Understanding Mechanisms of RKIP Regulation to Improve the Development of New Diagnostic Tools

Abstract

One of the most dangerous aspects of cancer cell biology is their ability to grow, spread and form metastases in the main vital organs. The identification of dysregulated markers that drive intracellular signalling involved in the malignant transformation of neoplastic cells and the understanding of the mechanisms that regulate these processes is undoubtedly a key objective for the development of new and more targeted therapies. RAF-kinase inhibitor protein (RKIP) is an endogenous tumour suppressor protein that affects tumour cell survival, proliferation, and metastasis. RKIP might serve as an early tumour biomarker since it exhibits significantly different expression levels in various cancer histologies and it is often lost during metastatic progression. In this review, we discuss the specific impact of transcriptional, post-transcriptional and post-translational regulation of expression and activation/inhibition of RKIP and focus on those tumours for which experimental data on all these factors are available. In this way, we could select how these processes cooperate with RKIP expression in (1) Lung cancer; (2) Colon cancer, (3) Breast cancer; (4) myeloid neoplasm and Multiple Myeloma, (5) Melanoma and (6) clear cell Renal Cell Carcinoma. Furthermore, since RKIP seems to be a key marker of the development of several tumours and it may be assessed easily in various biological fluids, here we discuss the potential role of RKIP dosing in more accessible biological matrices other than tissues. Moreover, this objective may intercept the still unmet need to identify new and more accurate markers for the early diagnosis and prognosis of many tumours.

Circulating RKIP and pRKIP Might Be Novel Potential Biomarkers of Early-Stage Lung Cancer: Results from a Pilot Study

“…In fact, in most of the studies published so far, significant reduction in RKIP levels has been described, correlated proportionally with the aggressiveness and ability of tumors to form metastases. Thus, there is a close association between reduced RKIP expression and the progression of various cancers including NSCLC [18]. However, most of the cited studies mainly focused on the expression RKIP in tumour tissues, while there is little evidence on blood expression of RKIP and pRKIP.…”

“…In this context, there is a growing interest for Raf Kinase Inhibitor Protein (RKIP), an endogenous inhibitor of Raf Kinase, widely expressed in human tissues. RKIP function is finely regulated at translational [13] and post-translational levels by microRNAs [14,15] and post translational modifications such phosphorylation [16,17] that inhibit its function and, in turn, activate the Raf kinase pathway, a key regulator of many cellular functions, such as proliferation, differentiation, survival, and angiogenesis often involved in the progression of many neoplasms [18]. A number of independent studies have shown that RKIP is frequently downregulated in many types of neoplasms, including non-small cell lung cancer (NSCLC) [19], and its downregulation is often associated with an increase in invasiveness and the ability to form metastases [20] which, overall, contributes to a greater severity [21] and worse overall survival, especially in advanced-stage NSCLC [22].…”

Manipulating RKIP reverses the metastatic potential of breast cancer cells

“…However, the deletion events happen in only a minority of samples. By contrast, several transcription factors and small RNAs were found to target RKIP in cancer cells selectively ( 45 ). We proposed MTDH as a novel factor that controls the RKIP transcription, which is essential for cancer progression ( 46 ).…”

Cross-Talks between RKIP and YY1 through a Multilevel Bioinformatics Pan-Cancer Analysis

“…On the other hand, downregulation or loss of RKIP expression has regularly been observed in many cancers, a fact that is mainly attributed to the altered epigenetic landscape (e.g., promoter methylation and epigenetic transcription silencing) rather than RKIP allele deletion or mutational events [54,55]. Although a pan-cancer computational analysis of RKIP expression and relevant associations with clinicopathological features including disease progression, metastasis, and therapeutic response are still missing from the literature, a general picture from individualized cancer types reveals that RKIP expression can be used as an independent prognostic marker for overall survival and disease-free survival [2,56]. Notably, the prognostic value of phosphorylated at Ser 153 RKIP protein levels (pSer153 RKIP), known to weaken its tumor suppressing activity, is still limited, as it has been studied in only a few cancer types [57][58][59][60][61].…”