胃癌肝转移相关新Hub基因的预测和验证
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摘要
[研究目的]分离在胃癌肝转移过程中起关键作用的关键基因(Hubs),建立能预测胃癌发生及其转移的新的生物学标志,为未来开展胃癌分子流病学研究奠定基础。
[研究方法] 2006年1月到2009年2月收集67例胃癌病人的手术切除标本,所有标本均于术后2小时内取回、分装和冻存;选择3例患者的胃癌肝转移及配对原发组织进行cDNA芯片检测,选择在3张芯片中基因表达变化倍数均≥1.6倍的基因作为差异表达基因;利用MILANO、Chilibot、UniHI和Endeavour等多种生物信息学软件工具,依次对差异表达基因进行系统的文献挖掘、蛋白质网络和功能相似性分析,最后预测胃癌肝转移相关的新Hub基因(相互作用基因数≥30);根据预测结果选择兴趣基因,采用定量RT-PCR技术,检测这些兴趣基因在另外8对胃癌肝转移及配对原发组织、57对胃癌原发灶及配对癌旁组织间的相对表达变化,并分析这些基因的相对表达变化与疾病分期之间的关系;采用免疫组化技术,检测兴趣基因所对应蛋白在11例胃癌肝转移、26例胃癌原位及26例胃癌癌旁组织中的表达模式,并将蛋白表达变化与转录水平表达变化进行比较。
[研究结果]芯片分析共确定272个差异表达基因,通路分析显示差异表达基因在13条KEGG通路上显著富集,其中8条通路已证明与肿瘤转移相关;文献注释结果显示272个差异表达基因中包含118个已知癌症相关基因和68个已知肿瘤转移相关基因;已知转移相关基因在118个癌症相关基因中的比例明显高于已知转移相关基因在Sanger中心的382个癌症普查基因中的比例(P<0.001),提示本研究所获得的272个差异表达基因显著富集了转移相关基因;蛋白质网络分析发现所获得的差异表达基因中存在一个由63个蛋白形成的亚网络,该亚网络包含60个相互作用、29个已知转移相关基因和37个Hub基因。统计分析显示,该网络不仅富集了已知转移相关基因(P<0.05),而且富集了Hub基因(P<0.05);利用Endeavour软件进行基因功能相似性分析,发现45个未报道与转移相关的基因与我们所设定的已知转移相关基因群的功能最为相似,其中8个基因为蛋白质亚网络中的Hub基因:NR3C1、NR4A2、HNRPA1、PSMB3、FBLN2、DARS、XAB2、CD8A。
根据预测结果和研究兴趣,9个基因(NR3C1、NR4A2、HNRPA1、XAB2、HSP90AA1、CCNE1、RPL17、FKBP1A和XAB2)被选择在临床样本中验证,定量RT-PCR分析结果显示:NR4A2在8例同时性胃癌肝转移样本中的表达水平显著低于其配对原发灶(P=0.001),而HSP90AA1的表达水平显著高于其配对原发灶(P=0.029);NR4A2、NR3C1、ARF3、XAB2以及NR4A2的两种替换剪切模式(SP8和SP-novel)在57例胃癌原发样本中的表达水平显著低于其配对癌旁组织(P<0.001),而CCNE1的表达水平显著高于其配对癌旁组织(P=0.001)。
HSP90AA1(P=0.043)和NR4A2(P=0.003)在胃癌肝转移组织中的蛋白表达水平分别高于和低于原发组织的表达水平, CCNE1(P=0.000)和NR3C1(P=0.005)在胃癌原发灶组织中的蛋白表达水平分别高于和低于癌旁正常组织的表达水平,上述结果与定量RT-PCR结果一致;HSP90AA1在胃癌原发灶中的蛋白表达水平高于癌旁正常组织(P=0.003),而定量RT-PCR未发现差异。在定量RT-PCR分析中显示:癌旁正常组织中NR4A2基因的表达水平显著高于原位组织,但免疫组化显示NR4A2蛋白在癌旁正常组织间质细胞中的表达水平高于原位肿瘤间质细胞细胞中的表达水平,而在癌旁胃腺组织上皮细胞中的表达水平低于原位胃癌上皮组织中的表达水平。
[研究结论] NR4A2可能是胃癌肝转移的诊断和预后标志,NR4A2可能参与胃癌上皮细胞的上皮-间质转化(EMT)过程;NR3C1、ARF3和XAB2与胃癌发生相关,可能是胃癌发生中的新型Hub基因;HSP90AA1可能是胃癌肝转移的预后标志,而CCNE1是胃癌发生的诊断标志,但尚需进一步研究。
[Bankground] Gastric cancer (GC) is the second leading cause of cancer death worldwide, although its incidence is decreasing. About 60% of new cases of GC occur in eastern Asia. Surgical resection is the most effective treatment for GC without distant metastasis. However, relapse after surgical treatment and distant metastasis contribute to the high GC-associated fatality. Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective, targeted approaches to diagnose and treat cancer metastasis.
