权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Involvement of membrane microdomains in oxidative stress-induced invasion of hepatoma cells

膜微区参与氧化应激诱导的肝癌细胞侵袭

基本信息

批准号：
17580296
负责人：
MIURA Yutaka
金额：
$ 2.43万
依托单位：
Tokyo University of Agriculture and Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

The possible involvement of membrane microdomains in oxidative stress-induced change in invasion of hepatoma cells was investigated. I have already reported that reactive oxygen species could promote hepatoma cell invasion and that the autocrine pathway between hepatoyte growth factor (HGF) and its receptor, c-met, is involved in this promotion. In this research, the decrease in the invasive activity under the hypoxia culture condition without changing HGF gene expression was observed, suggesting the presence of the novel regulation pathway in oxidative stress-induced change in hepatoma cell invasion. AH109A cells expressed integrins α2, α5, α6, β1 on their cell membrane and these integrins were proved to be localized in their membrane microdomains. Moreover, methyl-β-cyclodextrin affected AH109A invasion, suggesting the involvement of membrane microdomain in their invasion. So, the effect of oxidative stress, especially hypoxia, on hepatoma cell invasion was extensively investigated. AH109A cells, when cultured under the hypoxia condition, showed decreased invasive activities, but they did not show decreased adhesive activities to the normal cell monolayer and decreased HGF production. The expression level of c-met in AH109A cells did not change under the hypoxia culture condition. Recently the association of c-met with integrins is reported to be important in the promotion of cell motility by HGF. These results suggest that hypoxia may affect the association of c-met with integrins in membrane microdomains of AH109A cells, thus changing their invasive activities. Although further studies, such as co-immunoprecipitation assay of c-met and integrins, are thought to be needed to clarify the precise mechanism for hypoxia-induced reduction in invasive activities, some evidences for the possible involvement of membrane microdomains in oxidative stress-induced change in hapatoma invasion were obtained by this research.

研究了膜微区在氧化应激诱导的肝癌细胞侵袭变化中的可能参与。我已经报道了活性氧可以促进肝癌细胞的侵袭，肝细胞生长因子(HGF)及其受体c-MET之间的自分泌途径参与了这一促进作用。在本研究中，观察到在没有改变HGF基因表达的情况下，低氧培养条件下的侵袭活性降低，这表明在氧化应激诱导的肝癌细胞侵袭的变化中存在新的调控途径。AH109A细胞在细胞膜上表达整合素α-2、α-5、α-6、β-1，并证实这些整合素定位于细胞膜微区。此外，甲基-β-环糊精影响AH109A的侵袭，提示膜微区参与了它们的侵袭。因此，氧化应激，尤其是低氧对肝癌细胞侵袭的影响被广泛研究。在低氧条件下培养的AH109A细胞侵袭活性降低，但与正常细胞单层的黏附活性并未降低，HGF产生减少。缺氧培养条件下，AH109A细胞中c-met的表达水平无明显变化。最近，c-met与整合素的结合被报道在HGF促进细胞运动中起重要作用。这些结果提示，低氧可能影响AH109A细胞膜微区c-met与整合素的结合，从而改变其侵袭活性。虽然需要进一步的研究，如c-met和整合素的免疫共沉淀法，以阐明低氧诱导侵袭活性减少的确切机制，但本研究获得了一些证据，表明膜微域可能参与了氧化应激诱导的肝细胞瘤侵袭改变。