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

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.

Absence of RKIP expression is an independent prognostic biomarker for gastric cancer patients

“…Tissue microarray (TMA) slides with 3 µm-thick sections were subjected to immunohistochemical analysis according to the streptavidinbiotin peroxidase complex system (UltraVision Large Volume Detection System Anti-Polyvalent, HRP; LabVision Corporation, CA, USA), as previously described (27,30,39). Briefly, deparaffinised and rehydrated slides were submitted to heat-induced antigen retrieval for 20 min at 98˚C with 10 mM citrate buffer (pH 6.0).…”

“…For negative controls, primary antibodies were omitted and also replaced by a universal negative control antibody (CEA, rabbit anti-human, Dako Corporation, Carpinteria, CA, USA). Prostate carcinoma and GISTs cases, previously analysed (27,30,39), were used as positive and negative controls. Statistical analysis.…”

“…Previous studies have described low levels of RKIP in other metastatic tumors, such as breast and colorectal carcinoma (23,45), as well as in many other primary tumors, including GISTs (27), insulinoma (22), hepatocarcinoma (24), ovarian carcinoma (26), merckel cell carcinoma (16) and thyroid carcinoma (15), cutaneous squamous cell carcinoma (46) and nasopharyngeal carcinoma (17). Furthermore, loss of cytoplasmic RKIP has also been associated with poor prognosis in prostate, colorectal, GISTs and glial tumors (25,(27)(28)(29)(30).…”

“…Noteworthy, RKIP has been shown to be a prognostic marker in prostate cancer, colorectal carcinomas, gliomas and GISTs (25,(27)(28)(29)(30).…”

Raf Kinase Inhibitory Protein (RKIP): Functional Pleiotropy in the Mammalian Brain

“…78 However, in another report, Martinho et al found that only a small proportion (i.e., approximately 10%) of gliomas from human patients are associated with loss of RKIP expression. 79 Evidence from in vitro experiments using human glioma cell lines is consistent with a role of RKIP as a metastasis suppressor, since RKIP inhibition promotes cell migration, whereas its overexpression suppresses glioma cell invasion. 77,79 On the other hand, an in vivo assay using cultured human glioma cells implanted into chick chorioallantoic membrane did not find evidence for an effect of RKIP suppression on cellular proliferation and angiogenesis.…”