[Objective] To isolate hub genes responsible for gastric cancer metastasis, and establish novel biomarkers for the predition of gastric cancer and metastasis, and lay the groundwork for further molecular epidemiological study of gastric cancer.
[Methods] Tumor tissues of 67 patients were obtained from GC patients who had undergone curative surgery at Department of General Surgery of the 1st affiliated hospital, Second Military Medical University, from January 2006 to February 2009; The synchronous liver metastasis and their matched GC from 3 patients were used for double-colored cDNA microarray assay and differentially expressed genes with fold-change 1.6 or higher in each microarray data were selected for further bioinformatics and validation analyses. a novel intergrated bioinformatics methods for the prediction of gene function through combination of microarray technology, text mining, protein-protein interaction (PPI) and genes similarity analysis. Online bioinformatics tools, such as MILANO, Chilibot, UniHI and Endeavour, were used in turn for literature ananotaions and gene founction prediction. Then, the candidate genes were validated by using real-time quantitative RT-PCR and immunohistochemistry in synchronous liver metastasis verse the paired GC from 8 other patients and in GC verse the matched gastric mucosa from 57 patients. The protein expression patterns of candidate genes also were validated by using immunohistochemistry among distance metastasis, orthotopic cancer and adjacent mucosa of GC.
[Results] We selected 272 differentially expressed genes with fold-change 1.6 or higher in each microarray. KEGG pathway analysis showed that of the 13 enriched pathways, 8 were involved in cancer metastasis. Literature-based annotation with MILANO and Chilibot showed that the differentially expressed genes significantly enriched known metastasis-related genes. With the use of protein-protein interaction network, we found a sub-network significantly enriching the metastasis-related genes and hub genes. First 45 of un-annotated genes in Endeavour prioritization shared 8 hubs in the sub-network, containing NR3C1,NR4A2, HNRPA1, PSMB3, FBLN2, DARS, XAB2, and CD8A. Nine hubs,containing NR3C1, NR4A2, HNRPA1, XAB2, HSP90AA1, CCNE1, RPL17, FKBP1A, and XAB2 were then selected for validation by using quantitative RT-PCR in the sub-network. It was found that NR4A2 (P=0.001) was down-regulated, while HSP90AA1 (P=0.029) up-regulated, in synchronous liver metastasis verse the paired GC from 8 patients. NR4A2, NR3C1, ARF3, XAB2, and alternatively spliced variants of NR4A2, SP8 and SP-novel, were down-regulated (P<0.001 for each), while CCNE1 (P=0.001) up-regulated, in GC verse the matched gastric mucosa from 57 patients.
Immunohistochemistry showed that HSP90AA1(P=0.043) and NR4A2(P=0.003) protein were significantly up and down-regulated in the distant metastasis when compared to the orthotopic cancer of GC, respectively. CCNE1(P<0.001) and NR3C1(P=0.005) were also significantly up and down-regulated in orthotopic cancer compared to adjacent mucosa of GC. NR4A2 protein was significantly up-regulated in normal gastric mesenchymal cells (P=0.005) and significantly down-regulated in normal gastric epithelial cells (P<0.001) when compared to primary gastric cancer tissue.
[Conclusion] NR4A2 stands out as the most probable diagnostic and prognostic marker for GC. NR4A2 may play an important role in epithelial-mesenchymal transitions (EMT) of gastric cancer liver metastasis. NR3C1, ARF3, and XAB2 are novel hubs reversely associated with GC. HSP90AA1 is a potential prognostic marker, while CCNE1 a potential diagnostic marker, for GC.
