转录因子六 2 促进了 CYP4Z1 和假基因 CYP4Z2P 之间的竞争内源性 RNA 网络，负责维持乳腺癌细胞的干性。
Transcriptional factor six2 promotes the competitive endogenous RNA network between CYP4Z1 and pseudogene CYP4Z2P responsible for maintaining the stemness of breast cancer cells.
机构信息
Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
出版信息
J Hematol Oncol. 2019 Mar 4;12(1):23. doi: 10.1186/s13045-019-0697-6.
BACKGROUND
The expression of CYP4Z1 and the pseudogene CYP4Z2P has been shown to be specifically increased in breast cancer by our group and others. Additionally, we previously revealed the roles of the competitive endogenous RNA (ceRNA) network mediated by these genes (ceRNET_CC) in breast cancer angiogenesis, apoptosis, and tamoxifen resistance. However, the roles of ceRNET_CC in regulating the stemness of breast cancer cells and the mechanisms through which ceRNET_CC is regulated remain unclear.
METHODS
Transcriptional factor six2, CYP4Z1-3'UTR, and CYP4Z2P-3'UTR were stably overexpressed or knocked down in breast cancer cells via lentivirus infection. ChIP-sequencing and RNA-sequencing analysis were performed to reveal the mechanism through which ceRNET_CC is regulated and the transcriptome change mediated by ceRNET_CC. Clinical samples were used to validate the correlation between six2 and ceRNET_CC. Finally, the effects of the six2/ceRNET_CC axis on the stemness of breast cancer cells and chemotherapy sensitivity were evaluated by in vitro and in vivo experiments.
RESULTS
We revealed that ceRNET_CC promoted the stemness of breast cancer cells. Mechanistically, six2 activated ceRNET_CC by directly binding to their promoters, thus activating the downstream PI3K/Akt and ERK1/2 pathways. Finally, we demonstrated that the six2/ceRNET_CC axis was involved in chemoresistance.
CONCLUSIONS
Our results uncover the mechanism through which ceRNET_CC is regulated, identify novel roles for the six2/ceRNET_CC axis in regulating the stemness of breast cancer cells, and propose the possibility of targeting the six2/ceRNET_CC axis to inhibit breast cancer stem cell (CSC) traits.
背景
本课题组及其他课题组已证实 CYP4Z1 和假基因 CYP4Z2P 的表达在乳腺癌中特异性增加。此外，我们之前揭示了这些基因（ceRNET_CC）介导的竞争性内源性 RNA（ceRNA）网络在乳腺癌血管生成、细胞凋亡和他莫昔芬耐药中的作用。然而，ceRNET_CC 在调节乳腺癌细胞干性中的作用以及 ceRNET_CC 受调控的机制尚不清楚。
方法
通过慢病毒感染，在乳腺癌细胞中稳定过表达或敲低转录因子六蛋白 2、CYP4Z1-3'UTR 和 CYP4Z2P-3'UTR。进行 ChIP-seq 和 RNA-seq 分析，以揭示 ceRNET_CC 受调控的机制和 ceRNET_CC 介导的转录组变化。临床样本用于验证六蛋白 2 与 ceRNET_CC 之间的相关性。最后，通过体外和体内实验评估六蛋白 2/ceRNET_CC 轴对乳腺癌细胞干性和化疗敏感性的影响。
结果
我们揭示了 ceRNET_CC 促进了乳腺癌细胞的干性。机制上，六蛋白 2 通过直接结合其启动子激活 ceRNET_CC，从而激活下游的 PI3K/Akt 和 ERK1/2 通路。最后，我们证实了六蛋白 2/ceRNET_CC 轴参与了化疗耐药。
结论
我们的研究结果揭示了 ceRNET_CC 受调控的机制，确定了六蛋白 2/ceRNET_CC 轴在调节乳腺癌细胞干性中的新作用，并提出了靶向六蛋白 2/ceRNET_CC 轴抑制乳腺癌干细胞（CSC）特性的可能性。
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