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生物信息学分析鉴定出四跨膜蛋白家族为胃癌的核心基因。

Tetraspanin family identified as the central genes detected in gastric cancer using bioinformatics analysis.

机构信息

Department of Oncology and Chemotherapy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China.

Department of Tumor Combined Therapy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China.

出版信息

Mol Med Rep. 2018 Oct;18(4):3599-3610. doi: 10.3892/mmr.2018.9360. Epub 2018 Aug 8.

Abstract

Gastric cancer has become a serious disease in the past decade. It has the second highest mortality rate among the four most common cancer types, leading to ~700,000 mortalities annually. Previous studies have attempted to elucidate the underlying biological mechanisms of gastric cancer. The present study aimed to obtain useful biomarkers and to improve the understanding of gastric cancer mechanisms at the genetic level. The present study used bioinformatics analysis to identify 1,829 differentially expressed genes (DEGs) which were obtained from the GSE54129 dataset. Using protein‑protein interaction information from the Search Tool for the Retrieval of Interacting Genes database, disease modules were constructed for gastric cancer using Cytoscape software. In the Gene Ontology analysis of biology processes, upregulated genes were significantly enriched in 'extracellular matrix organization', 'cell adhesion' and 'inflammatory response', whereas downregulated DEGs were significantly enriched in 'xenobiotic metabolic process', 'oxidation‑reduction process' and 'steroid metabolic process'. During Kyoto Encyclopedia of Genes and Genomes analysis, upregulated DEGs were significantly enriched in 'extracellular matrix‑receptor interaction', 'focal adhesion' and 'PI3K‑Akt signaling pathway', whereas the downregulated DEGs were significantly enriched in 'chemical carcinogenesis', 'metabolism of xenobiotics by cytochrome P450' and 'peroxisome'. The present study additionally identified 10 hub genes from the DEGs: Tumor protein p53 (TP53), C‑X‑C motif chemokine ligand 8 (CXCL8), tetraspanin 4 (TSPAN4), lysophosphatidic acid receptor 2 (LPAR2), adenylate cyclase 3 (ADCY3), phosphoinositide‑3‑kinase regulatory subunit 1 (PIK3R1), neuromedin U (NMU), C‑X‑C motif chemokine ligand (CXCL12), fos proto‑oncogene, AP‑1 transcription factor subunit (FOS) and sphingosine‑1‑phosphate receptor 1 (S1PR1), which have high degrees with other DEGs. The survival analysis revealed that the high expression of ADCY3, LPAR2, S1PR1, TP53 and TSPAN4 was associated with a lower survival rate, whereas high expression of CXCL8, FOS, NMU and PIK3R1 was associated with a higher survival rate. No significant association was identified between CXCL12 and survival rate. Additionally, TSPAN1 and TSPAN8 appeared in the top 100 DEGs. Finally, it was observed that 4 hub genes were highly expressed in gastric cancer tissue compared with para‑carcinoma tissue in the 12 patients; the increased TSPAN4 was significant (>5‑fold). Tetraspanin family genes may be novel biomarkers of gastric cancer. The findings of the present study may improve the understanding of the molecular mechanisms underlying the development of gastric cancer.

摘要

胃癌在过去十年中已成为一种严重的疾病。它是四种最常见癌症类型中死亡率第二高的癌症,每年导致约 70 万人死亡。先前的研究试图阐明胃癌的潜在生物学机制。本研究旨在获得有用的生物标志物,并提高对胃癌遗传水平机制的理解。本研究使用生物信息学分析从 GSE54129 数据集获得了 1829 个差异表达基因(DEG)。使用来自 Search Tool for the Retrieval of Interacting Genes 数据库的蛋白质-蛋白质相互作用信息,使用 Cytoscape 软件为胃癌构建疾病模块。在生物学过程的基因本体论分析中,上调基因在“细胞外基质组织”、“细胞粘附”和“炎症反应”中显著富集,而下调的 DEGs 则在“异生物质代谢过程”、“氧化还原过程”和“类固醇代谢过程”中显著富集。在京都基因和基因组百科全书中分析时,上调的 DEGs 显著富集在“细胞外基质-受体相互作用”、“粘着斑”和“PI3K-Akt 信号通路”中,而下调的 DEGs 则显著富集在“化学致癌作用”、“细胞色素 P450 代谢异生物质”和“过氧化物酶体”中。本研究还从 DEGs 中鉴定出 10 个枢纽基因:肿瘤蛋白 p53(TP53)、C-X-C 基序趋化因子配体 8(CXCL8)、四跨膜蛋白 4(TSPAN4)、溶血磷脂酸受体 2(LPAR2)、腺苷酸环化酶 3(ADCY3)、磷酸肌醇-3-激酶调节亚基 1(PIK3R1)、神经调节素 U(NMU)、C-X-C 基序趋化因子(CXCL12)、fos 原癌基因,AP-1 转录因子亚基(FOS)和鞘氨醇-1-磷酸受体 1(S1PR1),它们与其他 DEGs 的关联度较高。生存分析表明,ADCY3、LPAR2、S1PR1、TP53 和 TSPAN4 的高表达与较低的生存率相关,而 CXCL8、FOS、NMU 和 PIK3R1 的高表达与较高的生存率相关。CXCL12 与生存率之间未发现显著相关性。此外,TSPAN1 和 TSPAN8 出现在前 100 个 DEG 中。最后,在 12 名患者中观察到 4 个枢纽基因在胃癌组织中的表达高于癌旁组织,其中 TSPAN4 的增加显著(>5 倍)。四跨膜蛋白家族基因可能是胃癌的新型生物标志物。本研究的结果可能有助于提高对胃癌发生发展分子机制的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fa2/6131613/fcb5292929ec/MMR-18-04-3599-g00.jpg

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