Dear Colleagues,

Raf Kinase Inhibitor Protein (RKIP) is a physiologically-relevant modulator of Raf-MEK-Erk, and NF-κB signaling cascades. It has since been found to modulate several additional signaling pathways. The mechanisms by which RKIP inhibit Raf have been defined. The molecular mechanisms by which RKIP impinges on other signaling pathways remain underexplored. Through regulating key signaling cascades, RKIP prevents numerous pathological conditions including cancer progression and metastasis.

Expression of RKIP is significantly reduced in cancer metastases. Importantly, restoration of RKIP expression inhibited metastasis in cancer cells transplantation mouse models. The metastatic process is a complex cascade that consists of distinct steps. Specific classes of genes that either enhance or suppress the metastatic process have been identified. Gain-of-function mutations in enhancers and/or loss-of-function in suppressors are important events during the progression of cancers toward a metastatic phenotype. Others and we have identified RKIP as a member of the metastasis suppressor gene (MSG) family in prostate and breast cancers. Functionally, RKIP interfere with the metastasis cascade by regulating the activity of multiple metastasis genes. Published results support the concept that RKIP functions as a novel master regulator of metastasis and may represent a novel therapeutic target for patients afflicted with metastatic cancer.

Unlike other classical tumor suppressor genes, which usually have complete loss-of-function mutations in tumor cells, the expression levels of RKIP are decreased but remain detectable and the protein is functionally active. The presence of inducible active RKIP in cancer cells, its anti-tumorigenic functions, and its ability to regulate multiple metastasis genes therefore makes restoration of RKIP expression a key novel approach for therapeutic intervention.

RKIP expression is downregulated in multiple types of cancer. It has been shown that in established cancer cell lines, overexpression of transcription repressors or oncogenic miRNAs is the cause of downregulation of RKIP. Conceptually, one can restore RKIP expression by re-introducing a heterologous promoter controlled RKIP gene into cancer cells for expression, or by targeting the transcription repressors or miRNAs for inactivation. In this Special Issue of Cancers, we explore different options that one can employ to materialize the potential of targeting RKIP for anti-cancer metastasis therapy.

Dr. Kam C. Yeung
Guest Editor

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• Transcription regulators
• Metastasis
• miRNA
• RKIP
• Targeted Gene therapy