Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab.
Protein Expression Profiling of Giant Cell Tumors of Bone Treated with Denosumab.
复制标题
DOI：
10.1371/journal.pone.0148401
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Saito T
中科院分区：
文献类型：
--
作者：
Mukaihara K;Suehara Y;Kohsaka S;Akaike K;Tanabe Y;Kubota D;Ishii M;Fujimura T;Kazuno S;Okubo T;Takagi T;Yao T;Kaneko K;Saito T
骨巨细胞瘤（GCTB）是一种局部侵袭性溶骨性骨肿瘤。最近，一些临床试验表明，地舒单抗是一种新的和有效的治疗选择的侵略性和复发性GCTB。本研究旨在研究Denosumab治疗作用的分子机制。使用Denosumab处理前后采集的GCTB样本进行比较蛋白质组学分析。使用软件程序分析每个表达谱，以进一步了解受影响的生物网络。通过明胶酶谱法和免疫组织化学分析进一步评价鉴定的蛋白质之一。我们在Denosumab给药前和给药后样品中鉴定了13种一致上调的蛋白质和19种一致下调的蛋白质。使用这些图谱，软件程序鉴定了间接参与RANK/RANKL途径和几种非经典子途径（包括基质金属蛋白酶途径）的差异表达蛋白之间的分子相互作用。数据分析还表明，所鉴定的蛋白质在GCTB的溶骨过程中发挥关键的功能作用。在下调最多的蛋白质中，MMP-9的活性在地舒单抗处理的样品中显著降低，尽管通过免疫组织化学分析发现残留的基质细胞表达MMP-9。MMP-9在原发性GCTB样本中的表达水平与任何临床病理因素（包括患者预后）无关。尽管狄诺塞单抗的治疗作用表现为纤维骨组织替代肿瘤或破骨细胞样巨细胞减少，但狄诺塞单抗治疗后的残留肿瘤（仅由基质细胞组成）可能会导致骨破坏;因此狄诺塞单抗的治疗应用仍有必要用于这些病变。我们认为，蛋白表达模式和网络分析结果将有助于更好地了解地舒单抗给药对GCTB患者的影响。
Giant cell tumors of bone (GCTB) are locally aggressive osteolytic bone tumors. Recently, some clinical trials have shown that denosumab is a novel and effective therapeutic option for aggressive and recurrent GCTB. This study was performed to investigate the molecular mechanism underlying the therapeutic effect of denosumab. Comparative proteomic analyses were performed using GCTB samples which were taken before and after denosumab treatment. Each expression profile was analyzed using the software program to further understand the affected biological network. One of identified proteins was further evaluated by gelatin zymography and an immunohistochemical analysis. We identified 13 consistently upregulated proteins and 19 consistently downregulated proteins in the pre- and post-denosumab samples. Using these profiles, the software program identified molecular interactions between the differentially expressed proteins that were indirectly involved in the RANK/RANKL pathway and in several non-canonical subpathways including the Matrix metalloproteinase pathway. The data analysis also suggested that the identified proteins play a critical functional role in the osteolytic process of GCTB. Among the most downregulated proteins, the activity of MMP-9 was significantly decreased in the denosumab-treated samples, although the residual stromal cells were found to express MMP-9 by an immunohistochemical analysis. The expression level of MMP-9 in the primary GCTB samples was not correlated with any clinicopathological factors, including patient outcomes. Although the replacement of tumors by fibro-osseous tissue or the diminishment of osteoclast-like giant cells have been shown as therapeutic effects of denosumab, the residual tumor after denosumab treatment, which is composed of only stromal cells, might be capable of causing bone destruction; thus the therapeutic application of denosumab would be still necessary for these lesions. We believe that the protein expression patterns and the results of the network analysis will provide a better understanding of the effects of denosumab administration in patients with GCTB.