血管生成是腫瘤生長(zhǎng)和轉(zhuǎn)移的必要條件,。近年來(lái)研究發(fā)現(xiàn)，肝素類(lèi)化合物不僅具有抗凝血活性,，還可以抑制不同實(shí)驗(yàn)動(dòng)物模型的腫瘤血管生成,，但機(jī)制有待進(jìn)一步明確。
中科院上海藥物研究所糖生物學(xué)及糖化學(xué)實(shí)驗(yàn)室丁侃課題組對(duì)肝素的抗血管生成作用機(jī)制進(jìn)行了研究,。該研究發(fā)現(xiàn),，肝素處理后的內(nèi)皮細(xì)胞中miR-10b表達(dá)下調(diào)， miR-10b能夠通過(guò)靶向HoxD10的表達(dá)從而促進(jìn)血管生成,；而凝血酶（thrombin）可誘導(dǎo)miR-10b轉(zhuǎn)錄因子Twist的表達(dá),，從而促進(jìn)miR-10b的功能，進(jìn)一步下調(diào)HoxD10的表達(dá),，最終達(dá)到促進(jìn)血管生成的作用,。關(guān)鍵的是,，肝素可以和凝血酶結(jié)合進(jìn)而逆轉(zhuǎn)凝血酶的功效，起到抑制血管生成而達(dá)到抗腫瘤的作用,。
這些研究為肝素影響血管生成的作用機(jī)制研究提供了一條新的通路,。該發(fā)現(xiàn)已在線發(fā)表于6月3日的美國(guó)《生物化學(xué)期刊》（Journal of Biological Chemistry,2011,doi:10.1074/jbc.M111.224212）。
該項(xiàng)目主要由沈孝坤博士完成,。研究工作得到了國(guó)家自然科學(xué)基金委及中國(guó)科學(xué)院的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
Journal of Biological Chemistry doi:10.1074/jbc.M111.224212
Heparin impairs angiogenesis through inhibition of MicroRNA-10b
Xiaokun Shen, Jianping Fang, Xiaofen Lv, Zhichao Pei, Ying Wang, Songshan Jiang and Kan Ding
Heparin, which has been used as an anticoagulant drug for decades, inhibits angiogenesis, while thrombin promotes tumor-associated angiogenesis. However, the mechanisms underlying the regulation of angiogenesis by heparin and thrombin are not well understood. Here, we show that microRNA-10b (miR-10b) is down-regulated by heparin and up-regulated by thrombin in human microvascular endothelial cells (HMEC-1). Overexpression of miR-10b induces HMEC-1 cell migration, tube formation and angiogenesis, and downregulates homeobox D10 (HoxD10) expression via direct binding of miR-10b to the putative 3'UTR of HoxD10. In addition, HMEC-1 cell migration and tube formation are induced by HoxD10 knockdown, whereas angiogenesis is arrested when HoxD10 expression is increased after anti-miR-10b or heparin treatment. Furthermore, expression of miR-10b and its transcription factor Twist are up-regulated by thrombin, whereas HoxD10 expression is impaired by thrombin. Using quartz crystal microbalance (QCM) analysis, we show that heparin binds to thrombin, thereby inhibiting thrombin induced expression of Twist and miR-10b. However, the expression of miR-10b is not attenuated by heparin any more after thrombin expression is silenced by its siRNA. Interestingly, we find that heparin attenuates miR-10b expression and induces HoxD10 expression in vivo to inhibit angiogenesis and impair the growth of MDA-MB-231 tumor xenografts. These results provide insight into the molecular mechanism by which heparin and thrombin regulate angiogenesis.
