Survey of Raf Kinase Inhibitor Protein (RKIP) in Multiple Cancer Types

Abstract

Raf kinase inhibitor protein (RKIP), an inhibitor of several signaling pathways, has been shown to have metastasis suppressor gene activity and promote apoptosis. While first identified in prostate cancer, RKIP's anti-metastasis properties have now been demonstrated in multiple tumor types. Furthermore, loss of RKIP expression is observed in many cancers as they progress. In this review, we provide a survey of the many tumor types in which RKIP function or expression has been evaluated. Particular attention is focused on the expression of RKIP in clinical tissues and its prognostic significance. A PubMed search through May 2014 identified 56 publications detailing RKIP expression in clinical cancer tissues. The majority of studies revealed that loss of RKIP expression has prognostic value for overall survival, disease free survival, and presence of metastasis for most solid tumor cancers; whereas, RKIP expression correlated with tumor grade or stage in approximately only 50% of the publications. In summary, RKIP loss is a frequent occurrence in many solid tumor cancers and may serve as a viable prognostic biomarker.

Raf Kinase Inhibitor Protein Expression and Prognostic Value in Soft Tissue Sarcomas

“…On the other hand, our results showed a statistical correlation with the absence of RKIP molecule expression and poor prognosis of STSs (table 2). These data are in accordance with other papers from our group, evaluating the RKIP protein expression profile in different types of tumors such as gastrointestinal stromal tumors, bladder cancer, gastric cancer and gliomas [12,15,21,22,23,24,25,30]. Thus, in the present study we showed that RKIP immunohistochemistry loss is an independent prognostic factor in a well-characterized series of 87 STSs [16,17,18].…”

“…Loss of RKIP expression is pathologically linked to cancer development [9,12,13,14,15], and initial studies have characterized it as a metastasis suppressor [14]. RKIP is a bona fide inhibitor of RAF-MEK-1 by preventing activation of the RAF/MEK/ERK signal transduction [26].…”

“…RKIP has been shown to be a multifunctional protein in carcinogenesis, being implicated in the control of cellular growth, motility, epithelial to mesenchymal transition, differentiation, invasion and tumor metastasization [9,10,11]. Thus, many studies have implicated RKIP in the malignant progression of several human solid tumors, being an important prognostic biomarker for a number of tumors including prostate, colorectal, gastrointestinal stromal tumors, gastric adenocarcinoma of the intestinal subtype, hepatocellular carcinoma, pancreatic ductal adenocarcinoma and also high-grade gliomas [9,12,13,14,15]. …”

Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1

“…Octreotide may reduce the probability of invasion and metastasis in SKHep-1 cells by upregulating PEBP1. PEBP1 has been widely studied as a suppressor of tumor metastasis in many types of tumors [15]. Similarly, we observed lower expression of PEBP1 in highly invasive liver cancer cell line SK-Hep-1 and MHCC-97H as compared to minimally invasive cell line HepG2 and Huh7 (Fig.…”

“…RKIP can inhibit the activity of MAPK signaling through interaction with Raf-1, and is also involved in regulating PKC, G-protein-coupled receptors, and the NF-κB pathway [21]. Because PEBP1 can inhibit tumor metastasis, it is also considered a tumor suppressor gene [15].…”