Li Weiqing, Zhang Xugang, Li Zhitian, Jiang Fusheng, Zhao Hongwei, Wei Bo
Department of Thoracic Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China.
Department of Interventional Treatment, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China.
Oncol Lett. 2018 Jul;16(1):123-130. doi: 10.3892/ol.2018.8683. Epub 2018 May 10.
The aim of the present study was to identify genes with similar function to that of matrix metalloproteinases (MMPs) in invasive lung adenocarcinoma (AC) and to screen the transcription factors that regulate MMPs. The gene expression dataset GSE2514, including 20 invasive lung AC samples and 19 adjacent normal lung samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened using the limma package in R. Genes with similar function to MMPs were identified by K-means clustering. Their correlations with MMPs were validated using Pearson correlation analysis. The expression of MMPs in lung cancer and normal tissues was evaluated by western blot analysis. Protein-protein interaction (PPI) network and transcriptional regulatory network analyses were performed with Retrieval of Interacting Genes and Database for Annotation, Visualization and Integrated Discovery, respectively. As a result, 269 DEGs were identified between invasive lung AC samples and normal lung samples, including 78 upregulated and 191 downregulated genes. Four MMPs (MMP1, MMP7, MMP9 and MMP12), which were upregulated in lung AC, were clustered into one group with other genes, including NAD(P)H quinone oxidoreductase 1, claudin 3 (CLDN3), S100 calcium-binding protein P, serine protease inhibitor Kazal type 1, collagen type XI α 1 chain, periostin and desmoplakin (DSP), following cluster analysis. Pearson correlation analysis further confirmed correlations between MMP9-CLDN3, MMP9-DSP and MMP12-DSP. PPI network analysis also indicated multiple interactions between MMPs-associated genes. Furthermore, MMPs were commonly regulated by CCAAT/enhancer binding protein α transcription factor. These findings may provide further insight into the mechanisms of MMPs in invasive lung AC.
本研究的目的是在侵袭性肺腺癌（AC）中鉴定与基质金属蛋白酶（MMP）功能相似的基因，并筛选调控MMP的转录因子。从基因表达综合数据库下载了基因表达数据集GSE2514，其中包括20个侵袭性肺AC样本和19个相邻正常肺样本。使用R语言中的limma软件包筛选差异表达基因（DEG）。通过K均值聚类鉴定与MMP功能相似的基因。使用Pearson相关分析验证它们与MMP的相关性。通过蛋白质印迹分析评估肺癌组织和正常组织中MMP的表达。分别使用相互作用基因检索工具和注释、可视化与综合发现数据库进行蛋白质-蛋白质相互作用（PPI）网络和转录调控网络分析。结果，在侵袭性肺AC样本和正常肺样本之间鉴定出269个DEG，包括78个上调基因和191个下调基因。在肺AC中上调的四种MMP（MMP1、MMP7、MMP9和MMP12）与其他基因聚为一组，这些基因包括NAD（P）H醌氧化还原酶1、紧密连接蛋白3（CLDN3）、S100钙结合蛋白P、Kazal型1丝氨酸蛋白酶抑制剂、XI型胶原α1链、骨膜蛋白和桥粒斑蛋白（DSP）。Pearson相关分析进一步证实了MMP9与CLDN3、MMP9与DSP以及MMP12与DSP之间的相关性。PPI网络分析也表明MMP相关基因之间存在多种相互作用。此外，MMP通常受CCAAT/增强子结合蛋白α转录因子调控。这些发现可能为深入了解MMP在侵袭性肺AC中的作用机制提供进一步的线索。
