Down-regulation of caveolin-1, a candidate tumor suppressor gene, in sarcomas.
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.
Institute of Pathology, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität Berlin, Schumannstr. 20/21, 10117 Berlin, Germany. kai.wiechen@charite.de
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Wiechen
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Sers
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Agoulnik
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Arlt
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Dietel
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Schlag
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Schneider
D015153:Blotting, Western; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D018205:Neoplasms, Adipose Tissue / Q000378:metabolism; D018218:Neoplasms, Fibrous Tissue / Q000378:metabolism; D009379:Neoplasms, Muscle Tissue / Q000378:metabolism; D009383:Neoplasms, Vascular Tissue / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D004791:Enzyme Inhibitors; D005419:Flavonoids; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one