Meng Lingjiao, Zheng Yang, Liu Sihua, Ju Yingchao, Ren Shuguang, Sang Yang, Zhu Yonggang, Gu Lina, Liu Fei, Zhao Yang, Zhang Xiaochong, Sang Meixiang
Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, People's Republic of China; Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, People's Republic of China.
Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, People's Republic of China.
Cancer Lett. 2021 Oct 28;519:117-129. doi: 10.1016/j.canlet.2021.06.026. Epub 2021 Jun 30.
ZEB1 is an important transcription factor that plays a critical role in TGF-β-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the mechanisms by which ZEB1 regulates metastasis in esophageal squamous cell carcinoma (ESCC) remain largely unknown. Here, we identified a novel circular RNA, circ-DOCK5, the biogenesis of which is directly regulated by ZEB1 and ZEB1-repressed RNA-binding protein eIF4A3. Tissue microarray analysis identified circ-DOCK5 to be downregulated in ESCC tissues, and its downregulation correlated with poor prognosis. Moreover, circ-DOCK5 increased the stability of miR-627-3p by functioning as a "reservoir" for miR-627-3p to partially reverse the ZEB1-enhanced migration and invasion in ESCC. MiR-627-3p inhibited the expression of TGFB2 and the secretion of TGF-β, which further resulted in downregulation of ZEB1 and suppression of TGF-β-induced EMT. In vivo experiments showed that ZEB1 promoted metastasis in ESCC by regulating expression of circ-DOCK5. Therefore, the present study revealed that ZEB1-mediated downregulation of circ-DOCK5 facilitates metastasis in ESCC by forming a positive feedback loop with TGF-β by altering the miR-627-3p/TGFB2 signaling. Targeting this signaling pathway may help suppress progression in ESCC.
ZEB1是一种重要的转录因子，在转化生长因子-β（TGF-β）诱导的上皮-间质转化（EMT）和肿瘤转移中起关键作用。然而，ZEB1在食管鳞状细胞癌（ESCC）中调节转移的机制仍 largely unknown。在此，我们鉴定了一种新型环状RNA，circ-DOCK5，其生物合成直接受ZEB1和ZEB1抑制的RNA结合蛋白eIF4A3调控。组织芯片分析显示circ-DOCK5在ESCC组织中下调，其下调与预后不良相关。此外，circ-DOCK5通过作为miR-627-3p的“储存库”发挥作用，增加miR-627-3p的稳定性，以部分逆转ZEB1增强的ESCC细胞迁移和侵袭。miR-627-3p抑制TGFB2的表达和TGF-β的分泌，进而导致ZEB1下调并抑制TGF-β诱导的EMT。体内实验表明，ZEB1通过调节circ-DOCK5的表达促进ESCC转移。因此，本研究揭示ZEB1介导的circ-DOCK5下调通过改变miR-627-3p/TGFB2信号通路与TGF-β形成正反馈环，促进ESCC转移。靶向该信号通路可能有助于抑制ESCC的进展。
