MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis
MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis
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MEGF6 通过 TGF beta/SMAD 信号通路促进结直肠癌转移中上皮细胞向间质细胞的转变
DOI：
10.1159/000489374
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Wang, Xishan
中科院分区：
文献类型：
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作者：
Hu, Hanqing;Wang, Meng;Wang, Xishan
背景/目的：结直肠癌（CRC）是一种发病率和死亡率高的恶性肿瘤，其起源于累积的遗传事件。虽然已经做了很多努力来阐明这种疾病的遗传机制，它仍然是未知的。在这里，我们发现了多个表皮生长因子样结构域蛋白6（MEGF6）在CRC中的新作用，即它通过转化生长因子β（TGF β）/SMAD信号通路诱导上皮-间充质转化（EMT）以促进CRC转移。方法：使用R软件分析来自Gene Expression Omnibus数据库的RNA测序数据。基于癌症基因组图谱结肠腺癌（TCGA-COAD）队列，研究MEGF6的临床意义。用针对MEGF6的小干扰RNA转染HCT8R、HCT116和LoVo CRC细胞，用MTT细胞增殖和集落形成试验评价它们的增殖和对氟尿嘧啶的敏感性。蛋白质印迹分析检测与细胞生长相关的蛋白。通过Annexin V/碘化丙啶染色评估细胞凋亡，并进行transwell分析以评估MEGF6在细胞迁移中的参与。通过定量PCR和蛋白质印迹法评估EMT和TGF β/SMAD信号传导的标志物，并在TCGA结肠和肾腺癌队列中评估MEGF6与这些标志物之间的相关性。结果：MEGF6在HCT 8R细胞中表达上调。此外，MEGF6在肿瘤组织中显著过表达，并预测TCGA-COAD队列的生存率较差。MEGF6可促进结直肠癌细胞的生长，抑制细胞凋亡，并通过诱导EMT促进结直肠癌的转移。最后，我们发现TGF β/SMAD信号触发Slug的表达，Slug调节MEGF6介导的EMT。结论：MEGF6可能是一种促进细胞增殖、抑制细胞凋亡的癌基因。MEGF6还可以通过TGF β/SMAD信号转导介导的EMT加速细胞迁移。(C)2018作者（S）由S发布。Karger AG，巴塞尔
Background/Aims: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGF beta)/SMAD signaling pathway. Methods: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGF beta/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. Results: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGF beta/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. Conclusions: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGF beta/SMAD signaling-mediated EMT. (C) 2018 The Author(s) Published by S. Karger AG, Basel