Role of microRNAs in the regulation of RKIP and signaling pathways in cancer

Raf kinase inhibitor protein (RKIP), also known as Phosphatidyl Ethanolamine Binding Protein (PEBP1), is a pivotal modulator of multiple intracellular signaling cascades involved in tumorigenesis, progression, metastasis, and cancer therapy resistance. In recent years, increasing evidence has highlighted the regulatory role of non-coding RNAs, particularly microRNAs (miRNAs), in modulating RKIP expression and activity across various types of cancer. This review aims to comprehensively summarize current knowledge on the post-transcriptional regulation of RKIP by miRNAs, elucidating their impact on tumor biology. For this purpose, a systematic analysis of published experimental studies was conducted, focusing on both solid and hematological malignancies. The review discusses how miRNAs, such as miR-23a, miR-27a, miR-224, miR-181a, and others, directly or indirectly suppress RKIP, contributing to enhanced proliferation, invasion, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) traits, and radioresistance. Additionally, long non-coding RNAs (lncRNAs) like XIST and PEBP1P2 were identified as factors able to modulate RKIP suppression by acting as molecular sponges for miRNAs or stabilizing RKIP transcripts. All the data presented in the manuscript are supported by diverse experimental approaches, including transcriptional analyses, functional in vitro assays (migration, invasion, apoptosis), gain- and loss-of-function experiments, luciferase reporter assays, and in vivo xenograft models, further validating the miRNA-RKIP axis involved in the progression of multiple tumors. In conclusion, this review provides an integrated view of the complex post-transcriptional network governing RKIP regulation in cancer, underscoring the potential of targeting RKIP-associated non-coding RNA axes for innovative therapeutic strategies aimed at halting tumor progression and overcoming treatment resistance.