Quantitative proteomic profiling of pleomorphic human sarcoma identifies CLIC1 as a dominant pro-oncogenic receptor expressed in diverse sarcoma types.
Quantitative proteomic profiling of pleomorphic human sarcoma identifies CLIC1 as a dominant pro-oncogenic receptor expressed in diverse sarcoma types.
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DOI：
10.1021/pr4010713
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发表时间：
2014-04
影响因子：
4.4
通讯作者：
E. Murray;L. Hernychova;M. Scigelová;J. Ho;M. Nekulová;J. R. O'Neill;R. Nenutil;K. Veselý;S. R. Dundas;C. Dhaliwal;H. Henderson;R. L. Hayward;D. Salter;B. Vojtěšek;T. Hupp
中科院分区：
文献类型：
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作者：
E. Murray;L. Hernychova;M. Scigelová;J. Ho;M. Nekulová;J. R. O'Neill;R. Nenutil;K. Veselý;S. R. Dundas;C. Dhaliwal;H. Henderson;R. L. Hayward;D. Salter;B. Vojtěšek;T. Hupp
肉瘤是一种罕见的癌症，在结缔组织（如肌肉、骨骼、神经、软骨和脂肪）中发展，临床需求高度未满足。患者的预后较差，手术和术后放疗是患者的标准治疗。更好地了解肉瘤的分子病理学可能有助于开发新的治疗方法。有几十种肉瘤亚型需要靶向治疗，最常研究的包括尤文肉瘤和骨肉瘤。在这里，我们启动了一个基于蛋白质组学的目标发现计划，以确定在成人最常见的肉瘤：高级别多形性软组织肉瘤中的“主导”促癌信号转导靶点。我们已经进行了蛋白质组筛选使用串联质量标签同量异位素标记的三个高级别未分化多形性肉瘤活检从不同的组织部位。我们确定了三种肉瘤中常见的失调蛋白质，并进一步验证了最具渗透性的受体CLIC 1，使用来自两个不同人群的免疫组化，代表了300多名患者。CLIC 1在广泛的人类肉瘤中的优势表达表明，研究这种相对未探索的信号通路可能为疾病机制提供新的见解，并促进新的CLIC 1靶向治疗药物的开发。
Sarcomas are rare forms of cancer with a high unmet clinical need that develop in connective tissue, such as muscle, bone, nerves, cartilage, and fat. The outcome for patients is poor, with surgery and postoperative radiotherapy the standard treatment for patients. A better understanding of the molecular pathology of sarcoma may allow for the development of novel therapeutics. There are dozens of sarcoma subtypes where there is a need for targetted therapeutics, with the most commonly studied including Ewing's sarcoma and osteosarcoma. Here we initiate a proteomics-based target-discovery program to define "dominant" pro-oncogenic signaling targets in the most common sarcoma in adults: high-grade pleiomorphic soft tissue sarcoma. We have carried out a proteome screen using tandem mass tag isobaric labeling on three high-grade undifferentiated pleomorphic sarcoma biopsies from different tissue sites. We identified the commonly dysregulated proteins within the three sarcomas and further validated the most penetrant receptor as CLIC1, using immunohistochemistry arising from two different population cohorts representing over 300 patients. The dominant expression of CLIC1 in a broad range of human sarcomas suggests that studying this relatively unexplored signaling pathway might provide new insights into disease mechanism and facilitate the development of new CLIC1 targeted therapeutics.