Identification of RRAS gene related to nasopharyngeal carcinoma based on pathway and network-based analyses.
Identification of RRAS gene related to nasopharyngeal carcinoma based on pathway and network-based analyses.
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基于通路和网络分析的鼻咽癌相关RRAS基因鉴定
DOI：
10.21037/tcr.2019.04.04
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发表时间：
2019-04
影响因子：
0.9
通讯作者：
Mai S
中科院分区：
文献类型：
--
作者：
Xiao R;Shi L;Yang T;Zhang M;Wang H;Mai S
鼻咽癌是一种高度侵袭性的肿瘤，主要分布在亚洲东部和东南部。鼻咽癌在头颈部肿瘤中预后较差，分子靶向治疗临床疗效有限。方法回顾PubMed数据库中的出版物，提取与鼻咽癌相关的基因。利用在线工具WebGestalt对这些基因进行基因本体（GO）和京都基因与基因组百科全书（KEGG）途径富集分析。接下来，利用Jaccard系数（JC）和重叠系数（OC）两个参数分析每对选择通路的串扰。利用蛋白-蛋白相互作用（PPI）网络结合枢纽基因提取技术预测npc相关新基因。采用Western blotting、qRT-PCR和免疫组化（IHC）技术检测候选基因在鼻咽癌细胞和组织中的表达，采用细胞功能检测方法探讨候选基因对鼻咽癌细胞的影响。结果共鉴定出552个基因，构建了npc相关基因集（NPCgset）。进一步利用KEGG通路分析中富集的通路进行串扰分析，并将其分为两个模块：一个与癌变过程相关，另一个与免疫应答相关。从NPCgset中选取8个基因构建PPI网络，选取两个枢纽基因PIK3CA和AKT1。分析与PIK3CA相互作用的蛋白；其中，RRAS在鼻咽癌中表达下调，与鼻咽癌患者预后不良相关。此外，RRAS抑制HK1和5-8F细胞系的增殖、侵袭和上皮间质转化（EMT）。结论我们的研究可能有助于探索NPCgset的生物学过程，并提示RRAS可能在NPC中发挥肿瘤抑制基因的作用。
Background Nasopharyngeal carcinoma (NPC) is a highly aggressive neoplasm mainly distributed in the eastern and southeastern parts of Asia. NPC has a poor prognosis among head and neck cancers, and molecular-targeted therapies showed limited clinical efficacy. Methods We reviewed publications in the PubMed database and extracted genes associated with NPC. The online tool WebGestalt was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for these genes. Next, the two parameters, Jaccard Coefficient (JC) and Overlap Coefficient (OC), were used to analyze the crosstalk of each pair of selected pathways. The new NPC-related genes were predicted by protein-protein interaction (PPI) network combined with hub genes extraction. Western blotting, qRT-PCR, and immunohistochemistry (IHC) were used to detect the expression of candidate genes in NPC cells and tissues, and cellular function assays were used to explore the effects of genes on NPC cells. Results A total of 552 genes were identified and used to build an NPC-related gene set (NPCgset). Pathways enriched in KEGG pathway analysis were further used for crosstalk analysis and were grouped into two modules: one was related to the carcinogenesis process, and the other was correlated with the immune response. Eight genes from the NPCgset were selected to build a PPI network, and two hub genes PIK3CA and AKT1 were chosen. Proteins interacting with PIK3CA were analyzed; among them, the expression of RRAS was down-regulated in NPC and associated with poor prognosis of NPC patients. Furthermore, RRAS suppressed proliferation, invasion and the epithelial-mesenchymal transformation (EMT) of the HK1 and 5-8F cell lines. Conclusions Our study may help to explore the biological processes underlying NPCgset and suggests that RRAS may act as a tumor suppressor gene in NPC.
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