Additive effect on survival of Raf kinase inhibitor protein and signal transducer and activator of transcription 3 in high‐grade glioma

Abstract

BACKGROUND:Animal studies have shown cooperative contribution of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways in glioblastoma formation. However, this joint action has not yet been confirmed in human studies. METHODS: The expression of Raf kinase inhibitory protein (RKIP) was examined in 159 patients with high-grade and low-grade gliomas and correlated with previously obtained data on the activation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the PI3K/Akt/mTOR signaling pathway. RESULTS: RKIP expression was associated with a longer overall survival in high-grade glioma cases without showing a direct or inverse correlation with tyrosine-705 phosphorylation of STAT3 (pSTAT3). Notably, RKIP-positive and pSTAT3 negative cases demarcate a patients group with exceptionally long survival, exceeding the prognostic impact of each single marker. CONCLUSIONS:The results of this study indicated that 1) RKIP expression correlates with tumor grade and is a marker for good prognosis in high-grade gliomas; 2) RKIP expression and lack of pSTAT3 have a cumulative prognostic impact; and 3) RKIP and pSTAT3 are likely to operate independently to influence survival. These findings represented the first human evidence of an additive effect of 2 distinct signaling pathways in high-grade glioma, suggesting that simultaneous inhibition of multiple pathways should be considered as a treatment strategy for these patients.

Loss of RKIP expression during the carcinogenic evolution of endometrial cancer

“…In human breast carcinoma and metastatic colorectal carcinoma, RKIP expression is lost in lymph node metastases but not in primary tumours 18–20. In several solid tumours, loss of cytoplasmic RKIP has also been associated with poor prognosis such as in prostate, colorectal, gastrointestinal stromal tumours, gastric adenocarcinoma of the intestinal subtype, high grade gliomas, hepatocellular carcinoma and pancreatic ductal adenocarcinoma 19 23 24 28 32 33. By contrast, many studies, including ours, have shown the absence of RKIP in primary tumours independently of associations with the presence of tumour aggressiveness and metastasis 21 22 26 29–31 45 46.…”

Molecular prognostic factors in glioblastoma: state of the art and future challenges

“…The decreased expression of PTEN (at RNA or protein levels), or loss of heterozygosity of chromosome 10q, which encompasses the PTEN gene, were reported as indicators of shorter GBM patient survival [97]; however, this is still controversial [98]. Another recent example is the prognostic value of RAF kinase inhibitor, the expression of which was reported to associate with longer overall survival of GBM patients [99]. In the future, novel studies aiming to understand how the integrated analysis of several molecular components of growth signaling pathways may help clarify the true prognostic value of these biomarkers and lead to their integration into the clinical management of GBM patients.…”

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

“…77 A third clinical study showed that overall survival was best for high-grade gliomas that are positive for RKIP and negative for STAT3 (signal transducer and activator of transcription 3) expression. 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.…”