Humanin activates integrin αV-TGFβ axis and leads to glioblastoma progression

Abstract

Abstract The molecular mechanism of glioblastoma multiforme (GBM) spread in the brain remains poorly understood. Here, we investigated the mechanism underlying intracranial GBM progression. We found that the mitochondria-derived peptide, humanin, enhances GBM progression via intra-tumoral activation of the integrin alpha V (ITGAV)–TGF beta (TGFβ) signaling axis. In GBM tissues, humanin was significantly upregulated in the tumor area relative to the corresponding normal region. Multiple in vitro pharmacological and genetic approaches revealed that humanin activates the ITGAV pathway, inducing cellular attachment and filopodia formation, aiding the subsequent migration of attached glioblastoma cells via intracellular TGFβR signaling activation. Furthermore, our in vivo orthotopic GBM model supports the pro-tumoral function of humanin, showing a correlation between poor survival and aggressive invasiveness. Tumor protrusions and induced angiogenesis were noted in the humanin-treated group compared with the control. Public databases analysis revealed that genes in the ITGAV–TGFβR axis were significantly associated with poor prognosis in patients with GBM. Collectively, these findings provide evidence of humanin as a pro-tumoral factor, making it a novel biological target for treating GBM.