National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, China.
Department of Pharmacy, Southwest Hospital, Third Military Medical University, Chongqing, China.
Cancer Sci. 2018 May;109(5):1393-1403. doi: 10.1111/cas.13583. Epub 2018 Apr 22.
Gastric cancer (GC) is among the most fatal cancers in China. MicroRNAs (miRNAs) are versatile regulators during GC development and progression. miR-491-5p has been demonstrated to act as a tumor suppressor in several types of cancer. However, the role of miR-491-5p in GC metastasis remains unknown. Here, we found that miR-491-5p was significantly decreased in GC tissues compared with adjacent non-cancerous tissues, and low miR-491-5p level was associated with large tumor size. Overexpression of miR-491-5p significantly suppressed GC cell epithelial-to-mesenchymal transition (EMT) and tumor metastasis in vitro and in vivo. Mechanistically, SNAIL was identified as a direct target of miR-491-5p. The silencing of SNAIL phenocopied the tumor suppressive function of miR-491-5p, whereas re-expression of SNAIL in GC cells rescued the EMT markers and cell migratory ability that were inhibited by miR-491-5p. In addition, miR-491-5p inhibited FGFR4 indirectly. Inhibition of FGFR4 also decreased the SNAIL level and impaired EMT and cell migration. Taken together, these findings indicate that downregulation of miR-491-5p promoted GC metastasis by inducing EMT via regulation of SNAIL and FGFR4.
胃癌（GC）是中国最致命的癌症之一。microRNAs（miRNAs）在 GC 的发展和进展中是多功能的调节因子。miR-491-5p 已被证明在几种类型的癌症中起肿瘤抑制作用。然而，miR-491-5p 在 GC 转移中的作用尚不清楚。在这里，我们发现 miR-491-5p 在 GC 组织中的表达明显低于相邻的非癌组织，并且低水平的 miR-491-5p 与大肿瘤大小相关。miR-491-5p 的过表达显著抑制了 GC 细胞的上皮-间充质转化（EMT）和体内外的肿瘤转移。机制上，SNAIL 被鉴定为 miR-491-5p 的直接靶标。SNAIL 的沉默模拟了 miR-491-5p 的肿瘤抑制功能，而 SNAIL 在 GC 细胞中的重新表达挽救了被 miR-491-5p 抑制的 EMT 标志物和细胞迁移能力。此外，miR-491-5p 间接抑制 FGFR4。FGFR4 的抑制也降低了 SNAIL 水平，并损害了 EMT 和细胞迁移。总之，这些发现表明，miR-491-5p 的下调通过调节 SNAIL 和 FGFR4 诱导 EMT 促进了 GC 转移。
