Involvement of epidermal growth factor receptor and downstream molecules in bone and soft tissue tumors
Involvement of epidermal growth factor receptor and downstream molecules in bone and soft tissue tumors
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DOI：
10.1016/j.humpath.2006.12.005
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发表时间：
2007-06-01
期刊：
影响因子：
3.3
通讯作者：
Ooi, Akishi
中科院分区：
文献类型：
--
作者：
Dobashi, Yoh;Suzuki, Shioto;Ooi, Akishi
对39例骨/软组织肿瘤(BSTT)中表皮生长因子受体(EGFR)基因扩增、突变和蛋白过度表达/激活的相关性进行了研究。免疫组织化学染色显示，22.6%的肉瘤组织中有EGFR过表达，而良性病变中未见EGFR过表达。免疫印迹显示，在EGFR表达上调的肉瘤中，47.4%的肉瘤组织中有EGFR激活。在2例EGFR基因拷贝数高的恶性纤维组织细胞瘤中，EGFR表达和磷酸化水平显著升高，信号转导和转录激活因子3(Stat-3)被激活。4例发现点突变，其中3例为错义突变。在这3例中，2例有EGFR和Stat-3的激活。在无基因异常的病例中，EGFR在肉瘤和良性病变中均有上调，但仅在肉瘤中发现激活。然而，EGFR的激活与特定下游分子的激活并不特定相关。在3个下游级联中，Akt通路比Stat-3或细胞外信号相关蛋白激酶1/2更频繁地被激活，Stat-3在具有上皮性的肿瘤中被激活，包括滑膜肉瘤和脊索瘤。这些结果表明，持续的Stat-3激活可能是高水平的EGFR基因拷贝数导致的过度表达的EGFR下游的一个关键事件。相反，携带EGFR突变的肿瘤不一定激活EGFR或特定的下游级联反应。最后，在BSTT中，Akt是主要的分子。这些总体结果可能为EGFR及其下游分子的参与提供新的见解，并表明EGFR介导的级联通路是确定的BSTT亚群的分子靶向治疗的候选对象。(C)2007 Elsevier Inc.保留所有权利。
Correlations among epidermal growth factor receptor (EGFR) gene amplification, mutation, and overexpression/activation of proteins were investigated in 39 cases of bone/soft tissue tumors (BSTTs). By immunohistochemistry, EGFR overexpression was found in 22.6% of sarcomas, but not in benign lesions. By immunoblotting, among sarcoma cases showing upregulation of EGFR, 47.4% showed EGFR activation. In 2 cases of malignant fibrous histiocytoma with high level of EGFR gene copy numbers, EGFR expression and phosphorylation levels were significantly higher; and signal transducer and activator of transcription 3 (Stat-3) was activated. Point mutations were detected in 4 cases, 3 of which were missense mutations. In these 3 cases, activation of EGFR and Stat-3 was found in 2 cases. In the cases without gene aberrations, upregulation of the EGFR was found in both sarcomas and benign lesions; but activation was found only in sarcomas. However, EGFR activation did not specifically correlate with activation of particular downstream molecules. Among the 3 downstream cascades, Akt pathway was more frequently activated than those of Stat-3 or extracellular signal-related protein kinase 1/2, and Stat-3 was activated in tumors exhibiting an epithelial nature, including synovial sarcoma and chordoma. These results suggest that persistent Stat-3 activation may be a critical event downstream of overexpressed EGFR by high level of EGFR gene copy numbers. In contrast, tumors harboring EGFR mutation may not necessarily activate EGFR or specific downstream cascades. Finally, in BSTTs, Akt functions as a predominant molecule. These overall results could provide novel insights into the involvement of EGFR and downstream molecules and suggest that EGFR-mediated cascades are candidates for molecular targeting therapy in defined subsets of BSTTs. (c) 2007 Elsevier Inc. All rights reserved.