The miR-3648/FRAT1-FRAT2/c-Myc negative feedback loop modulates the metastasis and invasion of gastric cancer cells

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^*

来源：Oncogene, 2022, 41(43): 4823-4838.

DOI：10.1038/s41388-022-02451-2

• EPITHELIAL-MESENCHYMAL TRANSITION
• WNT SIGNALING PATHWAY
• MOLECULAR-CLONING
• TUMOR-METASTASIS
• IN-VITRO
• C-MYC
• PROLIFERATION
• FRAT1
• EXPRESSION
• REGULATOR

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/beta-catenin signalling pathway by downregulating FRAT1 and FRAT2 in GC. Interestingly, c-Myc, a downstream effector of Wnt/beta-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.

• 单位
  Southern Medical University