Transcriptome analysis of potential candidate genes and molecular pathways in colitis-associated colorectal cancer of Mkp-1-deficient mice.
Transcriptome analysis of potential candidate genes and molecular pathways in colitis-associated colorectal cancer of Mkp-1-deficient mice.
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DOI：
10.1186/s12885-021-08200-0
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发表时间：
2021-05-25
期刊：
影响因子：
3.8
通讯作者：
Tang X
中科院分区：
文献类型：
--
作者：
Hammad A;Zheng ZH;Namani A;Elshaer M;Wang XJ;Tang X
核磷酸酶促分裂原活化蛋白激酶磷酸酶-1（MKP-1）是通过调节促炎细胞因子的生物合成而对先天性免疫应答起关键性负调节作用。在主要由慢性炎症诱导的结直肠癌（CRC）中，除了Mkp-1功能紊乱外，还发现Mkp-1过表达，这可能在不同类型肿瘤的癌症发展中起作用。然而，Mkp-1影响CRC发展的潜在分子机制尚不清楚。在这里，我们使用RNA测序（RNA-seq）对Mkp-1 KO小鼠进行了全局基因表达谱分析，以使用转录组分析探索Mkp-1在CRC进展中的作用。使用氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）小鼠模型来检查在野生型小鼠和Mkp-1 KO小鼠中CRC发展的不同阶段期间发生的最显著的分子和信号传导变化。综合的生物信息学分析被用来阐明Mkp-1调控的分子过程。通过基因本体论（GO）、京都基因和基因组富集（KEGG）等方法对差异表达基因（DEG）进行鉴定和功能分析。然后，使用STRING数据库和Cytoscape软件进行蛋白质-蛋白质相互作用（PPI）网络分析。持续性DEG在腺瘤和癌阶段（分别为238和251）以及在WT和MKp-1 KO小鼠（分别为221和196）中不同。Mkp-1 KO调节癌症中典型激活的关键分子过程，特别是细胞粘附、离子转运、细胞外基质组织、对药物的反应、对缺氧的反应和对有毒物质的反应。这些通路与肿瘤的发生、发展和转移密切相关。从PPI网络分析中，确定了9个与CRC相关的枢纽基因。这些发现表明，MKp-1及其枢纽基因可能在癌症发展、预后和决定治疗结果中发挥关键作用。我们提供了线索，以建立MKP-1和结肠炎相关肿瘤发生之间的潜在联系，并确定需要进一步调查的领域。在线版本包含补充材料，可通过10.1186/s12885-021-08200-0获得。
The nuclear phosphatase mitogen-activate protein kinase phosphatase-1 (MKP-1) is a key negative regulator of the innate immune response through the regulation of the biosynthesis of proinflammatory cytokines. In colorectal cancer (CRC), which is induced mainly by chronic inflammation, Mkp-1 overexpression was found in addition to disturbances in Mkp-1 functions, which may play a role in cancer development in different types of tumors. However, the potential molecular mechanisms by which Mkp-1 influences CRC development is not clear. Here, we performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis. Azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were used to examine the most dramatic molecular and signaling changes that occur during different phases of CRC development in wild-type mice and Mkp-1 KO mice. Comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by Mkp-1. Differentially expressed genes (DEGs) were identified and functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software. Persistent DEGs were different in adenoma and carcinoma stage (238 & 251, respectively) and in WT and MKp-1 KO mice (221& 196, respectively). Mkp-1 KO modulated key molecular processes typically activated in cancer, in particular, cell adhesion, ion transport, extracellular matrix organization, response to drug, response to hypoxia, and response to toxic substance. It was obvious that these pathways are closely associated with cancer development and metastasis. From the PPI network analyses, nine hub genes associated with CRC were identified. These findings suggest that MKp-1 and its hub genes may play a critical role in cancer development, prognosis, and determining treatment outcomes. We provide clues to build a potential link between Mkp-1 and colitis-associated tumorigenesis and identify areas requiring further investigation. The online version contains supplementary material available at 10.1186/s12885-021-08200-0.
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