Epithelial membrane protein 3 regulates TGF-β signaling activation in CD44-high glioblastoma.

Fu Jun,Liangfang Shen,Jianghai Huang,Jidong Hong,Yiwei Liao,Yong Guo,Sailan Wen,Qin Liu

doi:10.18632/oncotarget.11102

Abstract

Although epithelial membrane protein 3 (EMP3) has been implicated as a candidate tumor suppressor gene for low grade glioma, its biological function in glioblastoma multiforme (GBM) still remains poorly understood. Herein, we showed that EMP3 was highly expressed in CD44-high primary GBMs. Depletion of EMP3 expression suppressed cell proliferation, impaired in vitro tumorigenic potential and induced apoptosis in CD44-high GBM cell lines. We also identified TGF-β/Smad2/3 signaling pathway as a potential target of EMP3. EMP3 interacts with TGF-βreceptor type 2 (TGFBR2) upon TGF-βstimulation in GBM cells. Consequently, the EMP3-TGFBR2 interaction regulates TGF-β/Smad2/3 signaling activation and positively impacts on TGF-βstimulated gene expression and cell proliferation in vitro and in vivo. Highly correlated protein expression of EMP3 and TGF-β/Smad2/3 signaling pathway components was also observed in GBM specimens, confirming the clinical relevancy of activated EMP3/TGF-β/Smad2/3 signaling in GBM. In conclusion, our findings revealed that EMP3 might be a potential target for CD44-high GBMs and highlight the essential functions of EMP3 in TGF-β/Smad2/3 signaling activation and tumor progression.

Highlights

The epithelial membrane protein 3 (EMP3) is a myelin-related gene that belongs to the peripheral myelin protein 22-kDa (PMP22) gene family [1]
Differential EMP3 mRNA expression was observed in gliomas, with the highest expression seen in glioblastoma multiforme (GBM)
TCGA GBM data analysis revealed that EMP3 mRNA expression was mostly distributed in TCGA Classical and Mesenchymal GBM subtypes compared to those in Proneural and Neural subtypes, with the highest EMP3 expression observed in Mesenchymal GBM subtypes (Figure 1B)

Summary

Introduction

The epithelial membrane protein 3 (EMP3) is a myelin-related gene that belongs to the peripheral myelin protein 22-kDa (PMP22) gene family [1]. EMP3 is expressed in most tissues, especially in peripheral blood leukocytes, ovary, intestine, and various embryonic tissues, and may regulate cell proliferation, cell-cell interactions, and apoptosis [2,3,4]. The EMP3 gene has been proposed as a candidate tumor suppressor gene on 19q13.3 in several human solid tumors, such as gliomas, neuroblastoma, pheochromocytoma, non-small cell lung cancer, and esophageal squamous cell carcinoma [5,6,7,8,9]. In these malignancies, EMP3 is frequently inactivated by a hypermethylation-mediated transcriptional gene silencing. Constitutive expression of EMP3 in neuroblastoma cell lines induces tumor suppressor-like features in murine xenograft models [11]

Methods

Results

Conclusion