Periostin is Oncogenic and Promotes EMT in Gliomas via Inhibition of RIN1-Mediated Endocytosis of EGFR

Abstract

Background: About 1/3 of all brain tumors are gliomas. Previous glioma studies have reported increased expression of Periostin (POSTN) in these cancerous tissues, but its role and mechanism in gliomas development remain unknown. Methods: Nanoscale liquid chromatography coupled to tandem mass spectrometry (Nano LC-MS/MS) and RNA sequencing were used to identify differential protein and mRNA expression in glioma samples from the clinic. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of POSTN in tissues and cells. The effects of POSTN on glioma cell migration and invasion were examined using wound-healing, transwell, and three-dimensional spheroid assays in vitro, and a xenograft nude-mouse model in vivo. POSTN’s effect on the stability, endocytosis, and degradation of EGFR was examined by immunoblotting and immunofluorescence. Truncated mutation analysis was performed to interrogate any direct interactions between POSTN and EGFR. Immunohistochemical staining was carried out to confirm the clinical significance of POSTN. Findings: In this study, POSTN was upregulated in gliomas and was associated with poor prognosis. POSTN depletion inhibited glioma epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. Furthermore, POSTN downregulation dampened EGFR signaling via promotion of EGFR endocytosis and degradation. In addition, POSTN was found to bind to EGFR and RIN1, inhibiting EGFR endocytosis and degradation, thus promoting the activation of the PI3K-AKT signaling pathway. Interpretation: These findings indicate the POSTN/EGFR/RIN1 axis inhibits EGFR endocytosis and degradation. Targeting POSTN/EGFR/RIN1 interactions may prove beneficial the treatment of gliomas. Funding Information: This work was supported by grants from National Natural Science Foundation of China (81772682), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: Our study protocol was approved by the Research Ethics Committee of Nanjing Medical University (Nanjing, Jiangsu, China).