鼻咽癌发病不同阶段分子标志物的鉴定及差异表达基因相互作用网络的构建
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摘要
【鼻咽癌差异基因表达谱分析】
本研究室曾利用上海博芯公司H80s高密度基因芯片构建了鼻咽癌基因组表达谱,利用监督聚类和Weighted Voting算法筛选到6个基因,包括鼻咽癌上调基因RB1、STMN_1、DSP和下调基因SERPINB6、AGTRL1和SYTL2。该6个基因代表的分类预测模型能将鼻咽癌和鼻咽慢性炎症上皮很好的区分开来,可能是鼻咽癌的候选分子标志物。
为充分挖掘所构建的鼻咽癌差异基因表达谱中所隐藏的表达规律,提炼出更有价值的生物学信息,本文利用微阵列显著性分析(significance analysis of microarray,SAM)软件再次分析了鼻咽癌差异基因表达谱数据,共有显著差异表达基因758个,其中鼻咽癌表达上调基因270个,表达下调基因488个,从而构建了鼻咽癌差异基因表达谱。用Ingenuity Pathway Analysis(IPA)在线通路分析软件、Gene Set Enrichment Analysis(GSEA)软件和DAVID软件等分析发现cell cycle pathway和TGFβpathway相关分子的变化与鼻咽癌发生密切相关。
【鼻咽癌发病不同阶段分子标志物的鉴定】
为进一步研究上述鼻咽癌差异表达基因、cell cycle pathway和TGFβpathway相关分子与鼻咽癌发生发展的关系及在鼻咽癌发生中的作用,评估这些差异表达基因是否可作为鼻咽癌的分子靶标,本研究制作了高密度点阵的鼻咽癌发病不同阶段的组织微阵列以验证这些差异表达基因相关分子的表达变化。筛选和鉴定鼻咽癌发病不同阶段生物靶点基因、寻找鼻咽癌早期诊断、侵袭转移、预后复发相关的分子标志物。具体如下:
1.鼻咽癌发病不同阶段组织微阵列的构建
利用本室已获得发明专利的组织芯片制备技术(专利授权号:ZL200410022818X)制备了包含正常鼻咽上皮、慢性炎症鼻咽上皮、不典型增生鼻咽上皮、鼻咽癌(含不同组织学类型、不同临床分期、有无淋巴结转移、放疗后正常及复发鼻咽癌组织)及癌旁组织的鼻咽癌发病不同阶段的含825个点阵的组织微阵列,包括淋巴瘤和喉癌标本及缺失组织,该微阵列共有896个点。其中正常和鼻咽炎性上皮141例、不典型增生鼻咽上皮98例、癌旁上皮88例、鼻咽癌(WHOⅠ型15例、WHOⅡ型402例、WHOⅢ型17例;临床分期Ⅰ期32例、Ⅱ期155例、Ⅲ期1 56例、Ⅳ期91例;有淋巴结转移283例、无淋巴结转移151例)、放疗后正常和复发的标本64例、淋巴瘤和喉癌标本57例。
2.鼻咽癌差异表达基因的验证
鼻咽癌发病不同阶段的组织微阵列证实在488个鼻咽癌表达下调基因中,SPLUNC1是鼻咽癌早期患病风险筛查的易感因子,NGX6、LTF与鼻咽癌侵袭转移密切相关,SPLUNC1、ClORF102、AGTRL1和SERPINB6与鼻咽癌临床进展密切相关,LTF、BRD7和C1ORF102能预测鼻咽癌患者预后。其中LTF、C1ORF102、SPLUNC1、BRD7、NAG7、NGX6是我室克隆的鼻咽癌候选抑瘤基因,AGTRL1和SERPINB6是我们前期用监督聚类和weighted voting算法筛选到的鼻咽癌候选分子标志物。
结合鼻咽癌发病不同阶段组织微阵列和real-time quantitativeRT-PCR证实cell cycle pathway中p27、p16、CDK4、RB1、CDK8等分子与cDNA microarray结果变化一致。利用鼻咽癌发病不同阶段组织微阵列证实TGFβpathway中TGFβⅡR、ACVRL1、INHBB、Axin2和p300/CBP分子在鼻咽癌中异常活化,说明cell cycle pathway和TGFβpathway在鼻咽癌发生发展过程中可能起到重要的作用。并且证实了EBV感染是鼻咽癌的一主要特征,鼻咽癌中cell cycle pathway和TGFβpathway的活化与EBV的感染密切相关。
3.构建鼻咽癌发病不同阶段的分子标志物系统
通过运用转录组学和组织微阵列等高通量技术,在大样本的基础上筛查并鉴定了SAM软件分析得到的鼻咽癌差异表达基因及我室克隆的鼻咽癌候选抑瘤基因SPLUNC1、C1ORF102、BRD7、NAG7、NGX6基因以及cell cycle pathway、TGFβpathway相关分子的表达,构建了鼻咽癌发病不同阶段的分子标志物系统:①证实SPLUNC1、p27、p16、p19是鼻咽癌早期诊断的理想分子标志物;②LTF、NAG7、SPLUNC1、ClORF102、CDK4、AGTRL1、INHBB和SERPINB6是与鼻咽癌临床进展相关的候选分子标志物;③NGX6、LTF、AGTRL1、INHBB和ACVRL1是与鼻咽癌淋巴结转移相关的候选分子标志物;④证实LTF、BRD7、CDK4、cyclin D1、RB1、EBER-1和ACVRL1是预测鼻咽癌放疗敏感与否的候选分子标志物;⑤LTF、BRD7、C1ORF102、ACVRL1、INHBB、cyclin D1是与鼻咽癌预后相关的候选分子标志物。鼻咽癌发病不同阶段的分子标志物的证实为鼻咽癌分子分型研究奠定了坚实的工作基础。