[研究方法] 2006年1月到2009年2月收集67例胃癌病人的手术切除标本,所有标本均于术后2小时内取回、分装和冻存;选择3例患者的胃癌肝转移及配对原发组织进行cDNA芯片检测,选择在3张芯片中基因表达变化倍数均≥1.6倍的基因作为差异表达基因;利用MILANO、Chilibot、UniHI和Endeavour等多种生物信息学软件工具,依次对差异表达基因进行系统的文献挖掘、蛋白质网络和功能相似性分析,最后预测胃癌肝转移相关的新Hub基因(相互作用基因数≥30);根据预测结果选择兴趣基因,采用定量RT-PCR技术,检测这些兴趣基因在另外8对胃癌肝转移及配对原发组织、57对胃癌原发灶及配对癌旁组织间的相对表达变化,并分析这些基因的相对表达变化与疾病分期之间的关系;采用免疫组化技术,检测兴趣基因所对应蛋白在11例胃癌肝转移、26例胃癌原位及26例胃癌癌旁组织中的表达模式,并将蛋白表达变化与转录水平表达变化进行比较。
[研究结果]芯片分析共确定272个差异表达基因,通路分析显示差异表达基因在13条KEGG通路上显著富集,其中8条通路已证明与肿瘤转移相关;文献注释结果显示272个差异表达基因中包含118个已知癌症相关基因和68个已知肿瘤转移相关基因;已知转移相关基因在118个癌症相关基因中的比例明显高于已知转移相关基因在Sanger中心的382个癌症普查基因中的比例(P<0.001),提示本研究所获得的272个差异表达基因显著富集了转移相关基因;蛋白质网络分析发现所获得的差异表达基因中存在一个由63个蛋白形成的亚网络,该亚网络包含60个相互作用、29个已知转移相关基因和37个Hub基因。统计分析显示,该网络不仅富集了已知转移相关基因(P<0.05),而且富集了Hub基因(P<0.05);利用Endeavour软件进行基因功能相似性分析,发现45个未报道与转移相关的基因与我们所设定的已知转移相关基因群的功能最为相似,其中8个基因为蛋白质亚网络中的Hub基因:NR3C1、NR4A2、HNRPA1、PSMB3、FBLN2、DARS、XAB2、CD8A。
根据预测结果和研究兴趣,9个基因(NR3C1、NR4A2、HNRPA1、XAB2、HSP90AA1、CCNE1、RPL17、FKBP1A和XAB2)被选择在临床样本中验证,定量RT-PCR分析结果显示:NR4A2在8例同时性胃癌肝转移样本中的表达水平显著低于其配对原发灶(P=0.001),而HSP90AA1的表达水平显著高于其配对原发灶(P=0.029);NR4A2、NR3C1、ARF3、XAB2以及NR4A2的两种替换剪切模式(SP8和SP-novel)在57例胃癌原发样本中的表达水平显著低于其配对癌旁组织(P<0.001),而CCNE1的表达水平显著高于其配对癌旁组织(P=0.001)。
HSP90AA1(P=0.043)和NR4A2(P=0.003)在胃癌肝转移组织中的蛋白表达水平分别高于和低于原发组织的表达水平, CCNE1(P=0.000)和NR3C1(P=0.005)在胃癌原发灶组织中的蛋白表达水平分别高于和低于癌旁正常组织的表达水平,上述结果与定量RT-PCR结果一致;HSP90AA1在胃癌原发灶中的蛋白表达水平高于癌旁正常组织(P=0.003),而定量RT-PCR未发现差异。在定量RT-PCR分析中显示:癌旁正常组织中NR4A2基因的表达水平显著高于原位组织,但免疫组化显示NR4A2蛋白在癌旁正常组织间质细胞中的表达水平高于原位肿瘤间质细胞细胞中的表达水平,而在癌旁胃腺组织上皮细胞中的表达水平低于原位胃癌上皮组织中的表达水平。
[研究结论] NR4A2可能是胃癌肝转移的诊断和预后标志,NR4A2可能参与胃癌上皮细胞的上皮-间质转化(EMT)过程;NR3C1、ARF3和XAB2与胃癌发生相关,可能是胃癌发生中的新型Hub基因;HSP90AA1可能是胃癌肝转移的预后标志,而CCNE1是胃癌发生的诊断标志,但尚需进一步研究。
[Bankground] Gastric cancer (GC) is the second leading cause of cancer death worldwide, although its incidence is decreasing. About 60% of new cases of GC occur in eastern Asia. Surgical resection is the most effective treatment for GC without distant metastasis. However, relapse after surgical treatment and distant metastasis contribute to the high GC-associated fatality. Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective, targeted approaches to diagnose and treat cancer metastasis.
