The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells.
The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells.
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DOI：
10.1038/s41388-022-02451-2
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发表时间：
2022-10
期刊：
影响因子：
8
通讯作者：
Wang, Jide
中科院分区：
文献类型：
--
作者：
Tang, Weimei;Pei, Miaomiao;Li, Jiaying;Xu, Nanzhu;Xiao, Wushuang;Yu, Zhen;Zhang, Jieming;Hong, Linjie;Guo, Zheng;Lin, Jianjiao;Dai, Weiyu;Xiao, Yizhi;Wu, Xiaosheng;Liu, Guangnan;Zhi, Fachao;Li, Guoxin;Xiong, Jing;Chen, Ye;Zhang, Hui;Xiang, Li;Li, Aimin;Liu, Side;Wang, Jide
尽管癌细胞中miRNAs的异常表达已被广泛接受，但miR-3648在胃癌（GC）中进展和转移的分子机制仍不清楚。miR-3648表达下调，其在GC细胞中的异位表达显著抑制细胞增殖和转移。机制分析表明，miR-3648直接靶向FRAT 1或FRAT 2，并在体外和体内抑制FRAT 1或FRAT 2介导的侵袭和运动。此外，FRAT 1与FRAT 2在物理上相互作用。此外，FRAT 1过表达促进GC细胞侵袭，而siRNA介导的FRAT 2在FRAT 1过表达的GC细胞中的抑制逆转了其侵袭潜力。此外，miR-3648通过下调胃癌中的FRAT 1和FRAT 2来失活Wnt/β-catenin信号通路。有趣的是，c-Myc，Wnt/β-catenin信号传导的下游效应子，也被miR-3648过表达下调。反过来，c-Myc通过与miR-3648启动子结合来负调控miR-3648表达。此外，在新鲜胃样本中，miR-3648表达水平与c-Myc、FRAT 1和FRAT 2表达呈负相关。我们的研究表明，miR-3648是一种肿瘤抑制性miRNA，miR-3648/FRAT 1-FRAT 2/c-Myc负反馈环可能是GC进展的关键调节因子。
Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the molecular mechanisms underlying miR-3648 progression and metastasis in gastric cancer (GC) remain unclear. miR-3648 expression is downregulated and its ectopic expression in GC cells significantly suppressed cell proliferation and metastasis. Mechanistic analyses indicated that miR-3648 directly targets FRAT1 or FRAT2 and inhibits FRAT1- or FRAT2-mediated invasion and motility in vitro and in vivo. Moreover, FRAT1 physically interacted with FRAT2. Furthermore, FRAT1 overexpression promoted GC cell invasion, whereas siRNA-mediated repression of FRAT2 in FRAT1-overexpressing GC cells reversed its invasive potential. Besides, miR-3648 inactivated the Wnt/β-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/β-catenin signalling, was also downregulated by miR-3648 overexpression. In turn, c-Myc negatively regulated miR-3648 expression by binding to the miR-3648 promoter. In addition, miR-3648 expression levels were negatively correlated with c-Myc, FRAT1, and FRAT2 expression in fresh gastric samples. Our studies suggest that miR-3648 acts as a tumour-suppressive miRNA and that the miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop could be a critical regulator of GC progression.
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