Down-regulation of caveolin-1, a candidate tumor suppressor gene, in sarcomas
Down-regulation of caveolin-1, a candidate tumor suppressor gene, in sarcomas
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DOI：
10.1016/s0002-9440(10)64031-x
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发表时间：
2001-03-01
影响因子：
6
通讯作者：
Schneider, U
中科院分区：
文献类型：
--
作者：
Wiechen, K;Sers, C;Schneider, U
小凹是质膜微区，与多种细胞内信号通路的调节有关。先前的研究表明，caveolae 的主要结构蛋白 Caveolin-1 可以起到肿瘤抑制因子的作用。 Caveolin-1 在终末分化的间充质细胞中高表达，包括脂肪细胞、内皮细胞和平滑肌细胞。为了研究caveolin-1是否是人类间质肿瘤中可能的肿瘤抑制因子，我们使用免疫组织化学分析了正常间质组织、22种良性和79种恶性间质肿瘤中的表达。发现 Caveolin-1 在纤维瘤、平滑肌瘤、血管瘤和脂肪瘤中的表达水平与正常间充质组织相当。 Caveolin-1的表达在6个分化良好的脂肪肉瘤中的4个中轻微减少，在3个纤维肉瘤中的3个、20个平滑肌肉瘤中的17个、16个粘液样/圆形细胞/多形性脂肪肉瘤中的16个、8个血管肉瘤中的5个、18个恶性纤维组织细胞瘤中的15个和8个滑膜肉瘤中的8个中强烈减少或消失。免疫组织化学结果通过许多肿瘤的蛋白质印迹分析得到证实。在非致瘤性人成纤维细胞系 IMR-90 中检测到高水平的 Caveolin-1 24-kd α-和 21-kd β-亚型。相比之下，在 HT-1080 人纤维肉瘤细胞中，caveolin-1 强烈下调。我们发现，通过用特异性抑制剂 PD 98059 抑制丝裂原激活的蛋白激酶信号通路，在 HT-1080 细胞中，caveolin-1 的 α-异构体被有效上调，而 DNA 甲基化的特异性抑制剂 5-aza-2'-脱氧胞苷仅略微上调 Caveolin-1。此外，在 HT-1080 纤维肉瘤细胞中重新表达 Caveolin-1 可有效抑制集落形成。由此我们得出结论，caveolin-1 很可能在人类肉瘤中充当抑癌基因。
Caveolae are plasma membrane microdomains that have been implicated in the regulation of several intracellular signaling pathways. Previous studies suggest that caveolin-1, the main structural protein of caveolae, could function as a tumor suppressor. Caveolin-1 is highly expressed in terminally differentiated mesenchymal cells including adipocytes, endothelial cells, and smooth muscle cells. To study whether caveolin-1 is a possible tumor suppressor in human mesenchymal tumors, we have analyzed the expression using immunohistochemistry in normal mesenchymal tissues, 22 benign and 79 malignant mesenchymal tumors. Caveolin-1 was found to be expressed in fibromatoses, leiomyomas, hemangiomas, and lipomas at high levels comparable to normal mesenchymal tissues. The expression of caveolin-1 was slightly reduced in four of six well-differentiated liposarcomas and strongly reduced or lost in three of three fibrosarcomas, 17 of 20 leiomyosarcomas, 16 of 16 myxoid/round cell/pleomorphic liposarcomas, five of eight angiosarcomas, 15 of 18 malignant fibrous histiocytomas, and eight of eight synovial sarcomas. The immunohistochemical findings were confirmed by Western blot analysis in a number of tumors. High levels of both the 24-kd [alpha]- and the 21-kd [beta]-isoform of caveolin-1 were detected in the nontumorigenic human fibroblast cell line IMR-90. In contrast, in HT-1080 human fibrosarcoma cells, caveolin-1 is strongly down-regulated. We show that the [alpha]-isoform of caveolin-1 is potently up-regulated in HT-1080 cells by inhibition of the mitogen-activated protein kinase-signaling pathway with the specific inhibitor PD 98059, whereas the specific inhibitor of DNA methylation 5-aza-2'-deoxycytidine only marginally up-regulates caveolin-1. In addition, re-expression of caveolin-1 in HT-1080 fibrosarcoma cells potently inhibited colony formation. From these we conclude that caveolin-1 is likely to act as a tumor suppressor gene in human sarcomas.