MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK

Abstract

Intestinal-type gastric cancer (GC) of the Lauren classification system has specific epidemiological characteristics and carcinogenesis patterns. MicroRNAs (miRNAs) have prognostic significance, and some can be used as prognostic biomarkers in GC. In this study, we identified miR-1224 as a potential survival-related miRNA in intestinal-type GC patients by The Cancer Genome Atlas (TCGA) analysis. Using quantitative real-time PCR (qRT-PCR), we showed that the relative expression of miR-1224 was significantly decreased in intestinal-type GC tissues compared to matched adjacent normal mucosa tissues ( p < 0.01). We found that high miR-1224 expression was associated with no lymph-node metastasis ( p < 0.05) and good prognosis ( p = 0.028) in 90 intestinal-type GC tissues. Transfection of intestinal-type GC cells with miR-1224 mimics showed that miR-1224 suppressed cell migration in vitro (wound healing assay and Transwell migration assay), whereas the transfection of cells with miR-1224 inhibitor promoted cell migration in vitro . miR-1224 also suppressed intestinal-type GC cell metastasis in a xenograft mouse model. Furthermore, bioinformatics, luciferase reporter, Western blotting, and immunohistochemistry (IHC) studies demonstrated that miR-1224 directly bound to the focal adhesion kinase (FAK) gene, and downregulated its expression, which decreased STAT3 and NF-κB signaling and subsequent the epithelial-to-mesenchymal transition (EMT). Repression of FAK is required for the miR-1224-mediated inhibition of cell migration in intestinal-type GC. The present study demonstrated that miR-1224 is downregulated in intestinal-type GC. miR-1224 inhibits the metastasis of intestinal-type GC by suppressing FAK-mediated activation of the STAT3 and NF-κB pathways, and subsequent EMT. miR-1224 could represent an important prognostic factor in intestinal-type GC.

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“…Overexpression of miR-1224-5p predicts good prognosis in intestinal-type gastric cancer and glioma. [29][30][31] miR-1224-5p inhibits the progression of gastric cancer and glioma by directly inhibiting FAK and CREB1. 29,31 In addition to its role in cancer, overexpression of miR-1224-5p observably inhibits the migration, invasion, and proliferation of keloid fibroblasts and represses proliferation of hepatocytes after acute liver failure.…”

MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways

“…The first study showing the relationship between miR-1224-5p and human cancer demonstrated that downregulated miR-1224 promotes cell proliferation in bladder cancer (14). Later, other studies revealed that miR-1224-5p is greatly decreased in intestinal-type gastric cancer and inhibits cell migration and metastasis by inhibiting focal adhesion kinase in vitro and in vivo (15). Nymark et al reported that miR-1224-5p is remarkably decreased in asbestos-related lung cancer (16).…”

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“…Hu et al found that miR-23a has role in promoting tumor growth and apoptosis via target gene PDCD4 in gastric cancer [54]. A recent study found association of miR-1224 in tumor metastasis in gastric cancer [57]. It was found that let-7 family is related with tumorigenesis in breast cancer [55].…”