【鼻咽癌差异表达基因相互作用网络的构建】
将SAM软件筛选到的758个鼻咽癌差异表达基因输入IngenuityPathway Analysis(IPA)在线软件分析基因生物学功能和相互作用网络,137个基因在其基因网络数据库中,127个基因有功能/通路数据。变化最显著的有9个network,这些基因网络主要涉及DNA复制与修复、细胞周期、肿瘤发生、基因表达、细胞信号等方面。其中SPLUNC1参与了基因表达和肿瘤发生等生物学过程,并受维甲酸(retinoic acid,RA)调控,RA可能通过调控SPLUNC1的表达而抑制鼻咽癌细胞生长;SERPINB6参与了细胞运动和免疫应答等生物学过程。
【Analysis of Nasopharyngeal Carcinoma Differentially Expressed Gene Profiling】
We selected the H80s high-density chip to construct the nasopharyngeal carcinoma(NPC) differentially expressed gene profiling and found that a set of 6 unique genes may be the candidate molecular markers by supervised clustering and weighted voting class prediction models.Because it predicted NPC from non-cancerous tissues most accurately.Among the 6 genes,RB1,STMN1 and DSP were up-regulated in NPC,SERPINB6,STYL2 and AGTRL1 were down-regulated in NPC.
In order to find out much more valuable information from the NPC differentially expressed gene profiling,we analyzed the NPC differentially expressed gene profiling data using significance analysis of microarray(SAM) once again and found that there were 758 notably differentially expressed genes in which 270 genes were up-regulated in NPC tissues and 488 genes were down-regulated in NPC tissues.Thus we constructed the NPC differentially expressed gene profiling.Using Ingenuity Pathway Analysis(IPA),Gene Set Enrichment Analysis(GSEA) and DAVID to analyze the NPC differentially expressed gene profiling data and found that cell cycle pathway and TGFβpathway correlated molecular markers were closely associated with NPC tumorigenesis.
【Identification of Molecular Markers for Nasopharyngeal Carcinoma with Different Stages】
To further study the relationship and effect between differentially expressed genes,cell cycle pathway and TGFβpathway correlated molecules and NPC tumorigenesis,and evaluate whether the differentially expressed genes could be as molecular targets for NPC.We made high density TMA with different stages of NPC to validate their expression level.It is important to screen and validate target genes of NPC with different stages and looking for biomarkers of early diagnosis, metastasis and prognosis for NPC.
