Key Laboratory of Experimental Animal and Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou 310013, China.
Department of Clinical Laboratory Medicine, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China.
Int J Biol Macromol. 2019 Jul 1;132:470-477. doi: 10.1016/j.ijbiomac.2019.03.221. Epub 2019 Mar 29.
Circulating exosomal microRNAs (exomiR) have been demonstrated to be novel diagnostic biomarkers for various cancers. In this study, we found that circulating exomiR-1229 levels were significantly increased in the serum exosomes of patients with colorectal cancer (CRC) and significantly associated with tumor size, lymphatic metastasis, TNM stage and poor survival. Treatment with siRNA-Drosha, siRNA-ALIX and GW4869 repressed the expression of exomiR-1229 secreted from CRC cells. Both CRC-derived exosomes and exomiR-1229 mimic promoted the tubulogenesis of HUVECs, but transfection with exomiR-1229 inhibitor anta-miR-1229 significantly suppressed tube formation. Subsequently, HIPK2 was identified as a target of exomiR-1229 and responsible for the effect of exomiR-1229 on angiogenesis of HUVECs. ExomiR-1229 inhibited the protein expression of HIPK2, thereby activating VEGF pathway. Finally, anta-miR-1229 effectively inhibited tumor growth and angiogenesis in the nude mouse xenograft model. These results highlighted a novel mechanism of CRC angiogenesis and the biological roles of exomiR-1229.
循环外泌体 microRNAs（exomiR）已被证明是各种癌症的新型诊断生物标志物。在本研究中，我们发现结直肠癌（CRC）患者血清外泌体中的循环 exomiR-1229 水平显著升高，并且与肿瘤大小、淋巴转移、TNM 分期和预后不良显著相关。用 siRNA-Drosha、siRNA-ALIX 和 GW4869 处理可抑制 CRC 细胞分泌的 exomiR-1229 的表达。CRC 来源的外泌体和 exomiR-1229 模拟物均可促进 HUVEC 的管状形成，但转染 exomiR-1229 抑制剂 anta-miR-1229 可显著抑制管形成。随后，鉴定 HIPK2 为 exomiR-1229 的靶标，负责 exomiR-1229 对 HUVEC 血管生成的影响。exomiR-1229 抑制 HIPK2 蛋白表达，从而激活 VEGF 通路。最后，anta-miR-1229 可有效抑制裸鼠异种移植模型中的肿瘤生长和血管生成。这些结果突出了 CRC 血管生成的新机制和 exomiR-1229 的生物学作用。
