited attention into their specific functions via the mRNA profiling. Here it is reported elevated expression and selective enrichment of INAVA mRNA in both plasma‐ and tissue‐derived EVs from ovarian cancer patients, which is positively correlated with distant metastasis and poor prognosis. Functionally, INAVA mRNA, upon uptake and translation, activates normal ovarian fibroblasts (NOFs) and drives extensive peritoneum metastasis in the orthotopic xenograft mouse model. Mechanistically, INAVA competitively binds with high mobility group protein A2 (HMGA2) and consequently inhibit its interaction with vaccinia‐related kinase 1 (VRK1), leading to reduced HMGA2 phosphorylation on Ser105. Interestingly, this inhibitory phosphorylation stabilizes HMGA2 via blocking tripartite motif‐containing 21 (TRIM21) ‐mediated K48‐linked ubiquitylation, and ultimately enhances the transcription of STAT3 to activate NOFs. Lastly, a cell‐permeable peptide that disrupts the INAVA–HMGA2 interaction leads to attenuated NOF activation and provides a promising strategy for ovarian cancer therapy.https://doi.org/10.1002/advs.202500912extracellular vesiclesfibroblast activationinnate immunity activatorovarian cancerpost‐translational modifications interaction |
| spellingShingle | Lingkai Gu Zhangjin Shen Shizhen Shen Conghui Wang Yuwan Liu Xinyi Wei Mengxia Zheng Jiaxin Gu Xiaojing Chen Yi Sun Junfen Xu Yan Lu Weiguo Lu The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 Advanced Science extracellular vesicles fibroblast activation innate immunity activator ovarian cancer post‐translational modifications interaction |
| title | The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 |
| title_full | The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 |
| title_fullStr | The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 |
| title_full_unstemmed | The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 |
| title_short | The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2 |
| title_sort | inava mrna in extracellular vesicles activates normal ovarian fibroblasts by phosphorylation ubiquitylation crosstalk of hmga2 |
| topic | extracellular vesicles fibroblast activation innate immunity activator ovarian cancer post‐translational modifications interaction |
| url | https://doi.org/10.1002/advs.202500912 |
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