[Objective] To isolate hub genes responsible for gastric cancer metastasis, and establish novel biomarkers for the predition of gastric cancer and metastasis, and lay the groundwork for further molecular epidemiological study of gastric cancer.
[Methods] Tumor tissues of 67 patients were obtained from GC patients who had undergone curative surgery at Department of General Surgery of the 1st affiliated hospital, Second Military Medical University, from January 2006 to February 2009; The synchronous liver metastasis and their matched GC from 3 patients were used for double-colored cDNA microarray assay and differentially expressed genes with fold-change 1.6 or higher in each microarray data were selected for further bioinformatics and validation analyses. a novel intergrated bioinformatics methods for the prediction of gene function through combination of microarray technology, text mining, protein-protein interaction (PPI) and genes similarity analysis. Online bioinformatics tools, such as MILANO, Chilibot, UniHI and Endeavour, were used in turn for literature ananotaions and gene founction prediction. Then, the candidate genes were validated by using real-time quantitative RT-PCR and immunohistochemistry in synchronous liver metastasis verse the paired GC from 8 other patients and in GC verse the matched gastric mucosa from 57 patients. The protein expression patterns of candidate genes also were validated by using immunohistochemistry among distance metastasis, orthotopic cancer and adjacent mucosa of GC.
[Results] We selected 272 differentially expressed genes with fold-change 1.6 or higher in each microarray. KEGG pathway analysis showed that of the 13 enriched pathways, 8 were involved in cancer metastasis. Literature-based annotation with MILANO and Chilibot showed that the differentially expressed genes significantly enriched known metastasis-related genes. With the use of protein-protein interaction network, we found a sub-network significantly enriching the metastasis-related genes and hub genes. First 45 of un-annotated genes in Endeavour prioritization shared 8 hubs in the sub-network, containing NR3C1,NR4A2, HNRPA1, PSMB3, FBLN2, DARS, XAB2, and CD8A. Nine hubs,containing NR3C1, NR4A2, HNRPA1, XAB2, HSP90AA1, CCNE1, RPL17, FKBP1A, and XAB2 were then selected for validation by using quantitative RT-PCR in the sub-network. It was found that NR4A2 (P=0.001) was down-regulated, while HSP90AA1 (P=0.029) up-regulated, in synchronous liver metastasis verse the paired GC from 8 patients. NR4A2, NR3C1, ARF3, XAB2, and alternatively spliced variants of NR4A2, SP8 and SP-novel, were down-regulated (P<0.001 for each), while CCNE1 (P=0.001) up-regulated, in GC verse the matched gastric mucosa from 57 patients.
Immunohistochemistry showed that HSP90AA1(P=0.043) and NR4A2(P=0.003) protein were significantly up and down-regulated in the distant metastasis when compared to the orthotopic cancer of GC, respectively. CCNE1(P<0.001) and NR3C1(P=0.005) were also significantly up and down-regulated in orthotopic cancer compared to adjacent mucosa of GC. NR4A2 protein was significantly up-regulated in normal gastric mesenchymal cells (P=0.005) and significantly down-regulated in normal gastric epithelial cells (P<0.001) when compared to primary gastric cancer tissue.
[Conclusion] NR4A2 stands out as the most probable diagnostic and prognostic marker for GC. NR4A2 may play an important role in epithelial-mesenchymal transitions (EMT) of gastric cancer liver metastasis. NR3C1, ARF3, and XAB2 are novel hubs reversely associated with GC. HSP90AA1 is a potential prognostic marker, while CCNE1 a potential diagnostic marker, for GC.
引文
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