Moesin Is a Glioma Progression Marker That Induces Proliferation and Wnt/β-Catenin Pathway Activation via Interaction with CD44

Abstract

Moesin is an ERM family protein that connects the actin cytoskeleton to transmembrane receptors. With the identification of the ERM family protein NF2 as a tumor suppressor in glioblastoma, we investigated roles for other ERM proteins in this malignancy. Here, we report that overexpression of moesin occurs generally in high-grade glioblastoma in a pattern correlated with the stem cell marker CD44. Unlike NF2, moesin acts as an oncogene by increasing cell proliferation and stem cell neurosphere formation, with its ectopic overexpression sufficient to shorten survival in an orthotopic mouse model of glioblastoma. Moesin was the major ERM member activated by phosphorylation in glioblastoma cells, where it interacted and colocalized with CD44 in membrane protrusions. Increasing the levels of moesin competitively displaced NF2 from CD44, increasing CD44 expression in a positive feedback loop driven by the Wnt/b-catenin signaling pathway. Therapeutic targeting of the moesin-CD44 interaction with the small-molecule inhibitor 7-cyanoquinocarcinol (DX-52-1) or with a CD44-mimetic peptide specifically reduced the proliferation of glioblastoma cells overexpressing moesin, where the Wnt/b-catenin pathway was activated. Our findings establish moesin and CD44 as progression markers and drugable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/b-catenin pathway. Cancer Res; 73(3); 1142-55. Ó2012 AACR.

ERM proteins in cancer progression

“…Mechanistically, this can be achieved by PI3K/Akt-mediated phosphorylation (downstream of CD44 activation) of b-catenin at S552, as previously suggested to induce b-catenin translocation to the nucleus (Fang et al, 2007). The results presented in this recent study, therefore, suggest that moesin represents a target for glioblastoma therapy (Zhu et al, 2013).…”

“…Recently, Zhu et al demonstrated a correlation between the high expression of moesin and high-grade glioblastoma tumours without any significant changes in the expression levels of ezrin or radixin (Zhu et al, 2013) and also observed elevated moesin expression in established glioblastoma cell lines (Zhu et al, 2013). Here, moesin was found to colocalise with CD44 at membrane extensions, and the authors propose that moesin competes with the tumour suppressor NF2 for binding to CD44 in order to activate CD44-induced growth signalling.…”

“…Overexpression of moesin might, therefore, displace the tumour suppressor NF2 during glioblastoma progression and promote growth-signalling pathways. Interestingly, one pathway that is predominantly activated downstream of moesin-CD44 is the Wnt/b-catenin pathway (Zhu et al, 2013). The interaction between moesin and CD44 was found to induce transcription of b-catenin, as well as translocation of b-catenin from the membrane to the nucleus.…”

Daidzein derivative daid002 inhibits glioblastoma growth via disrupting the interaction between moesin and CD44

“…Importantly, CD44 and moesin expression patterns is closely related to poor prognosis [11]. Additional, in comparison with a normal human astrocyte (NHA) cell line, increased moesin levels and higher CD44 levels were detected in 10 glioblastoma cell lines [12]. Recently, moesin was regard as a glioma progression marker with higher expression in higher grade of glioma in human specimen.…”

“…Recently, moesin was regard as a glioma progression marker with higher expression in higher grade of glioma in human specimen. Moesin phosphorylation induced by CD44/moesin combination promoted cell migration in glioblastoma and CD44/ moesin/β-catenin signaling served as a potential target to inhibit cell proliferation [12]. β-catenin activation played a crucial role in glioblastoma cell differentiation, while CD44, a hyaluronic acid (HA) receptor, was involved in several physiological processes including cell migration, wound healing, leukocyte homing, tumor cell migration and metastasis, and in the meantime referred as a cell surface marker of the cancer stem cells.…”