血管生成是肿瘤生长和转移的必要条件。近年来研究发现，肝素类化合物不仅具有抗凝血活性，还可以抑制不同实验动物模型的肿瘤血管生成，但机制有待进一步明确。

中科院上海药物研究所糖生物学及糖化学实验室丁侃课题组对肝素的抗血管生成作用机制进行了研究。该研究发现，肝素处理后的内皮细胞中miR-10b表达下调， miR-10b能够通过靶向HoxD10的表达从而促进血管生成；而凝血酶（thrombin）可诱导miR-10b转录因子Twist的表达，从而促进miR-10b的功能，进一步下调HoxD10的表达，最终达到促进血管生成的作用。关键的是，肝素可以和凝血酶结合进而逆转凝血酶的功效，起到抑制血管生成而达到抗肿瘤的作用。

这些研究为肝素影响血管生成的作用机制研究提供了一条新的通路。该发现已在线发表于6月3日的美国《生物化学期刊》（Journal of Biological Chemistry,2011,doi:10.1074/jbc.M111.224212）。

该项目主要由沈孝坤博士完成。研究工作得到了国家自然科学基金委及中国科学院的资助。

原文出处：

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.