microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells
microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells
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DOI：
10.1158/1078-0432.ccr-08-1818
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发表时间：
2009-04-01
影响因子：
11.5
通讯作者：
Garcia-Foncillas, Jesus
中科院分区：
文献类型：
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作者：
Bandres, Eva;Bitarte, Nerea;Garcia-Foncillas, Jesus
目的：微小核糖核酸（miRNA）是一类小分子RNA，作为基因表达的转录后调节因子发挥作用。近期有证据表明，一些miRNA可作为癌基因或肿瘤抑制因子。本研究旨在评估miRNA表达与胃癌患者临床结局之间的潜在关联。
实验设计：通过实时聚合酶链反应（real - time PCR）对21例均接受手术切除后放化疗的Ⅲ期胃癌患者的石蜡包埋肿瘤样本中250种人类成熟miRNA的表达进行检测。我们确定了与无病生存期和总生存期相关的miRNA，并对包括另外24例患者在内的结果进行了评估。进行了体外细胞增殖和放射敏感性研究以支持临床数据。
结果：结果显示，miR - 451的下调与更差的预后相关。通过原位杂交在上皮细胞中检测到miR - 451，并且与非肿瘤组织相比，其在胃癌和结直肠癌中的表达降低。在胃癌和结直肠癌细胞中过表达miR - 451可降低细胞增殖并增加对放疗的敏感性。基因芯片和生物信息学分析确定新的癌基因巨噬细胞移动抑制因子（MIF）为miR - 451的一个潜在靶标。事实上，miR - 451的过表达下调了MIF的信使核糖核酸（mRNA）和蛋白质水平，并降低了含MIF靶序列的报告基因的表达。此外，我们发现肿瘤胃活检组织中miR - 451和MIF的表达呈显著负相关。
结论：这些发现支持了miR - 451作为癌症增殖调节因子的作用，并为开发针对放化疗耐药癌症的有效疗法开辟了新的视角。
Purpose: micro RNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical Outcome in patients with gastric cancer.Experimental Design: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data.Results: The results revealed that down-regulation of miR-451 was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451 in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451, In fact, overexpression of miR-451 down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR-451 and MIF expression in tumoral gastric biopsies.Conclusions: These findings support the role of miR-451 as a regulator of cancer proliferation and open new perspectives for the development of effective therapies for chemoradioresistant cancers.