The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.
The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition.
复制标题
FUS/circEZH2/KLF5/反馈环路通过增强上皮间质转化促进CXCR4诱导的乳腺癌肝转移
DOI：
10.1186/s12943-022-01653-2
复制
发表时间：
2022-10-12
期刊：
影响因子：
37.3
通讯作者：
Tang, Hailin
中科院分区：
文献类型：
--
作者：
Liu, Peng;Wang, Zehao;Ou, Xueqi;Wu, Peng;Zhang, Yue;Wu, Song;Xiao, Xiangsheng;Li, Yuehua;Ye, Feng;Tang, Hailin
乳腺癌的转移导致了世界范围内大多数癌症相关死亡。根据最近的研究，环状rna与乳腺癌的肿瘤发生和转移有关。然而，circrna在肝转移性乳腺癌中的生物学机制尚不清楚。微阵列分析三对原发性BC组织和匹配的肝转移标本鉴定出circEZH2。我们使用RT-qPCR和FISH检测来证实circEZH2的存在、特征和表达。在体内和体外实验中，circEZH2均具有促进肿瘤转移的致瘤作用。采用一系列生物信息学分析、Western blot、RNA pull-down、RIP、ChIP和动物实验来定义涉及FUS、circEZH2、miR-217-5p、KLF5、FUS、CXCR4以及上皮和间质转化的反馈回路。在我们的研究中，circEZH2被证实在BC肝转移中表达上调，并预测乳腺癌患者预后较差。过表达circEZH2显著增强了BC细胞的活力和侵袭性，而敲低circEZH2则会产生相反的效果。此外，过表达的circEZH2在体内促进肿瘤发生和肝转移。此外，circEZH2可以吸附miR-217-5p上调KLF5，从而激活FUS转录，从而促进circEZH2的反剪接程序。同时，KLF5可以通过转录上调CXCR4，加速乳腺癌的上皮和间质转化。因此，我们建立了一个新的反馈回路FUS/circEZH2/KLF5/CXCR4， circEZH2可能成为新的生物标志物和BC患者治疗的潜在靶点。在线版本包含补充材料，可在10.1186/s12943-022-01653-2获得。
Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. Consequently, a novel feedback loop FUS/circEZH2/KLF5/CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients’ therapy. The online version contains supplementary material available at 10.1186/s12943-022-01653-2.
登录
查看更多内容
circRNA生物合成的调控
影响因子：
4.1
作者：
Chen, Ling-Ling;Yang, Li
通讯作者：
Yang, Li
影响因子：
4.1
作者：
Dudekulay, Dawood B.;Panda, Amaresh C.;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
影响因子：
56.9
作者：
Kapranov, Philipp;Cheng, Jill;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
影响因子：
3.8
作者：
Eng, Lee Guek;Dawood, Shaheenah;Dent, Rebecca
通讯作者：
Dent, Rebecca
影响因子：
64.8
作者：
Correia, Ana Luisa;Guimaraes, Joao C.;Bentires-Alj, Mohamed
通讯作者：
Bentires-Alj, Mohamed