Pseudogene MAPK6P4-encoded functional peptide promotes glioblastoma vasculogenic mimicry development

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cancer Research

Background:

• Glioma, particularly glioblastoma (GBM), is a highly malignant brain tumor with poor therapeutic outcomes.
• Vasculogenic mimicry (VM), a tumor angiogenesis alternative, hinders anti-angiogenic therapies in glioma.
• VEGFR2 and VE-cadherin are established molecular markers for VM in tumors.

Purpose of the Study:

• To investigate the role of pseudogene MAPK6P4 in GBM proliferation, invasion, and VM.
• To elucidate the molecular mechanisms by which MAPK6P4 influences GBM VM formation.
• To identify potential therapeutic targets for glioma treatment.

Main Methods:

• In vitro assays assessing GBM cell proliferation, migration, and invasion.
• Western blotting and immunofluorescence to analyze protein expression (VEGFR2, VE-cadherin, KLF15, LDHA).
• In vivo studies using orthotopic and subcutaneous xenograft nude mouse models of GBM.

Main Results:

• MAPK6P4 deficiency significantly repressed VEGFR2 and VE-cadherin expression, inhibiting GBM cell proliferation, migration, invasion, and VM.
• MAPK6P4-encoded peptide P4-135aa promoted GBM VM by phosphorylating KLF15, enhancing its stability and nuclear entry.
• KLF15 activated LDHA, which promoted VEGFR2 and VE-cadherin lactylation, increasing their protein levels.

Conclusions:

• Pseudogene MAPK6P4 plays a crucial role in promoting GBM VM formation through the KLF15-LDHA axis.
• Targeting the MAPK6P4/P4-135aa/KLF15/LDHA pathway offers a potential strategy for comprehensive glioma treatment.
• This study reveals novel molecular targets for overcoming therapeutic resistance in glioblastoma.