The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation.
The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation.
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环状RNA circ-ERBIN通过miR-125a-5p和miR-138-5p/4EBP-1介导的不依赖帽的HIF-1 α翻译促进结直肠癌的生长和转移
DOI：
10.1186/s12943-020-01272-9
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发表时间：
2020-11-23
期刊：
影响因子：
37.3
通讯作者：
Li JM
中科院分区：
文献类型：
--
作者：
Chen LY;Wang L;Ren YX;Pang Z;Liu Y;Sun XD;Tu J;Zhi Z;Qin Y;Sun LN;Li JM
环状RNA （circRNAs）和缺氧已被发现在包括结直肠癌（CRC）在内的癌症的发病和进展中发挥关键作用。然而，调控低氧CRC转移的特异性circrna的表达和功能，以及在CRC中调控HIF-1α水平的相关circrna仍不清楚。采用qRT-PCR检测CRC细胞和组织中circRNAs和mRNA的表达。荧光原位杂交法（FISH）分析了circ-ERBIN的位置。利用circ-ERBIN过表达和敲低细胞系进行体外和体内功能实验，包括CCK8、集落形成、EdU测定、transwell、肿瘤生长和转移模型。机制上，荧光素酶报告试验，免疫印迹和免疫组织化学染色。Circ-Erbin在CRC细胞中高表达，Circ-Erbin过表达促进CRC在体内外的增殖、迁移和转移。值得注意的是，circ-Erbin过表达通过增加CRC中缺氧诱导因子（HIF-1α）的表达显著促进血管生成。在机制上，circ-Erbin作为miR-125a-5p和miR-138-5p的海绵，加速了CRC细胞中HIF-1α的帽无关蛋白翻译，miR-125a-5p和miR-138-5p协同靶向真核翻译起始因子4E结合蛋白1（4EBP-1）。我们的研究结果揭示了circ-Erbin通过miR-125a-5p-5p/miR-138-5p/4EBP-1轴介导HIF-1α活化的关键机制，circ-Erbin是CRC治疗的潜在靶点。本文附有补充信息：10.1186/s12943-020-01272-9。
Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). However, the expressions and functions of the specific circRNAs in regulating hypoxia-involved CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC remain elusive. qRT-PCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression and knockdown cell lines in vitro and in vivo, including CCK8, colony formation, EdU assay, transwell, tumor growth and metastasis models. Mechanistically, luciferase reporter assay, western blots and immunohistochemical stainings were performed. Circ-Erbin was highly expressed in the CRC cells and Circ-Erbin overexpression facilitated the proliferation, migration and metastasis of CRC in vitro and in vivo. Notably, circ-Erbin overexpression significantly promoted angiogenesis by increasing the expression of hypoxia induced factor (HIF-1α) in CRC. Mechanistically, circ-Erbin accelerated a cap-independent protein translation of HIF-1α in CRC cells as the sponges of miR-125a-5p and miR-138-5p, which synergistically targeted eukaryotic translation initiation factor 4E binding protein 1(4EBP-1). Our findings uncover a key mechanism for circ-Erbin mediated HIF-1α activation by miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and circ-ERBIN is a potential target for CRC treatment. Supplementary information accompanies this paper at 10.1186/s12943-020-01272-9.
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