CS-17 * UPREGULATION OF THE ENDOPLASMIC RETICULUM CHAPERONE, PROLYL 4-HYDROXYLASE, BETA POLYPEPTIDE (P4HB) PROMOTES INVASION, ANGIOGENESIS AND GROWTH VIA EGFR/MAPK (ERK) SIGNALLING PATHWAY IN MALIGNANT GLIOMA

Abstract

BACKGROUND: Tumor invasion and vascularization are typical hallmarks in malignant glioma with the majority showing elevated expression and activation of the epidermal growth factor receptor (EGFR). Our group has previously shown that prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, was intimately related to chemoresistance in malignant glioma. The role of P4HB in determining other glioblastoma malignant phenotypes, however, remains unknown. METHODS: We studied both the in vitro and in vivo behaviors of globlastoma cells with established P4HB-overexpression. We also studied P4HB expression profiles in clinical specimens and publicly available microarray database. Hierarchical clustering graphically was performed to detect differential gene expression patterns between low and high P4HB tumors. The effect of P4HB in determining EGFR signaling and functioning were also studied. RESULTS: We found that inhibition of P4HB would dyregulate EGFR/MAPK-mediated angiogenic and invasive phenotypes of malignant glioma. Clinical analysis on human glioma specimens and Gene Expression Omnibus (GEO) expression profiles showed that excessive P4HB were correlated with high-grade malignancy, angiogenesis and invasion. Functionally, upregulation of P4HB conferred glioma cells with malignant characteristics including proliferation, invasion and angiogenesis in vitro, and tumor growth in orthotopic mouse model. Genetic and pharmacologic inhibitions of oncogenic P4HB were found to suppress EGFR/MAPK signaling. CONCLUSION: Our study is the first to describe a mechanistic link between P4HB-EGFR-mediated MAPK activation and glioma progression, invasion and angiogenesis. The findings uncovered a novel and promising anti-glioma mechanism related to P4HB-mediated retardation of EGFR/MAPK signal transduction. Targeting P4HB with small molecular agents may provide an alternative therapeutic approach by deactivating several critical downstream events that mediate the aggressive and resistant behaviors of glioblastoma.