1.Construction of Nasopharyngeal Carcinoma Tissue Microarray with Different Stages
The tissue microarray(TMA) of NPC with different stages was made according to the patent technology(ZL 200410022818X).There are 896 dots on the TMA including normal and chronic inflammation nasopharyngeal epithelium(NPE),dysplastic NPE,adjacent epithelium of NPC,NPC(WHOⅠ,WHOⅡ,WHOⅢ;clinical stageⅠ,clinical stageⅡ, clinical stageⅢ,clinical stageⅣ;lymph node metastasis,without lymph node metastasis),normal NPE of NPC after radiation and relapse of NPC after radiation,lymphoma and laryngocarcinoma.The actual dots of TMA are 825 excluding lymphoma and laryngocarcinoma,and loss tissues.The 825 tissues included 141 cases normal and chronic inflammation NPE,98 cases dysplastic NPE,88 cases adjacent epithelium of NPC,434 cases NPC(15 cases WHOⅠ,402 cases WHOⅡ,17 cases WHOⅢ;32 cases clinical stageⅠ,155 cases clinical stageⅡ,156 cases clinical stageⅢ,91 cases clinical stageⅣ;283 cases with lymph node metastasis,151 cases without lymph node metastasis),64 cases normal NPE of NPC after radiation and relapse of NPC after radiation.
2.Identification of Nasopharyngeal Carcinoma Differentially Expressed Genes
It was identified that SPLUNC 1 was a molecular target for the early diagnosis of NPC.NGX6,LTF and AGTRL1 were a group of candidate biomarkers forcasting the lymph node metastasis of NPC.SPLUNC1, C1ORF102,AGTRL1 and SERPINB6 were a group of candidate biomarkers related to clinical progression.LTF,BRD7 and C1ORF102 were a group of perfect candidate biomarkers related to the prognosis of NPC among the 488 down-regulated genes in NPC using TMA.LTF, C1ORF102,SPLUNC1,BRD7,NAG7 and NGX6 were candidate suppressor genes of NPC which were cloned by our laboratory.AGTRL1 and SERPINB6 were candidate molecular markers of NPC by supervised clustering and weighted voting class prediction models by us before.
The expression level of 27,p16,CDK4,RB1 and CDK8 which belong to cell cycle pathway was in accordance with cDNA microarray combine real-time quantitative RT-PCR with NPC TMA in different stages.We confirmed the aberrant activation of TGFβIIR、ACVRL1、INHBB、Axin2 and p300/CBP which belong to TGFβpathway using NPC TMA with different stages.This suggested that cell cycle pathway and TGFβpathway may play an important role in NPC tumorigenesis. We also confirmed that EBV infection is the main characteristic of NPC. The activated cell cycle pathway and TGFβpathway in NPC may be closely associated with EBV infection.
3.Construction of Molecular Markers for Nasopharyngeal Carcinoma with Different Stages
Using a series of large scale screening techniques from transcriptomics and TMA to identify differentially expressed genes and candidate NPC suppressor genes such as SPLUNC1,C1ORF102,BRD7, NAG7,NGX6 and cell cycle pathway and TGFβpathway members,we had preliminary constructed a molecular marker system in different stages of NPC:①SPLUNC1,p16,p27,and p19,a group of molecular targets for the early diagnosis of NPC.②LTF,NAG7,SPLUNC1,C1ORF102, CDK4,AGTRL1,INHBB and SERPINB6,a group of candidate biomarkers related to clinical progression.③NGX6,LTF,AGTRL1, INHBB and ACVRL1,a group of candidate biomarkers forcasting the lymph node metastasis of NPC.④LTF,BRD7,CDK4,Cyclin D1,RB1, EBER-1 and ACVRL1,a group of candidate biomarkers forcasting radiation sensitivity of NPC.⑤LTF,BRD7,C1ORF102,ACVRL1, INHBB,cyclin D1,a group of perfect candidate biomarkers related to the prognosis of NPC.The validation of biomarkers for NPC with different stages lay a substaintial foundation for molecular classification research of NPC.
【Construction of Nasopharyngeal Carcinoma Differentially Expressed Genes Crosstalk Networks】
The 758 differentially expressed genes were imported into IPA software to study the biological function and crosstalk networks associated with NPC tumorigenesis.The results showed that only 137 genes were in the network database and 127 genes had the functions or took part in some pathways.Among these networks,there were 9 notably changed networks.These networks involved in DNA replication and repair,cell cycle,cancer,gene expression,cell signaling and so on. SPLUNC1 participated in gene expression and cancer and regulated by retinoic acid(RA).We speculated that RA suppressed NPC cells growth maybe through regulating the expression of SPLUNC1.SERPINB6 participated in cell movement and immune response.
