Tumor-promoting EGFRvIII/c-Jun/IGFBP3 signaling circuit is induced by TGF-β-EGFRvIII transactivation in glioblastoma

Abstract Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor with a median survival of less than one year. EGFR and EGFRvIII amplification are significant genetic signature in GBM. Currently, the treatment targeting EGFRvIII cannot effectively prolong the survival of patients. TGF-β is secreted by a variety of cells in the GBM immunosuppressive microenvironment, mediating the malignant progression of EGFRvIII-expressing GBMs, but the precise mechanism is still unclear. Our data demonstrated that IGFBP3 is produced by TGF-β and EGFRvIII signal transactivation. The transcription factor c-Jun activation is essential for the production of IGFBP3. IGFBP3 knockdown not only decreased the activation of TGF-β and EGFRvIII signaling pathways, but also reduced the malignant behaviors of EGFRvIII-expressing GBM cells. In vivo data also showed that IGFBP3 knockdown prolonged tumor growth and reduced tumor volume in xenograft models. Through analysis of 80 clinical specimens showed that the expression of EGFRvIII and IGFBP3 in GBM tissues was significantly increased and positively correlated. In conclusion, TGF-β regulates the production of IGFBP3 through the EGFRvIII/c-Jun/IGFBP3 signal axis, therefore, IGFBP3 may serve as a promising therapeutics target for EGFRvIII-positive GBMs.