microRNA-33a prevents epithelial-mesenchymal transition, invasion, and metastasis of gastric cancer cells through the Snail/Slug pathway

Abstract

Invasion and metastasis are responsible for the majority of deaths in gastric cancer (GC). microRNA-33a (miR-33a) might function as a tumor suppressor in multiple cancers. Here, we describe the regulation and function of miR-33a in GC and mechanisms involved in epithelial-mesenchymal transition (EMT) and metastasis. First, GC tissues and adjacent normal tissues were collected. miR-33a upregulation or SNAI2 depletion on GC cells were introduced to assess the detailed regulatory mechanism of them. We assessed the expression of miR-33a, SNAI2, Snail/Slug signaling pathway-related genes, and EMT-related markers in GC tissues and cells. miR-33a distribution in GC tissues and adjacent normal tissues was measured. Cell proliferation, migration and invasion, and cell cycle distribution were assessed. In nude mice, GC tumor growth and lymph node metastasis were observed. Furthermore, the predicative value of miR-33a in the prognosis of GC patients was evaluated. The obtained results indicated that lowly expressed miR-33a, highly expressed SNAI2, activated Snail/Slug, and increased EMT were identified in GC tissues. miR-33a was located mainly in the cytoplasm. miR-33a targeted and negatively regulated SNAI2. MKN-45 and MKN-28 cell lines were selected for in vitro experiments. Upregulated miR-33a expression or siRNA-mediated silencing of SNAI2 suppressed the activation of Snail/Slug, whereby GC cell proliferation, invasion and migration, EMT, tumor growth, and lymph node metastasis were inhibited. High expression of miR-33a was a protective factor influencing the prognosis of GC. This study suggests that miR-33a inhibited EMT, invasion, and metastasis of GC through the Snail/Slug signaling pathway by modulating SNAI2 expression. NEW & NOTEWORTHY miR-33a targets and inhibits the expression of SNAI2, overexpression of SNAI2 activates the Snail/Slug signaling pathway, the Snail/Slug signaling pathway promotes GC cell proliferation, invasion, and metastasis, and overexpression of miR-33a inhibits cell proliferation, invasion, and metastasis. This study provides a new therapeutic target for the treatment of GC.

Bile acids increase intestinal markers via FXR/SNAI2/miR-1 axis in the stomach

“…We also provided evidence that SNAI2 could stimulate the expression of intestinal markers in gastric cells and primary cultured cells. These results are partly consistent with some studies showing that SNAI2 promotes the malignant transformation of gastric cells through an EMT dependent manner [36][37][38][39]. Nevertheless, in this study, we rst identi ed that SNAI2 was augmented in IM tissues and could promote the expression of intestinal markers in gastric cells.…”

Role of microRNA‑33a in malignant cells (Review)

“…In addition, miR-33a downregulates Snail and Slug levels, and inhibition of the Snail/Slug signaling pathway hinders migration and invasion of these cells (Fig. 2B) (42). Wu et al (43) have revealed that lncRNA CASC15 is a miRNA sponge in gastric cancer cells, as in hepatoma cells.…”

Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

“…Among them are miR-30a [70], miR-122 [95], miR-182 [115], and miR-203 [115] and miR-204 [116]. SLUG is targeted in in oral squamous cell carcinoma by miR-204 [116]; glioblastoma by miR-203 [117]; in lung cancer by miR-1 [118]; in breast cancer by miR-124 [119,120], miR-30a [70], miR-497 [121], miR-1271 [122], and miR-203 [123,124]; in gastric cancer by miR-33a [125]; in lung cancer by miR-218 [126]; in clear cell renal cell carcinoma by miR-1 [127]; in osteosarcoma by miR-124 [128]; and in gingival fibroblasts by miR-200b [129]. Similarly to SNAIL, miRNAs-SLUG action regulates EMT in cancer progression, as well as different processes, such as the modulation of cancer stem cells' activity.…”

“…Cancer/Cell Type References miR-1 lung cancer [118] miR-30a breast cancer [70] miR-33a gastric cancer [125] miR-124 breast cancer [119,120] osteosarcoma [128] glioma [130] miR-200b gingival fibroblasts [129] miR-203 glioblastoma [117] breast cancer [123,124] miR-204 oral squamous cell carcinoma [116] miR-218 lung cancer [126] miR-497 breast cancer [121] miR-630 dermal microvascular endothelial cells [131] miR-1271 breast cancer [122]…”