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The INAVA mRNA in Extracellular Vesicles Activates Normal Ovarian Fibroblasts by Phosphorylation-Ubiquitylation

Lingkai Gu1, Zhangjin Shen2, Shizhen Shen3

  • 1Zhejiang Key Laboratory of Maternal and Infant Health, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 23, 2025
PubMed

Insights

INAVA mRNA in extracellular vesicles promotes ovarian cancer metastasis by activating fibroblasts. Disrupting this interaction offers a potential therapeutic strategy for ovarian cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Ovarian cancer is frequently diagnosed at advanced stages with metastasis.
  • Extracellular vesicles (EVs) are implicated in tumor metastasis, but their specific mRNA functions are underexplored.
  • INAVA mRNA's role in ovarian cancer progression requires further investigation.

Purpose of the Study:

  • To investigate the function of INAVA mRNA within extracellular vesicles in ovarian cancer metastasis.
  • To elucidate the molecular mechanism by which INAVA mRNA promotes ovarian cancer progression.
  • To explore therapeutic strategies targeting the INAVA-mediated pathway.

Main Methods:

  • Analysis of INAVA mRNA expression in plasma- and tissue-derived EVs from ovarian cancer patients.
  • Functional studies using orthotopic xenograft mouse models to assess metastasis.
  • Investigation of molecular interactions involving INAVA, HMGA2, VRK1, TRIM21, and STAT3.
  • Development and testing of a cell-permeable peptide to disrupt INAVA-HMGA2 interaction.

Main Results:

  • Elevated INAVA mRNA expression in EVs from ovarian cancer patients correlates with distant metastasis and poor prognosis.
  • Uptake and translation of INAVA mRNA activate normal ovarian fibroblasts (NOFs), driving peritoneal metastasis.
  • INAVA inhibits HMGA2 phosphorylation by VRK1, preventing TRIM21-mediated degradation and enhancing STAT3 transcription.
  • A peptide disrupting the INAVA-HMGA2 interaction attenuates NOF activation.

Conclusions:

  • INAVA mRNA in EVs is a key driver of ovarian cancer metastasis by activating fibroblasts through a novel molecular pathway.
  • Targeting the INAVA-HMGA2 interaction presents a promising therapeutic avenue for ovarian cancer treatment.
Keywords:
extracellular vesiclesfibroblast activationinnate immunity activatorovarian cancerpost‐translational modifications interaction

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