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中华结直肠疾病电子杂志 ›› 2020, Vol. 09 ›› Issue (04) : 363 -369. doi: 10.3877/cma.j.issn.2095-3224.2020.04.007

所属专题: 文献

论著

基于权重基因共表达分析的结肠癌肝转移相关基因挖掘与验证
高博1,(), 陈卓妙语1, 王秋生1   
  1. 1. 100044 北京大学人民医院普通外科
  • 收稿日期:2020-05-22 出版日期:2020-08-25
  • 通信作者: 高博
  • 基金资助:
    国家自然科学基金青年项目(No. 81800573); 北京大学人民医院科研与发展基金青年项目(No. RDY2018-06)

The mining and verification of colorectal cancer liver metastasis-related genes based on weighted gene coexpression analysis

Bo Gao1,(), Zhuomiaoyu Chen1, Qiusheng Wang1   

  1. 1. Deapartment of General Surgery, Peking University People's Hospital, Beijing 100044, China
  • Received:2020-05-22 Published:2020-08-25
  • Corresponding author: Bo Gao
  • About author:
    Corresponding author: Gao Bo, Email:
引用本文:

高博, 陈卓妙语, 王秋生. 基于权重基因共表达分析的结肠癌肝转移相关基因挖掘与验证[J/OL]. 中华结直肠疾病电子杂志, 2020, 09(04): 363-369.

Bo Gao, Zhuomiaoyu Chen, Qiusheng Wang. The mining and verification of colorectal cancer liver metastasis-related genes based on weighted gene coexpression analysis[J/OL]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2020, 09(04): 363-369.

目的

挖掘结肠癌肝转移过程中的核心基因模块和分子靶点,并验证其对临床预后及结肠癌转移能力的影响。

方法

基于GEO数据库结肠癌肝转移测序样本,利用权重基因共表达网络分析(WGCNA)技术筛选转移相关基因模块。利用MCODE软件进一步挖掘结肠癌肝转移相关核心子模块并分析其功能。基于TCGA数据库,进行子模块基因对结肠癌预后影响的大临床样本验证。分子生物学方法验证子模块基因对结肠癌细胞系HCT116迁移和侵袭能力的影响。

结果

WGCNA分析筛选出5个基因模块,其中模块1与结肠癌肝转移关系密切。模块1共包含4个核心子模块,主要参与G蛋白偶联受体信号调节、表观遗传学调控、mRNA的剪接调节等功能。大临床样本验证发现子模块4中的FOXC1基因与结肠癌患者生存率密切相关。敲减FOXC1在HCT116细胞中的表达后,HCT116的迁移能力(t=3.123,P=0.035)和侵袭能力(t=2.936,P=0.043)受到显著抑制。

结论

本研究筛选出的结肠癌肝转移相关子模块可能具有重要的促转移作用,子模块基因FOXC1与结肠癌患者较差的生存率相关并具有促结肠癌转移能力。

Objective

To explore the core gene modules and molecular target in the process of colorectal cancer liver metastasis and to verify its impact on clinical prognosis and colorectal cancer metastasis ability.

Methods

Based on the sequencing samples of colorectal cancer liver metastasis in GEO database, WGCNA was used to screen metastasis-related gene modules. Using MCODE software to further explore the core sub-modules and analyze their function. TCGA database was used to analysis the effect of the target gene on the survival rate of colorectal cancer patients. Using molecular biology methods to verify the effect of sub-module genes on the migration and invasion of HCT116.

Results

A total of 5 modules were identified, and module 1 was closely related to colorectal cancer liver metastasis. Module 1 included 4 core sub-modules. The function of the sub-modules included adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway, epigenetic regulation, mRNA splicing and so on. Large clinical sample verification found that the FOXC1 gene in sub-module 4 was closely related to the survival rate of colon cancer patients. After knocking down the expression of FOXC1 in HCT116 cells, the migration (t=3.123, P=0.035) and invasion (t=2.936, P=0.043) of HCT116 was significantly inhibited.

Conclusion

The sub-modules related to liver metastasis of colon cancer screened in this study may have an important role in promoting metastasis. The sub-module gene FOXC1 is associated with the poor prognosis of colon cancer patients and promotes colon cancer metastasis.

图1 根据结肠癌肝转移进展过程的GSE72718数据集样本分组
图2 结肠癌肝转移相关WGCNA模块筛选。2A:结肠癌肝转移数据的WGCNA分析;2B:模块1基因表达热图,红色为高表达,绿色为低表达
图3 模块1基因的PPI互作网络
图4 模块1PPI网络中的4个子模块
图5 子模块的功能(GO)富集分析。DAVID数据库生成的GO功能条目以条形图展示。条形图的长度表示每个条目的富集分数
图6 大临床样本证实发生FOXC1差异表达的结肠癌患者预后较差
图7 FOXC1的敲减效果验证。7A:Real-time PCR结果显示FOXC1 mRNA在FOXC1-siRNA组中的表达明显低于对照组,*P<0.05;7B:Western blot结果显示FOXC1蛋白在FOXC1-siRNA组中的表达明显低于对照组
图8 Transwell实验证实FOXC1-siRNA组中HCT116细胞的迁移和侵袭能力均明显低于对照组。8A:迁移实验;8B:侵袭实验,*P<0.05
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