本研究室曾利用上海博芯公司H80s高密度基因芯片构建了鼻咽癌基因组表达谱,利用监督聚类和Weighted Voting算法筛选到6个基因,包括鼻咽癌上调基因RB1、STMN_1、DSP和下调基因SERPINB6、AGTRL1和SYTL2。该6个基因代表的分类预测模型能将鼻咽癌和鼻咽慢性炎症上皮很好的区分开来,可能是鼻咽癌的候选分子标志物。
为充分挖掘所构建的鼻咽癌差异基因表达谱中所隐藏的表达规律,提炼出更有价值的生物学信息,本文利用微阵列显著性分析(significance analysis of microarray,SAM)软件再次分析了鼻咽癌差异基因表达谱数据,共有显著差异表达基因758个,其中鼻咽癌表达上调基因270个,表达下调基因488个,从而构建了鼻咽癌差异基因表达谱。用Ingenuity Pathway Analysis(IPA)在线通路分析软件、Gene Set Enrichment Analysis(GSEA)软件和DAVID软件等分析发现cell cycle pathway和TGFβpathway相关分子的变化与鼻咽癌发生密切相关。
【鼻咽癌发病不同阶段分子标志物的鉴定】
为进一步研究上述鼻咽癌差异表达基因、cell cycle pathway和TGFβpathway相关分子与鼻咽癌发生发展的关系及在鼻咽癌发生中的作用,评估这些差异表达基因是否可作为鼻咽癌的分子靶标,本研究制作了高密度点阵的鼻咽癌发病不同阶段的组织微阵列以验证这些差异表达基因相关分子的表达变化。筛选和鉴定鼻咽癌发病不同阶段生物靶点基因、寻找鼻咽癌早期诊断、侵袭转移、预后复发相关的分子标志物。具体如下:
1.鼻咽癌发病不同阶段组织微阵列的构建
利用本室已获得发明专利的组织芯片制备技术(专利授权号:ZL200410022818X)制备了包含正常鼻咽上皮、慢性炎症鼻咽上皮、不典型增生鼻咽上皮、鼻咽癌(含不同组织学类型、不同临床分期、有无淋巴结转移、放疗后正常及复发鼻咽癌组织)及癌旁组织的鼻咽癌发病不同阶段的含825个点阵的组织微阵列,包括淋巴瘤和喉癌标本及缺失组织,该微阵列共有896个点。其中正常和鼻咽炎性上皮141例、不典型增生鼻咽上皮98例、癌旁上皮88例、鼻咽癌(WHOⅠ型15例、WHOⅡ型402例、WHOⅢ型17例;临床分期Ⅰ期32例、Ⅱ期155例、Ⅲ期1 56例、Ⅳ期91例;有淋巴结转移283例、无淋巴结转移151例)、放疗后正常和复发的标本64例、淋巴瘤和喉癌标本57例。
2.鼻咽癌差异表达基因的验证
鼻咽癌发病不同阶段的组织微阵列证实在488个鼻咽癌表达下调基因中,SPLUNC1是鼻咽癌早期患病风险筛查的易感因子,NGX6、LTF与鼻咽癌侵袭转移密切相关,SPLUNC1、ClORF102、AGTRL1和SERPINB6与鼻咽癌临床进展密切相关,LTF、BRD7和C1ORF102能预测鼻咽癌患者预后。其中LTF、C1ORF102、SPLUNC1、BRD7、NAG7、NGX6是我室克隆的鼻咽癌候选抑瘤基因,AGTRL1和SERPINB6是我们前期用监督聚类和weighted voting算法筛选到的鼻咽癌候选分子标志物。
结合鼻咽癌发病不同阶段组织微阵列和real-time quantitativeRT-PCR证实cell cycle pathway中p27、p16、CDK4、RB1、CDK8等分子与cDNA microarray结果变化一致。利用鼻咽癌发病不同阶段组织微阵列证实TGFβpathway中TGFβⅡR、ACVRL1、INHBB、Axin2和p300/CBP分子在鼻咽癌中异常活化,说明cell cycle pathway和TGFβpathway在鼻咽癌发生发展过程中可能起到重要的作用。并且证实了EBV感染是鼻咽癌的一主要特征,鼻咽癌中cell cycle pathway和TGFβpathway的活化与EBV的感染密切相关。
3.构建鼻咽癌发病不同阶段的分子标志物系统
通过运用转录组学和组织微阵列等高通量技术,在大样本的基础上筛查并鉴定了SAM软件分析得到的鼻咽癌差异表达基因及我室克隆的鼻咽癌候选抑瘤基因SPLUNC1、C1ORF102、BRD7、NAG7、NGX6基因以及cell cycle pathway、TGFβpathway相关分子的表达,构建了鼻咽癌发病不同阶段的分子标志物系统:①证实SPLUNC1、p27、p16、p19是鼻咽癌早期诊断的理想分子标志物;②LTF、NAG7、SPLUNC1、ClORF102、CDK4、AGTRL1、INHBB和SERPINB6是与鼻咽癌临床进展相关的候选分子标志物;③NGX6、LTF、AGTRL1、INHBB和ACVRL1是与鼻咽癌淋巴结转移相关的候选分子标志物;④证实LTF、BRD7、CDK4、cyclin D1、RB1、EBER-1和ACVRL1是预测鼻咽癌放疗敏感与否的候选分子标志物;⑤LTF、BRD7、C1ORF102、ACVRL1、INHBB、cyclin D1是与鼻咽癌预后相关的候选分子标志物。鼻咽癌发病不同阶段的分子标志物的证实为鼻咽癌分子分型研究奠定了坚实的工作基础。
