miR-542-3p抑制肿瘤新生血管的机制研究

发布时间：2018-02-20 01:05

本文关键词： 血管生长素新生血管血管生成素2 mi R-542-3p　出处：《清华大学》2015年博士论文　论文类型：学位论文

【摘要】：新生血管在肿瘤的生长、侵袭和转移中发挥着关键作用。研究表明,靶向新生血管的治疗策略对多种癌症都具有显著疗效。血管生成素2是新生血管过程中的重要因子。靶向血管生成素2的方法是一种极具潜力的癌症治疗策略。虽然mi RNA逐渐成为新生血管的重要调控因子,但是尚未有关于调控血管生成素2的mi RNA的报道。在本研究中,我们首次报道了mi R-542-3p可以靶向血管生成素2,通过抑制血管生成素2的促新生血管活性从而抑制肿瘤进展。在体外培养的血管内皮细胞中,mi R-542-3p能够结合血管生成素2 m RNA的3’非翻译区,从而抑制血管生成素2 m RNA的翻译。在血管内皮细胞中过表达mi R-542-3p可以抑制其新生血管活性。对荷瘤鼠施加mi R-542-3p能够抑制肿瘤生长、新生血管和转移。此外,在人的乳腺癌临床样本中,mi R-542-3p的表达水平与癌症的恶性程度负相关。为了进一步了解mi R-542-3p抑制新生血管活性的机理,我们筛选了肿瘤细胞分泌的、可能参与调控mi R-542-3p表达的胞外因子。研究发现,肿瘤细胞分泌的血管生长素可以下调血管内皮细胞的mi R-542-3p。无论在体外还是体内模型中,对肿瘤细胞过表达血管生长素都可以通过抑制mi R-542-3p激活内皮细胞的新生血管活性。深入研究发现,血管生长素可以抑制CCAAT/enhancer binding protein beta(CEBPB)和POU class 2 homeobox 1(POU2F1),后两者都是mi R-542-3p的转录因子,从而揭示了一个新的肿瘤细胞和内皮细胞之间的新生血管调控机制。此外,乳腺肿瘤中的血管生长素水平与疾病进展具有显著的相关性。乳腺癌患者血浆内的血管生长素含量在转移的患者中高于非转移患者。综上,我们的研究揭示了一个新的肿瘤新生血管调控机制:肿瘤细胞分泌的血管生长素作用于血管内皮细胞,抑制转录因子CEBPB和POU2F1的表达,进而下调mi R-542-3p,最终激活促新生血管蛋白血管生成素2的表达。因此,血管生长素和mi R-542-3p是潜在的抗新生血管治疗靶点和监测乳腺癌疾病进展的生物标志物。
[Abstract]:Neovascularization plays a key role in tumor growth, invasion and metastasis. Angiopoietin 2 is an important factor in angiogenesis, and angiopoietin 2 is a promising strategy for cancer treatment. Although mi RNA has gradually become an important regulator of neovascularization, However, no reports have been made on the regulation of angiopoietin 2 by mi RNA. We report for the first time that mi R-542-3p can target angiopoietin 2 and inhibit tumor progression by inhibiting angiopoietin-2 angiogenesis activity. In vitro cultured vascular endothelial cells, mi R-542-3p can bind to angiopoietin. The 3'untranslated area of 2 m RNA, Thus inhibiting the translation of angiopoietin 2 m RNA. Overexpression of mi R-542-3p in vascular endothelial cells can inhibit its neovascularization activity. The application of mi R-542-3p to tumor-bearing mice can inhibit tumor growth, neovascularization and metastasis. In clinical samples of human breast cancer, the expression level of miR-542-3p is negatively correlated with the malignancy of cancer. In order to further understand the mechanism of inhibition of angiogenesis by mi R-542-3p, we screened the tumor cell secreted. It was found that angiogenin secreted by tumor cells could down-regulate the expression of mi R-542-3p in vascular endothelial cells, both in vitro and in vivo. Angiogenin overexpression in tumor cells can inhibit angiogenesis of endothelial cells induced by mi R-542-3p. It was found that angiogenin could inhibit CCAAT/enhancer binding protein Beta BPBand POU class 2 homeobox 1POU2F1, both of which were transcription factors of mi R-542-3p. This reveals a new mechanism of neovascularization regulation between tumor cells and endothelial cells. The levels of angiotensin in breast tumors were significantly correlated with the progression of the disease. The plasma levels of angiotensin in breast cancer patients were higher than those in non-metastatic patients. Our study revealed a new mechanism of tumor neovascularization regulation: angiogenin secreted by tumor cells acts on vascular endothelial cells and inhibits the expression of transcription factors CEBPB and POU2F1. Therefore, angiogenin and miR-542-3p are potential targets for anti-angiogenic therapy and biomarkers for monitoring the progression of breast cancer.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.5

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