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

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.

Integrative Analysis of DNA Methylation and Gene Expression Identify a Three-Gene Signature for Predicting Prognosis in Lower-Grade Gliomas

“…Previous studies reported that CpG island hypermethylation in the EMP3 promoter region is frequent in LGGs [28-30]. Moreover, EMP3 promoter hypermethylation is associated with a favorable prognostic significance in OS in patients with oligodendroglial and glioblastoma [29, 31, 32]. In line with previous studies, we found that promoter methylation in EMP3 correlated negatively with its expression and lower EMP3 expression predicted better prognosis in LGGs patients.…”

Characterization of the epithelial membrane protein 3 interaction network reveals a potential functional link to mitogenic signal transduction regulation

“…EMP3 was reported to potentially have an influence on signal transduction and cell proliferation in different cancer cell lines by several studies and the results of our interaction screening further support this hypothesis. To verify if EMP3 has an influence on signal transduction and cell viability we generated cell lines with a stable knockdown of EMP3.…”

“…EMP3 promoter methylation was significantly associated with IDH1/2 mutations and was a favorable prognostic marker in patients with oligodendroglial tumors . Analogous, in glioblastoma low EMP3 expression also was a favorable prognostic marker, while high expression was associated with shorter patient survival …”

“…In glioblastoma cell lines transcriptional silencing of EMP3 also inhibited cell proliferation and increased apoptosis in vitro and in a xenograft mouse model. It was found that EMP3 interacted with transforming growth factor beta receptor 2 (TGFBR2) upon TGF‐ß stimulation and consequently increased activation of TGF‐ß/Smad2/3 signaling and downstream gene expression …”

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

“…Hyaluronic acid (HA), a main component of the ECM, is a natural ligand to CD44 has been used as a targeting moiety for CD44 overexpressing cancers, facilitating preferential uptake, and potent therapeutic efficacy (Orian, ). Recently, CD44 has also been found to be increased in glioma cells compared to healthy astrocytes (Jun et al, ), and has been implicated to directly impact glioma invasion (Jun et al, ; Pietras et al, ). Quercetin (3,3′,4′,5,7‐pentahydroxyflavone) is a well known anti‐ cancer and anti‐inflammatory flavonoid naturally found in whole grains like brown rice, quinoa, red wine, apples, and several vegetables like elder, capers, red onion, and other natural sources very common in the traditional Mediterranean diet (Ikizler, Erkasap, Dernek, Kural, & Kaygisiz, ).…”