Shvartsur Anna, Givechian Kevin B, Garban Hermes, Bonavida Benjamin
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Biological Sciences, USC Dana and David Dornsife College of Letters, Arts and Sciences at the University of Southern California, Los Angeles, CA, 90089, USA.
J Exp Clin Cancer Res. 2017 May 5;36(1):62. doi: 10.1186/s13046-017-0535-z.
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.
多发性骨髓瘤（MM）是一种克隆性浆细胞肿瘤性疾病，起源于一种称为意义未明的单克隆丙种球蛋白病（MGUS）的惰性癌前疾病。MM是一种生物学上复杂的异质性疾病，这体现在接受相同治疗的患者有不同的临床反应。因此，对阶段特异性生物标志物进行分子鉴定将有助于采用更个体化的精准诊断/预后方法、有效的治疗方案，并有助于识别新的治疗分子靶点。转移抑制因子/抗耐药因子Raf-1激酶抑制蛋白（RKIP）在大多数癌症中表达较低，在转移性肿瘤中往往几乎不存在。RKIP抑制Raf/MEK/ERK1/2和NF-κB信号通路。然而，所有检测的肿瘤均显示RKIP水平较低，相反，我们最近的研究结果表明，RKIP在MM细胞系和患者来源的肿瘤组织中主要以其无活性的磷酸化形式过度表达。与其他肿瘤相比，MM中RKIP过度表达的潜在机制尚不清楚。我们在Oncomine平台（Life Technologies）上检查了转录组数据集，以了解RKIP与MM前期和MM中其他基因产物的共表达情况。发现在MM前期和MM中，几种基因产物的转录要么共同过度表达（即RKIP、Bcl-2和DR5），要么表达不足（即Bcl-6和TNFR2）。值得注意的是，在MM前期观察到差异表达的促凋亡基因存在显著负相关：Fas和TNF-α过度表达，YY1表达不足，而在MM中抗凋亡基因的表达情况为：YY1过度表达，Fas和TNF-α表达不足。基于对上述各种基因的mRNA水平分析以及蛋白质水平的报道研究，我们构建了各种方案，说明了RKIP（活性/无活性）与已鉴定的基因产物之间可能存在的相互作用，这些相互作用构成了MM中RKIP过度表达的机制。显然，这种相互作用需要在MM细胞系和患者来源的肿瘤组织中进行实验验证。如果得到验证，MM前期和MM之间的差异分子特征可能会导致对该疾病及其疾病阶段进行更精确的诊断/预后评估，也将为MM前期和MM识别新的分子治疗靶点。
