Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myelomaReport as inadecuate




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Journal of Experimental and Clinical Cancer Research

, 36:62

First Online: 05 May 2017Received: 22 December 2016Accepted: 26 April 2017DOI: 10.1186-s13046-017-0535-z

Cite this article as: Shvartsur, A., Givechian, K.B., Garban, H. et al. J Exp Clin Cancer Res 2017 36: 62. doi:10.1186-s13046-017-0535-z

Abstract

Multiple myeloma MM is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance MGUS. MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic-prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor-anti-resistance factor Raf-1 kinase inhibitor protein RKIP is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf-MEK-ERK1-2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform Life Technologies for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed i.e., RKIP, Bcl-2, and DR5 or underexpressed i.e., Bcl-6 and TNFR2 in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP active-inactive and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis-prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.

KeywordsCancer Multiple myeloma Prognosis RKIP Signaling cross-talks Signature Therapy AbbreviationsMMMultiple myeloma

pRKIpPhosphorylated Raf kinase inhibitor protein

PTENPhosphatase and tensin homolog

RKIPRaf kinase inhibitor protein

Snai1Snail Family Zinc Finger 1

Snai2Snail Family Zinc Finger 2

YY1Yin Yang 1

Electronic supplementary materialThe online version of this article doi:10.1186-s13046-017-0535-z contains supplementary material, which is available to authorized users.





Author: Anna Shvartsur - Kevin B. Givechian - Hermes Garban - Benjamin Bonavida

Source: https://link.springer.com/



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