Downregulation of RKIP Is Associated with Poor Outcome and Malignant Progression in Gliomas

Sara Granja,Paulo Costa,Vera Miranda-Gonçalves,Teresa Jaraquemada,Cláudia Caeiro,Margarida Damasceno,Olga Martinho,Mrinalini Honavar,José M Lopes,Rui M Reis,Marsha R Rosner

doi:10.1371/journal.pone.0030769

Abstract

Malignant gliomas are highly infiltrative and invasive tumors, which precludes the few treatment options available. Therefore, there is an urgent need to elucidate the molecular mechanisms underlying gliomas aggressive phenotype and poor prognosis. The Raf Kinase Inhibitory protein (RKIP), besides regulating important intracellular signaling cascades, was described to be associated with progression, metastasis and prognosis in several human neoplasms. Its role in the prognosis and tumourigenesis of gliomas remains unclear.In the present study, we found that RKIP protein is absent in a low frequency (10%, 20/193) of glioma tumors. Nevertheless, the absence of RKIP expression was an independent prognostic marker in glioma. Additionally, by in vitro downregulation of RKIP, we found that RKIP inhibition induces a higher viability and migration of the cells, having no effect on cellular proliferation and angiogenesis, as assessed by in vivo CAM assay.In conclusion, this is the largest series studied so far evaluating the expression levels of this important cancer suppressor protein in glioma tumors. Our results suggest that in a subset of tumors, the absence of RKIP associates with highly malignant behavior and poor survival of patients, which may be a useful biomarker for tailored treatment of glioma patients.

Highlights

Gliomas are the most frequent primary brain tumors and include a variety of different histological tumor types and World Health Organization (WHO) malignancy grades
Further studies have shown that Raf Kinase Inhibitory Protein (RKIP) role is tumor-type specific, and in most cancer types, such as colorectal carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, and GISTs loss of RKIP expression is linked to advanced tumor stages and worse clinical outcome [25,26,27,28,29,30,31,32]
RKIP positivity was found in the cytoplasm of the great majority of samples (Figure 1), nuclear expression was observed in a few cases

Summary

Introduction

Gliomas are the most frequent primary brain tumors and include a variety of different histological tumor types and World Health Organization (WHO) malignancy grades. Histopathology is the gold standard for the typing and grading of gliomas; additional biological markers are needed for an advanced and more objective glioma classification, for a better prediction of prognosis and more targeted a tailored therapeutic decision-making. In this regard, to date the number of biomarkers used in neurooncology routine are rather limited to combined deletions of the chromosome arms 1p and 19q in oligodendroglial tumors, MGMT hypermethylation in glioblastomas and IDH1 mutations in diffuse gliomas [5,6,7]. Further studies have shown that RKIP role is tumor-type specific, and in most cancer types, such as colorectal carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, and GISTs loss of RKIP expression is linked to advanced tumor stages and worse clinical outcome [25,26,27,28,29,30,31,32]

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