Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis.
Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis.
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miR-6868-5p/FOXM1 回路失调有助于结直肠癌血管生成
DOI：
10.1186/s13046-018-0970-5
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发表时间：
2018-11-28
期刊：
影响因子：
--
通讯作者：
Chu X
中科院分区：
文献类型：
--
作者：
Wang Y;Wu M;Lei Z;Huang M;Li Z;Wang L;Cao Q;Han D;Chang Y;Chen Y;Liu X;Xue L;Mao X;Geng J;Chen Y;Dai T;Ren L;Wang Q;Yu H;Chen C;Chu X
转录因子叉头盒M1 （FOXM1）是结直肠癌（CRC）进展的关键调节因子。然而，导致FOXM1在结直肠癌中失调的调控机制尚不清楚。双荧光素酶报告基因检测确定FOXM1是miR-6868-5p的靶标。体外验证miR-6868-5p和FOXM1在结直肠癌血管生成中的功能。构建瘤内注射模型，探讨miR-6868-5p对体内血管生成的影响。染色质免疫沉淀法用于评估H3K27me3与miR-6868启动子的直接结合。通过综合分析，我们发现miR-6868-5p是FOXM1的有效调节因子。CRC细胞中miR-6868-5p的过表达抑制了共培养内皮细胞的血管生成特性，而miR-6868-5p的沉默则具有相反的效果。在裸鼠体内递送miR-6868-5p可阻断肿瘤血管生成，从而抑制肿瘤生长。FOXM1的修复逆转了miR-6868-5p对肿瘤血管生成的作用。进一步的机制研究表明，FOXM1促进IL-8的产生，IL-8负责miR-6868-5p/FOXM1轴调控的血管生成。反过来，FOXM1通过ezh2介导的miR-6868-5p启动子上的H3K27me3抑制miR-6868-5p的表达，从而形成一个反馈回路。在临床上，miR-6868-5p水平在结直肠癌组织中下调，并与肿瘤标本中微血管密度以及FOXM1和IL-8水平呈负相关。总之，这些数据确定了miR-6868-5p是FOXM1表达的新决定因素，并建立了CRC血管生成的miR-6868-5p/FOXM1调控回路，为CRC治疗提供了潜在的靶点。本文的在线版本（10.1186/s13046-018-0970-5）包含补充资料，授权用户可使用。
Transcription factor forkhead box M1 (FOXM1) is a crucial regulator in colorectal cancer (CRC) progression. However, the regulatory mechanisms causing dysregulation of FOXM1 in CRC remain unclear. Dual-luciferase reporter assay was conducted to determine FOXM1 as miR-6868-5p target. The function of miR-6868-5p and FOXM1 in CRC angiogenesis was verified in vitro. Intratumoral injection model was constructed to explore the effect of miR-6868-5p on angiogenesis in vivo. Chromatin immunoprecipitation assays were used to assess direct binding of H3K27me3 to the miR-6868 promoter. Through integrated analysis, we identified miR-6868-5p as the potent regulator of FOXM1. Overexpression of miR-6868-5p in CRC cells inhibited the angiogenic properties of co-cultured endothelial cells, whereas silencing of miR-6868-5p had opposite effects. In vivo delivery of miR-6868-5p blocked tumor angiogenesis in nude mice, resulting in tumor growth inhibition. Rescue of FOXM1 reversed the effect of miR-6868-5p on tumor angiogenesis. Further mechanistic study revealed that FOXM1 promoted the production of IL-8, which was responsible for the miR-6868-5p/FOXM1 axis-regulated angiogenesis. Reciprocally, FOXM1 inhibited miR-6868-5p expression through EZH2-mediated H3K27me3 on miR-6868-5p promoter, thus forming a feedback circuit. Clinically, the level of miR-6868-5p was downregulated in CRC tissues and inversely correlated with microvessel density as well as levels of FOXM1 and IL-8 in tumor specimens. Together, these data identify miR-6868-5p as a novel determinant of FOXM1 expression and establish a miR-6868-5p/FOXM1 regulatory circuit for CRC angiogenesis, providing potential target for CRC treatment. The online version of this article (10.1186/s13046-018-0970-5) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Lee, Y. S.;Choi, I.;Ning, Y.;Kim, N. Y.;Khatchadourian, V.;Yang, D.;Chung, H. K.;Choi, D.;LaBonte, M. J.;Ladner, R. D.;Venkata, K. C. Nagulapalli;Rosenberg, D. O.;Petasis, N. A.;Lenz, H-J;Hong, Y-K
通讯作者：
Hong, Y-K
影响因子：
50.3
作者：
Chang CJ;Yang JY;Xia W;Chen CT;Xie X;Chao CH;Woodward WA;Hsu JM;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
51.1
作者：
Bagnoli, Marina;Canevari, Silvana;Mezzanzanica, Delia
通讯作者：
Mezzanzanica, Delia
影响因子：
11.2
作者：
Ren, Gang;Baritaki, Stavroula;Yeung, Kam C.
通讯作者：
Yeung, Kam C.
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.