李抄,陈定宇,张晓怡,赵艳,王琴容,周建奖,鲍丽雅,谢渊
LI Chao,CHEN Dingyu,Zhang Xiaoyi,ZHAO Yan,WANG Qinrong,ZHOU Jianjiang,BAO Liya,XIE Yuan

• 1:贵州医科大学地方病与少数民族性疾病教育部重点实验室贵州省医学分子生物学重点实验室贵州医科大学分子生物学重点实验室
• 2:贵州医科大学附院感染科肝炎实验室

摘要(Abstract)：

目的:利用癌症基因组图谱(TCGA)数据库及转录组数据分析组蛋白去乙酰化酶1(HDAC1)在胃癌(GC)中的表达情况、探讨HDAC1与临床参数的关系,并预测其在肿瘤发生发展中的可能机制。方法:从TCGA数据库中下载GC组织(GC组,371例)和正常胃组织(正常组,36例)的RNASeq数据和临床信息,比较正常组与GC组HDAC1 mRNA的表达差异;将GC组分为HDAC1 mRNA高表达组(高于均值)271例和HDAC1 mRNA低表达组(低于均值)100例,分析GC患者HDAC1表达量与临床病理参数的相关性及其预后;利用LinkedOmics数据库分析与HDAC1表达相关的基因,Omicsbean-Canner预测HDAC1基因相关信号通路及功能富集。结果:GC组标本HDAC1基因平均表达量明显高于正常组(t=688,P<001);GC患者HDAC1基因表达与患者的年龄、T分期、AJCC分期及幽门螺杆菌(Hpylori)感染等病理参数呈正相关性(P<005),但与性别、N分期及M分期等病理参数无相关性(P> 005);Kaplan-Meier分析结果表明,HDAC1基因表达与生存无相关性(P> 005);GC组患者HADC1基因表达与AK2(adenylate kinase 2)、EIF3I(eukaryotic translation initiation factor 3 subunit I,)及MARCKSL1(MARCKS like 1)等9 118个基因表达量呈正相关,与GNAL(G protein subunit alpha L)、ARMCX2(armadillo repeat containing X-linked 2)及CCDC46(centrosomal protein 112)等10 907个基因表达量呈负相关;HDAC1基因功能显著富集到细胞周期、notch信号通路及Transcriptional misregulation in cancer等。结论:HDAC1基因在GC样本中呈高表达,且HDAC1基因的表达与患者的年龄、T分期、AJCC分期及H. pylori感染等病理参数相关。
Objective: Using the Cancer Genome Atlas(TCGA) database and transcriptome data to analyze the expression of histone deacetylase 1(HDAC1) in gastric cancer(GC), explore the relationship betweenHDAC1 and clinical parameters, and predict its role in possible mechanisms in tumorigenesis.Method: RNASeq data and clinical information of GC tissues(GC group, 371 cases)and normal gastric tissues(normal group, 36 cases) were downloaded from the TCGA database,HDAC1 mRNA differential expression was compared between the normal group and the GC group; GC group was stratified byHDAC1 expression level intoHDAC1-high(the mean as cutoff, > mean, 271 cases) andHDAC1-low( < mean, 100 cases), which were used to analyze the correlation of HDAC1 expression levels with clinicopathological parameters and prognosis of GC patients. Moreover,LinkedOmics database was used to analyzeHDAC1-related genes. Furthermore, Omicsbean-Canner was used to predictHDAC1 gene-related signaling pathways and functional enrichment.Results: The average expression level ofHDAC1 gene was significantly higher in GC group than that in normal group(t= 6.88,P< 0. 01);HDAC1 gene expression in GC patients was positively correlated with age, T stage, AJCC stage, and H. pylori infection(P< 0. 05), but there was no correlation with gender, N stage, and M stage(P> 0. 05); Kaplan-Meier analysis showed no correlation betweenHDAC1 gene expression with overall survival(P> 0. 05). Additionally,HADC1 gene expression is positively correlated with the expression levels of 9 118 genes such asAK2( adenylate kinase 2),EIF3 I(eukaryotic translation initiation factor 3 subunit I),MARCKSL1(MARCKS like 1), while negatively associated withGNAL(G protein subunit alpha L),ARMCX2(Armadillo repeat containing X-linked2),CCDC46(centrosomal protein 112) and other 10 907 genes. Furthermore, enrichment analysis shows thatHDAC1 gene was significantly associated with the cell cycle, notch signaling pathway and transcriptional misregulation in cancer.Conclusion:HDAC1 gene was significantly overexpressed in GC, andHDAC1 gene expression level was related to the patient's age, T stage, AJCC stage, andH.pyloriinfection and other pathological parameters.

关键词(KeyWords)： 胃肿瘤;TCGA数据库;组蛋白去乙酰化酶1;转录组
gastric cancer(GC);TCGA database;histone deacetylase 1(HDAC1);transcriptome

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目（31660031,31960028）;; 贵州省科技计划项目黔科合平台人才项目[2017]5652;; 贵阳市科技计划项目筑科合同项目[(2017)5-16];; 贵州省科技基金项目[黔科合LH字(2016)7347]

作者(Author): 李抄,陈定宇,张晓怡,赵艳,王琴容,周建奖,鲍丽雅,谢渊
LI Chao,CHEN Dingyu,Zhang Xiaoyi,ZHAO Yan,WANG Qinrong,ZHOU Jianjiang,BAO Liya,XIE Yuan

