Weighted gene co-expression network analysis and connectivity map identifies lovastatin as a treatment option of gastric cancer by inhibiting HDAC2
Weighted gene co-expression network analysis and connectivity map identifies lovastatin as a treatment option of gastric cancer by inhibiting HDAC2
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DOI：
10.1016/j.gene.2018.09.040
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发表时间：
2019-01-10
期刊：
影响因子：
3.5
通讯作者：
Zou, Baicang
中科院分区：
文献类型：
--
作者：
Zhang, Li;Kang, Wenquan;Zou, Baicang
目的：基于加权基因共表达网络分析(WGCNA)和连接图分析(Cmap)，对可能对胃癌患者有积极作用的治疗化合物进行鉴定和验证。从基因表达总览(GEO)网站下载原始微阵列数据集(包括132个样本)。我们利用WGCNA对非特异性筛选后的共表达基因(模块)和模块化HUB基因进行鉴定。此外，这些差异表达的基因被提交给Cmap分析，以确定GC的候选治疗化合物。实验部分采用细胞计数试剂盒(CCK-8)和集落形成实验检测细胞生长抑制情况。用裸鼠体内建立的异种移植瘤来评估肿瘤的生长。结果：通过WGCNA和Cmap分析，我们发现了两种潜在的治疗化合物：组蛋白去乙酰酶(HDAC)抑制剂丙戊酸(VPA)和洛伐他汀。HDAC2在胃癌细胞系AGS、BGC-823、NCI-N87和MKN28中高表达。体外实验证实VPA和洛伐他汀对胃癌细胞的抑制作用呈剂量依赖性。VPA和洛伐他汀通过抑制HDAC2的表达诱导GC细胞凋亡。此外，顺铂对VPA的抑制作用和洛伐他汀对顺铂的抑制作用也呈剂量依赖关系，且顺铂对VPA的抑制具有协同作用。在异种移植中，也发现了类似的结果。结论：WGCNA能够识别与癌症预后相关的重要基因组。此外，使用Cmap分析基因表达特征是探索人类疾病潜在治疗方法的有力途径。洛伐他汀可能是治疗GC的一种潜在药物。
Objective: This study aimed to identifying and validating therapeutic compounds which might have positive effects on patients with gastric cancer (GC) based on weighted gene co-expression network analysis (WGCNA) and connectivity map (CMap).Methods: We performed WGCNA to gain insights into the molecular aspects of GC. Raw microarray datasets (including 132 samples) were downloaded from the Gene Expression Omnibus (GEO) website. We utilized the WGCNA to identify the coexpressed genes (modules) and modular hub genes after non-specific filtering. Furthermore, these differentially expressed genes were submitted to CMap analysis to identify candidate therapeutic compounds for GC. In experimental part, cell growth inhibition was evaluated by Cell Counting Kit-8 (CCK-8) and colony formation assays. Tumor growth was assessed using nude mice with xenografts established in vivo. QRT-PCR and western blot were used for determination of HDAC2 expression level and immunohistochemistry was performed to quantify HDAC2 in gastric tumor samples.Results: Through WGCNA and CMap analysis, we found two potential therapeutic compounds, the valproic acid (VPA), which is the histone deacetylase (HDAC) inhibitor and lovastatin. HDAC2 was overexpressed in gastric cancer cell lines including AGS, BGC-823, NCI-N87 and MKN28. Dose-dependent inhibition of gastric cancer cells by VPA and lovastatin was verified in vitro. Apoptosis of GC cells was induced after treatment with VPA and lovastatin through suppressing HDAC2 expression. Furthermore, the inhibition of VPA with cisplatin and lovastatin with cisplatin were also dose-dependent and cisplatin exhibited synergistic effects. In the xenografts, similar results were found.Conclusion: WGCNA was able to identify significant groups of genes associated with cancer prognosis. Moreover, analysis of gene expression signature using CMap is a powerful way to explore potential therapeutics for human diseases. For treating GC, lovastatin may be a potential drug.