Hypermethylation of DMTN promotes the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through Rac1 signaling activation
Hypermethylation of DMTN promotes the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through Rac1 signaling activation
复制标题
DMTN高甲基化通过Rac1信号激活调节肌动蛋白细胞骨架促进结直肠癌细胞转移
DOI：
10.1186/s13046-018-0958-1
复制
发表时间：
2018
影响因子：
11.3
通讯作者：
Ding Yan Qing
中科院分区：
文献类型：
--
作者：
Ye Ya Ping;Jiao Hong Li;Wang Shu Yang;Xiao Zhi Yuan;Zhang Dan;Qiu Jun Feng;Zhang Ling Jie;Zhao Ya Li;Li Ting Ting;Li Liang;Liao Wen Ting;Ding Yan Qing
结直肠癌（colorectal cancer，CRC）是最常见的消化道恶性肿瘤之一，DMTN是利用癌症基因组图谱（The Cancer Genome Atlas，TCGA）的CRC mRNA测序数据发现的一个转录差异表达基因。我们的初步工作表明，DMTN在结直肠癌组织中表达下调，并且Rac 1信号通路在DMTN低表达的结直肠癌组织中显著富集。然而，DMTN在结直肠癌发生发展中的具体功能和分子机制以及调控该基因下调的上游因素尚不清楚。采用体内外实验模型检测DMTN调控异常对结直肠癌细胞侵袭转移的影响。采用GSEA法探讨DMTN在大肠癌侵袭转移中的作用机制。Westernblot、Co-IP和GST-Pull-Down检测DMTN与ARHGEF 2的相互作用以及RAC 1信号通路的激活。采用亚硫酸氢盐基因组测序法（BSP）检测结直肠癌组织中DMTN基因启动子甲基化程度。结果发现DMTN基因在结直肠癌组织中的表达明显降低，其表达下调与结直肠癌的进展和预后有关，是结直肠癌患者预后的独立预测因素。过表达DMTN抑制大肠癌细胞的侵袭和转移，而敲低DMTN则促进大肠癌细胞的侵袭和转移。此外，DMTN基因的甲基化和缺失可解除与ARHGEF 2蛋白的结合，激活Rac 1信号通路，调节肌动蛋白细胞骨架的重排，促进大肠癌细胞的侵袭和转移。结论DMTN基因的下调可能通过激活Rac 1信号通路调节肌动蛋白细胞骨架而促进大肠癌细胞的转移。潜在地提供了新的治疗靶点，以使癌症精准医学能够用于CRC患者。
BackgroundColorectal cancer (CRC) is one of the most common digestive malignant tumors, and DMTN is a transcriptionally differentially expressed gene that was identified using CRC mRNA sequencing data from The Cancer Genome Atlas (TCGA). Our preliminary work suggested that the expression of DMTN was downregulated in CRC, and the Rac1 signaling pathway was significantly enriched in CRC tissues with low DMTN expression. However, the specific functions and underlying molecular mechanisms of DMTN in the progression of CRC and the upstream factors regulating the downregulation of the gene remain unclear.MethodsDMTN expression was analyzed in CRC tissues, and the relationship between DMTN expression and the clinicopathological parameters was analyzed. In vitro and in vivo experimental models were used to detect the effects of DMTN dysregulation on invasion and metastasis of CRC cells. GSEA assay was performed to explore the mechanism of DMTN in invasion and metastasis of CRC. Westernblot, Co-IP and GST-Pull-Down assay were used to detect the interaction between DMTN and ARHGEF2, as well as the activation of the RAC1 signaling. Bisulfite genomic sequence (BSP) assay was used to test the degree of methylation of DMTN gene promoter in CRC tissues.ResultsWe found that the expression of DMTN was significantly decreased in CRC tissues, and the downregulation of DMTN was associated with advanced progression and poor survival and was regarded as an independent predictive factor of CRC patient prognosis. The overexpression of DMTN inhibited, while the knockdown of DMTN promoted, invasion and metastasis in CRC cells. Moreover, hypermethylation and the deletion of DMTN relieved binding to the ARHGEF2 protein, activated the Rac1 signaling pathway, regulated actin cytoskeletal rearrangements, and promoted the invasion and metastasis of CRC cells.ConclusionOur study demonstrated that the downregulation of DMTN promoted the metastasis of colorectal cancer cells by regulating the actin cytoskeleton through RAC1 signaling activation, potentially providing a new therapeutic target to enable cancer precision medicine for CRC patients.