DOI: 10.19367/j.cnki.1000-2707.2020.02.002

参考文献(References)：

• [1] HIROYUKI Y, YOSHIYUKI W, TADATERU M, et al.An updated review of gastric cancer in the next-generation sequencing era:Insights from bench to bedside and vice versa[J]. World Journal of Gastroenterology, 2014, 20(14):3927-3937.
• [2] OH H J, LIM C H, YOON B H, et al. Fracture after gastrectomy for gastric cancer:A long-term follow-up observational study[J]. European Journal of Cancer, 2017,72(1):28-36.
• [3] CARNEIRO F. Hereditary gastric cancer[J]. European Journal of Cancer, 2018, 92(2):231-234.
• [4] ZHANG Y, ZHOU H B, SUN H X, et al. Association of peripheral blood leukocyte KIBRA methylation with gastric cancer risk:a case-control study.[J]. Cancer Medicine,2018, 7(6):2682-2690.
• [5] BURKITT M D, DUCKWORTH C A, WILLIAMS J M, et al.Helicobacter pylori-induced gastric pathology:Insights from in vivo and ex vivo models[J]. Disease Models and Mechanisms, 2017, 10(2):89-104.
• [6] ZHANG X Y, ZHANG P Y, ABOULSOUD M A. From inflammation to gastric cancer:Role ofHelicobacter pylori[J]. Oncology Letters, 2017, 13(2):543-548.
• [7] SILJA W, STEFFEN B. A novel basolateral type IV secretion model for theCagAoncoprotein ofHelicobacter pylori[J]. Microbial Cell, 2018, 5(1):60-62.
• [8]余森源，侯曦露，段晓伟，等．HDAC1在胃癌中的表达及其临床意义[J]．世界华人消化杂志，2015,23(33):5290-5295.
• [9] VE?CE?RA J,BáRTOVáE,KREJ?CíJ, et al. HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals[J].Journal of Cellular Physiology, 2018, 233(1):530-548.
• [10]SHI X N,GONG L B,LIU Y P, et al. 4-phenylbutyric acid promotes migration of gastric cancer cells by histone deacetylase inhibition-mediated IL-8 upregulation[J].Epigenetics, 2019, 9:1-14.
• [11]SANEI M H, MIRMOSAYYEB O, CHEHREI A, et al.5-year survival in Gastric adenocarcinoma with epithelial and stromal versican expression[J]. Iranian Journal of Pathology, 2019, 14(1):26-32.
• [12]HU B,WANG B,ZHAO B, et al. Thiosemicarbazonebased selective proliferation inactivators inhibit gastric cancer cell growth, invasion, and migration.[J]. Medchemcomm, 2017, 8(12):2173-2180.
• [13]李丹，余涛，曾智，等．基于Oncomine和TCGA数据库分析SLC2A1基因在肺腺癌中的表达意义[J]．现代药物与临床，2019(9):2807-2812.
• [14]张显萍，李莹，袁才佳，等．基于TCGA数据初步筛选胃癌预后相关基因[J]．临床检验杂志，2019,37(5):396-400.
• [15]JO Y K, PARK N Y, SHIN J H, et al. Up-regulation of UVRAG byHDAC1 inhibition attenuates 5FU-induced cell death in HCT116 colorectal cancer cells[J]. Anticancer Research, 2018, 38(1):271-277.
• [16]LAURENCE B, JANE L R, ANDREW P, et al. HDAC inhibitors enhance the immunotherapy response of melanoma cells[J]. Oncotarget, 2017, 8(47):83155-83170.
• [17]YAMAGOE S,KANNO T, KANNO Y,et al. Interaction of Histone Acetylases and Deacetylases In Vivo[J]. Molecular and Cellular Biology, 2003, 23(3):1025-1033.
• [18]XUAN Y S, WEI D, TIE Q L, et al. Histone deacetylase(HDAC)inhibitor, suberoylanilide hydroxamic acid(SAHA), induces apoptosis in prostate Cancer cell lines via the Akt/FOXO3a signaling pathway[J]. Medical Science Monitor International Medical Journal of Experimental&Clinical Research, 2017, 23(6):5793-5802.
• [19]HERSHEY J W. Regulation of protein synthesis and the role of EIF3 in cancer[J]. Brazilian Journal of Medical and Biological Research, 2010, 43(10):920-930.
• [20]AHLEMANN M, ZEIDLER R, LANG S, et al. Carcinoma-associated EIF3I overexpression facilitates mTORdependent growth transformation[J]. Molecular Carcinogenesis, 2006, 45(12):957-967.
• [21]CHEN Z Z, LIU Y T, YAO L T, et al. The long noncoding RNA lncZic2 drives the self-renewal of liver tumor-initiating cells via the protein kinase C substrates MARCKS and MARCKSL1[J]. Biological Chemistry, 2018, 293(21):7982-7992.
• [22]LI J, WANG J Y, YUE H R,et al. SNAI2 3'untranslated region promotes the invasion of ovarian cancer cells by inducing MARCKS expression[J]. Cancer, 2019, 10:2480-2487.
• [23]WU Y J, HU Z L, HU S D, et al. Glutamate dehydrogenase inhibits tumor growth in gastric cancer through the Notch signaling pathway[J]. Cancer Biomark, 2019,26:303-312.
• [24]CHUNG W C, ZHOU Y Y, ATFI A, et al. Downregulation of notch signaling in kras-induced gastric metaplasia[J]. Neoplasia, 2019, 21(8):810-821.
• [25]HIBDON E S, RAZUMILAVA N, KEELEY T M, et al.Notch and mTOR signaling pathways promote human gastric cancer cell proliferation[J]. Neoplasia, 2019, 21(7):702-712.
• [26]LI W, WANG D, SUN X, et al. ADAM17 promotes lymph node metastasis in gastric cancer via activation of the Notch and Wnt signaling pathways[J]. International Journal of Molecular Medicine,2019, 43(2):914-926.

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