【鼻咽癌差异表达基因相互作用网络的构建】
将SAM软件筛选到的758个鼻咽癌差异表达基因输入IngenuityPathway Analysis(IPA)在线软件分析基因生物学功能和相互作用网络,137个基因在其基因网络数据库中,127个基因有功能/通路数据。变化最显著的有9个network,这些基因网络主要涉及DNA复制与修复、细胞周期、肿瘤发生、基因表达、细胞信号等方面。其中SPLUNC1参与了基因表达和肿瘤发生等生物学过程,并受维甲酸(retinoic acid,RA)调控,RA可能通过调控SPLUNC1的表达而抑制鼻咽癌细胞生长;SERPINB6参与了细胞运动和免疫应答等生物学过程。
【Analysis of Nasopharyngeal Carcinoma Differentially Expressed Gene Profiling】
We selected the H80s high-density chip to construct the nasopharyngeal carcinoma(NPC) differentially expressed gene profiling and found that a set of 6 unique genes may be the candidate molecular markers by supervised clustering and weighted voting class prediction models.Because it predicted NPC from non-cancerous tissues most accurately.Among the 6 genes,RB1,STMN1 and DSP were up-regulated in NPC,SERPINB6,STYL2 and AGTRL1 were down-regulated in NPC.
In order to find out much more valuable information from the NPC differentially expressed gene profiling,we analyzed the NPC differentially expressed gene profiling data using significance analysis of microarray(SAM) once again and found that there were 758 notably differentially expressed genes in which 270 genes were up-regulated in NPC tissues and 488 genes were down-regulated in NPC tissues.Thus we constructed the NPC differentially expressed gene profiling.Using Ingenuity Pathway Analysis(IPA),Gene Set Enrichment Analysis(GSEA) and DAVID to analyze the NPC differentially expressed gene profiling data and found that cell cycle pathway and TGFβpathway correlated molecular markers were closely associated with NPC tumorigenesis.
【Identification of Molecular Markers for Nasopharyngeal Carcinoma with Different Stages】
To further study the relationship and effect between differentially expressed genes,cell cycle pathway and TGFβpathway correlated molecules and NPC tumorigenesis,and evaluate whether the differentially expressed genes could be as molecular targets for NPC.We made high density TMA with different stages of NPC to validate their expression level.It is important to screen and validate target genes of NPC with different stages and looking for biomarkers of early diagnosis, metastasis and prognosis for NPC.
