miR‐132‐3p boosts caveolae‐mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav‐1 signaling pathway

ABSTRACT Blood–brain tumor barrier (BTB) impedes the transportation of antitumor therapeutic drugs into brain tumors. Its mechanism is still unknown, but learning how to improve the BTB permeability is critical for drug intervention. Recently, microRNAs (miRNAs) have appeared as regulation factors of numerous biologic processes and therapeutic targets of diverse diseases. In this study, we have identified that miR‐132‐3p is an essential miRNA by increasing the transcellular transport through the BTB. We found that miR‐132‐3p expression was significantly up‐regulated in glioma endothelial cells (GECs). Furthermore we showed that miR132‐3p + greatly induced the endocytosis of cholera toxin subunit B and FITC–bovine serum albumin and up‐regulated the expression of p‐PKB, p‐Src and Tyr14 phosphorylation of caveolin‐1 (p‐Cav‐1), while phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression was markedly down‐regulated in GECs. Our results identify PTEN as a direct and functional downstream target of miR‐132‐3p, which is involved in the regulation of p‐PKB, p‐Src, and p‐Cav‐1. The inhibitors for PI3K and Src significantly reversed the increase of p‐Cav‐1 induced by miR‐132‐3p. Moreover, overexpression of PTEN greatly reduced the endocytosis of cholera toxin subunit B and the up‐regulation of p‐Cav‐1 induced by agomiR132‐3p, suggesting that miR132‐3p + increases the endothelial permeability by inhibition of PTEN expression. In addition, miR132‐3p + significantly increased the delivery of doxorubicin across the BTB in vitro and contributed to the accumulation of doxorubicin within the brain tumor tissue. Our results show that miR‐132‐3p contributes to the increased permeability of BTB by targeting PTEN/PI3K/PKB/Src/Cav‐1, thereby revealing a novel drug target for the treatment of brain gliomas.—Gu, Y., Cai, R., Zhang, C., Xue, Y., Pan, Y., Wang, J., Zhang, Z. miR‐132‐3p boosts caveolae‐mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav‐1 signaling pathway. FASEB J. 33, 441–454 (2019). www.fasebj.org