The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation–Ubiquitylation Crosstalk of HMGA2

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.