1.Construction of Nasopharyngeal Carcinoma Tissue Microarray with Different Stages
The tissue microarray(TMA) of NPC with different stages was made according to the patent technology(ZL 200410022818X).There are 896 dots on the TMA including normal and chronic inflammation nasopharyngeal epithelium(NPE),dysplastic NPE,adjacent epithelium of NPC,NPC(WHOⅠ,WHOⅡ,WHOⅢ;clinical stageⅠ,clinical stageⅡ, clinical stageⅢ,clinical stageⅣ;lymph node metastasis,without lymph node metastasis),normal NPE of NPC after radiation and relapse of NPC after radiation,lymphoma and laryngocarcinoma.The actual dots of TMA are 825 excluding lymphoma and laryngocarcinoma,and loss tissues.The 825 tissues included 141 cases normal and chronic inflammation NPE,98 cases dysplastic NPE,88 cases adjacent epithelium of NPC,434 cases NPC(15 cases WHOⅠ,402 cases WHOⅡ,17 cases WHOⅢ;32 cases clinical stageⅠ,155 cases clinical stageⅡ,156 cases clinical stageⅢ,91 cases clinical stageⅣ;283 cases with lymph node metastasis,151 cases without lymph node metastasis),64 cases normal NPE of NPC after radiation and relapse of NPC after radiation.
2.Identification of Nasopharyngeal Carcinoma Differentially Expressed Genes
It was identified that SPLUNC 1 was a molecular target for the early diagnosis of NPC.NGX6,LTF and AGTRL1 were a group of candidate biomarkers forcasting the lymph node metastasis of NPC.SPLUNC1, C1ORF102,AGTRL1 and SERPINB6 were a group of candidate biomarkers related to clinical progression.LTF,BRD7 and C1ORF102 were a group of perfect candidate biomarkers related to the prognosis of NPC among the 488 down-regulated genes in NPC using TMA.LTF, C1ORF102,SPLUNC1,BRD7,NAG7 and NGX6 were candidate suppressor genes of NPC which were cloned by our laboratory.AGTRL1 and SERPINB6 were candidate molecular markers of NPC by supervised clustering and weighted voting class prediction models by us before.
The expression level of 27,p16,CDK4,RB1 and CDK8 which belong to cell cycle pathway was in accordance with cDNA microarray combine real-time quantitative RT-PCR with NPC TMA in different stages.We confirmed the aberrant activation of TGFβIIR、ACVRL1、INHBB、Axin2 and p300/CBP which belong to TGFβpathway using NPC TMA with different stages.This suggested that cell cycle pathway and TGFβpathway may play an important role in NPC tumorigenesis. We also confirmed that EBV infection is the main characteristic of NPC. The activated cell cycle pathway and TGFβpathway in NPC may be closely associated with EBV infection.
3.Construction of Molecular Markers for Nasopharyngeal Carcinoma with Different Stages
Using a series of large scale screening techniques from transcriptomics and TMA to identify differentially expressed genes and candidate NPC suppressor genes such as SPLUNC1,C1ORF102,BRD7, NAG7,NGX6 and cell cycle pathway and TGFβpathway members,we had preliminary constructed a molecular marker system in different stages of NPC:①SPLUNC1,p16,p27,and p19,a group of molecular targets for the early diagnosis of NPC.②LTF,NAG7,SPLUNC1,C1ORF102, CDK4,AGTRL1,INHBB and SERPINB6,a group of candidate biomarkers related to clinical progression.③NGX6,LTF,AGTRL1, INHBB and ACVRL1,a group of candidate biomarkers forcasting the lymph node metastasis of NPC.④LTF,BRD7,CDK4,Cyclin D1,RB1, EBER-1 and ACVRL1,a group of candidate biomarkers forcasting radiation sensitivity of NPC.⑤LTF,BRD7,C1ORF102,ACVRL1, INHBB,cyclin D1,a group of perfect candidate biomarkers related to the prognosis of NPC.The validation of biomarkers for NPC with different stages lay a substaintial foundation for molecular classification research of NPC.
【Construction of Nasopharyngeal Carcinoma Differentially Expressed Genes Crosstalk Networks】
The 758 differentially expressed genes were imported into IPA software to study the biological function and crosstalk networks associated with NPC tumorigenesis.The results showed that only 137 genes were in the network database and 127 genes had the functions or took part in some pathways.Among these networks,there were 9 notably changed networks.These networks involved in DNA replication and repair,cell cycle,cancer,gene expression,cell signaling and so on. SPLUNC1 participated in gene expression and cancer and regulated by retinoic acid(RA).We speculated that RA suppressed NPC cells growth maybe through regulating the expression of SPLUNC1.SERPINB6 participated in cell movement and immune response.
引文
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