Meng Lingjiao, Liu Sihua, Liu Fei, Sang Meijie, Ju Yingchao, Fan Xiaojie, Gu Lina, Li Ziyi, Geng Cuizhi, Sang Meixiang
Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China; Department of Surgical Nursing, Hebei University of Chinese Medicine, Xingyuan Road, Shijiazhuang, Hebei 050200, P.R. China.
Mol Ther Nucleic Acids. 2020 Aug 19;22:124-137. doi: 10.1016/j.omtn.2020.08.015.
Zinc finger E-box binding homeobox 1 (ZEB1) has been widely recognized as an important driver of tumor growth and metastasis. However, nothing is known about ZEB1-regulated circular (circ)RNAs in cancer. In the current study, we evaluated the function of a novel ZEB1-regulated circRNA derived from the WWC3 gene locus, circWWC3 in breast cancer progression. We found that ZEB1 upregulated circWWC3 expression but not the linear WWC3 mRNA expression. circWWC3 is highly expressed in breast cancer tissues and is associated with the poor prognosis of breast cancer patients. Silencing of circWWC3 significantly suppresses the proliferation, migration, and invasion of breast cancer cells. Mechanically, circWWC3 upregulates multiple oncogenes' expression of the Ras signaling pathway through acting as the sponge of microRNA (miR)-26b-3p and miR-660-3p. Moreover, short hairpin (sh)RNA-mediated knockdown of circWWC3 partially antagonized ZEB1-mediated breast cancer growth and metastasis in vivo. Our findings reveal that ZEB1-mediated upregulation of circWWC3 promotes breast cancer progression through activating Ras signaling pathway, which provides a potential therapeutic target and prognostic biomarker for breast cancer.
锌指E盒结合同源框1（ZEB1）已被广泛认为是肿瘤生长和转移的重要驱动因素。然而，关于ZEB1调控的环状（circ）RNA在癌症中的作用尚无报道。在本研究中，我们评估了一种源自WWC3基因位点的新型ZEB1调控的circRNA，即circWWC3在乳腺癌进展中的作用。我们发现ZEB1上调circWWC3的表达，但不影响线性WWC3 mRNA的表达。circWWC3在乳腺癌组织中高表达，且与乳腺癌患者的不良预后相关。沉默circWWC3可显著抑制乳腺癌细胞的增殖、迁移和侵袭。机制上circWWC3通过充当微小RNA（miR）-26b-3p和miR-660-3p的海绵，上调Ras信号通路中多个癌基因的表达。此外，短发夹（sh）RNA介导的circWWC3敲低在体内部分拮抗了ZEB1介导的乳腺癌生长和转移。我们的研究结果表明，ZEB1介导的circWWC3上调通过激活Ras信号通路促进乳腺癌进展，这为乳腺癌提供了一个潜在的治疗靶点和预后生物标志物。
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