MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK
MicroRNA-1224 Inhibits Tumor Metastasis in Intestinal-Type Gastric Cancer by Directly Targeting FAK
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MicroRNA-1224 通过直接靶向 FAK 抑制肠型胃癌的肿瘤转移
DOI：
10.3389/fonc.2019.00222
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发表时间：
2019-04-04
影响因子：
4.7
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
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作者：
Wang, Jin;Wen, Ti;Liu, Yunpeng
Lauren分类系统的肠型胃癌（GC）具有特定的流行病学特征和癌变模式。MicroRNAs （miRNAs）具有预后意义，部分miRNAs可作为胃癌的预后生物标志物。在这项研究中，我们通过癌症基因组图谱（TCGA）分析发现miR-1224是肠型胃癌患者中潜在的与生存相关的miRNA。通过实时荧光定量PCR (qRT-PCR)，我们发现miR-1224在肠型GC组织中的相对表达量与匹配的邻近正常粘膜组织相比显著降低（p < 0.01）。我们发现，在90例肠型胃癌组织中，miR-1224高表达与无淋巴结转移（p < 0.05）和预后良好（p = 0.028）相关。转染miR-1224模拟物的肠型GC细胞显示，miR-1224在体外抑制细胞迁移（伤口愈合实验和Transwell迁移实验），而转染miR-1224抑制剂的细胞在体外促进细胞迁移。在异种移植小鼠模型中，miR-1224也抑制肠型胃癌细胞转移。此外，生物信息学、荧光素酶报告基因、Western blotting和免疫组织化学（IHC）研究表明，miR-1224直接与局灶黏附激酶（FAK）基因结合，并下调其表达，从而降低STAT3和NF-κB信号传导，进而降低上皮细胞到间质细胞的转化（EMT）。在肠型GC中，mir -1224介导的细胞迁移抑制需要抑制FAK。本研究表明miR-1224在肠型GC中下调。miR-1224通过抑制fak介导的STAT3和NF-κB通路的激活以及随后的EMT来抑制肠型GC的转移。miR-1224可能是肠型GC的一个重要预后因素。
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.