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Role of moesin in hyaluronan induced cell migration in glioblastoma multiforme.

ABSTRACT: A major barrier to effective treatment of glioblastoma multiforme (GBM) is the invasion of glioma cells into the brain parenchyma rendering local therapies such as surgery and radiation therapy ineffective. GBM patients with such highly invasive and infiltrative tumors have poor prognosis with a median survival time of only about a year. However, the mechanisms leading to increased cell migration, invasion and diffused behavior of glioma cells are still poorly understood.In the current study, we applied quantitative proteomics for the identification of differentially expressed proteins in GBMs as compared to non-malignant brain tissues.Our study led to the identification of 23 proteins showing overexpression in GBM; these include membrane proteins, moesin and CD44. The results were verified using Western blotting and immunohistochemistry in independent set of GBM and non-malignant brain tissues. Both GBM tissues and glioma cell lines (U87 / U373) demonstrated membranous expression of moesin and CD44, as revealed by immunohistochemistry and immunofluorescence, respectively. Notably, glioma cells transfected with moesin siRNA displayed reduced migration and invasion on treatment with hyaluronan (HA), an important component of the extracellular matrix in GBM. CD44, a transmembrane glycoprotein, acts as a major receptor for hyaluronan (HA). Using co-immunoprecipitation assays, we further demonstrated that moesin interacts with CD44 in glioma cells only after treatment with HA; this implicates a novel role of moesin in HA-CD44 signaling in gliomas.Our results suggest that development of inhibitors which interfere with CD44-moesin interactions may open a new avenue in the future to mitigate cellular migration in gliomas.

SUBMITTER: DeSouza LV

PROVIDER: S-EPMC3718631 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Role of moesin in hyaluronan induced cell migration in glioblastoma multiforme.

DeSouza Leroi V LV Matta Ajay A Karim Zia Z Mukherjee Joydeep J Wang X Simon XS Krakovska Olga O Zadeh Gelareh G Guha Abhijit A Siu Kw Michael KM

Molecular cancer 20130715

<h4>Background</h4>A major barrier to effective treatment of glioblastoma multiforme (GBM) is the invasion of glioma cells into the brain parenchyma rendering local therapies such as surgery and radiation therapy ineffective. GBM patients with such highly invasive and infiltrative tumors have poor prognosis with a median survival time of only about a year. However, the mechanisms leading to increased cell migration, invasion and diffused behavior of glioma cells are still poorly understood.<h4>M ...[more]

PMID: 23855374

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Project description:Proliferative diabetic retinopathy (PDR) involves persistent, uncontrolled formation of premature blood vessels with reduced number of pericytes. Our previous work showed that advanced glycation endproducts (AGEs) induced angiogenesis in human umbilical vein endothelial cells, mouse retina, and aortic ring, which was associated with moesin phosphorylation. Here we investigated whether moesin phosphorylation may contribute to pericyte detachment and the development of PDR. Primary retinal microvascular pericytes (RMPs) were isolated, purified from weanling rats, and identified by cellular markers α-SMA, PDGFR-β, NG2, and desmin using immunofluorescence microscopy. Effects of AGE-BSA on proliferation and migration of RMPs were examined using CCK-8, wound healing, and transwell assays. Effects on moesin phosphorylation were examined using western blotting. The RMP response to AGE-BSA was also examined when cells expressed the non-phosphorylatable Thr558Ala mutant or phospho-mimicking Thr558Asp mutant of moesin or were treated with ROCK inhibitor Y27632. Colocalization and interaction between CD44, phospho-moesin, and F-actin were observed. Experiments with cultured primary RMPs showed that AGE-BSA inhibited the proliferation, enhanced the migration, and increased moesin phosphorylation in a dose- and time-dependent manner. AGE-BSA also triggered the rearrangement of F-actin and promoted the interaction of CD44 with phospho-moesin in RMPs. These effects were abrogated in cells expressing the non-phosphorylatable moesin mutant and the application of ROCK inhibitor Y27632 attenuated AGE-induced alteration in cultured RMPs by abolishing the phosphorylation of moesin. However, those AGE-induced pathological process occurred in RMPs expressed the phospho-mimicking moesin without AGE-BSA treatment. It is concluded that AGEs could activate ROCK to mediate moesin phosphorylation at Thr558, and resulting phospho-moesin interacts with CD44 to form CD44 cluster, which might stimulate the migration of RMPs and subsequent RMP detachment in microvessel. This pathway may provide new drug targets against immature neovessel formation in PDR.

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Role of moesin in hyaluronan induced cell migration in glioblastoma multiforme.

Publications

Role of moesin in hyaluronan induced cell migration in glioblastoma multiforme.

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