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KHDRBS3 regulates the permeability of blood-tumor barrier via cDENND4C/miR-577 axis

Peiqi Wu1,2,3, Yang Gao1,2,3, Shuyuan Shen1,2,3

  • 1Department of Neurobiology, School of Life Sciences, China Medical University, 110122, Shenyang, China.

Cell Death & Disease
|July 13, 2019
PubMed

Insights

Researchers found that KHDRBS3 regulates the blood-tumor barrier (BTB) via the cDENND4C/miR-577 pathway. This mechanism enhances drug delivery for brain tumor chemotherapy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • The blood-tumor barrier (BTB) impedes drug delivery to brain tumors.
  • RNA-binding proteins and circular RNAs are emerging regulators of endothelial cell function.
  • Identifying pathways to enhance BTB permeability is crucial for effective glioma treatment.

Purpose of the Study:

  • To investigate the role of RNA-binding protein KHDRBS3 and circular RNA DENND4C (cDENND4C) in regulating BTB permeability.
  • To elucidate the molecular mechanism involving KHDRBS3, cDENND4C, and miR-577 in controlling BTB integrity.
  • To assess the potential of targeting this axis for improving chemotherapy drug delivery in gliomas.

Main Methods:

  • Enrichment analysis of KHDRBS3 and cDENND4C in glioma endothelial cells (GECs).
  • Investigating the interaction between KHDRBS3 and cDENND4C.
  • Assessing the impact of cDENND4C and miR-577 modulation on BTB permeability and tight junction proteins.
  • Evaluating the effect of KHDRBS3, cDENND4C, and miR-577 on doxorubicin delivery and glioma cell apoptosis.

Main Results:

  • KHDRBS3 binds to cDENND4C, enhancing its stability.
  • Knockdown of cDENND4C or overexpression of miR-577 increased BTB permeability by downregulating tight junction proteins.
  • cDENND4C functions as a molecular sponge for miR-577, inhibiting its effect on ZO-1, occludin, and claudin-1.
  • Targeted manipulation of KHDRBS3, cDENND4C, and miR-577 promoted doxorubicin delivery across the BTB, inducing glioma cell apoptosis.

Conclusions:

  • KHDRBS3 regulates BTB permeability through the cDENND4C/miR-577 axis.
  • This pathway offers a novel strategy for enhancing antitumor drug delivery across the BTB.
  • The findings provide a potential therapeutic approach for brain tumor chemotherapy.

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