Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma
Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-κB in human osteosarcoma
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DOI：
10.1042/cs20050286
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发表时间：
2006-06-01
期刊：
影响因子：
6
通讯作者：
Moldovan, Florina
中科院分区：
文献类型：
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作者：
Felx, Melanie;Guyot, Marie-Claude;Moldovan, Florina
本研究探讨了(I)ET-I及其前体BIG ET-1对骨肉瘤组织中基质金属蛋白酶(MMP2)和MMP9的合成和活性的影响，以及(Ii)ET-I受体拮抗剂对细胞侵袭的影响。用免疫印迹、酶谱、逆转录聚合酶链式反应、免疫组织化学、免疫荧光和Northern印迹等方法，我们发现这些细胞表达ET-I和ET-I受体(ETA和ETB)。此外，我们还发现ET-I显著诱导了基质金属蛋白酶-2的合成和活性，与基质金属蛋白酶-9相比，其活性显著增加。此外，抑制核因子-kappaB的激活抑制了基质金属蛋白酶-2的产生和活性，表明核因子-kappaB参与了细胞的分化、增殖和恶性转化。由于ET-I通过明胶酶诱导发挥自分泌介质的作用，而且抑制ETA受体有利于减少基础和ET-I诱导的骨肉瘤细胞的侵袭，靶向该受体可能成为成功治疗骨肉瘤的一种有吸引力的治疗选择。
In the present study, we have investigated the effect of (i) ET-I (endothelin-1) and its precursor, big ET-1, on MMP (matrix metal loproteinase)-2 and MMP-9 synthesis and activity in osteosarcoma tissue, and (ii) ET-I receptor antagonists on cell invasion. Using Western blotting, zymography, RT-PCR (reverse transcription-PCR), immunohistochemistry, immunofluorescence and Northern blotting, we have shown that ET-I and ET-I receptors (ETA and ETB) were expressed in these cells. Additionally, we have demonstrated that ET-I markedly induced the synthesis and activity of MMP-2, which was significantly increased when compared with MMP-9. Furthermore, inhibition of NF-kappa B (nuclear factor kappa B) activation blocked MMP-2 production and activity, indicating the involvement of NF-kappa B, a ubiquitous transcription factor playing a central role in the differentiation, proliferation and malignant transformation. Since ET-I acts as an autocrine mediator through gelatinase induction and because inhibition of ETA receptor is beneficial for reducing both basal and ET-I-induced osteosarcoma cell invasion, targeting this receptor could be an attractive therapeutic alternative for the successful treatment of osteosarcoma.