摘要
鼻咽癌(Nasopharyngeal carcinoma,NPC)是我国南方和东南亚高发的上皮性恶性肿瘤,鼻咽癌患者的治疗方式主要是放疗。流行病学及病因学研究表明:EB病毒(Epstein-Barr virus,EBV)、化学致癌物和遗传易感性与鼻咽癌发生密切相关。
鼻咽癌的发生发展是一个多阶段、多途径的过程,涉及多个基因的改变,但关于鼻咽癌相关肿瘤免疫机制的研究并不多。2002年Schreiber和Dunn在现代免疫学发展的基础上,根据可靠的实验证据,提出了肿瘤免疫编辑学说(cancer immunoediting)。肿瘤免疫编辑学说又称“3E学说”,主要阐释肿瘤发展过程中免疫系统呈现的3个连续的动力学时相:清除(elimination)、平衡(equilibrium)及逃逸(escape)。该学说在阐明肿瘤的发生发展机制、指导肿瘤的免疫诊断和免疫治疗方面有重要意义。
本研究小组前期工作曾多次进行鼻咽癌组织及细胞系基因芯片检测,探讨了众多基因与鼻咽癌发生发展的关系;并且结合多个实验室的鼻咽癌比较基因组杂交数据,以染色体区域为基本事件单位构建了鼻咽癌发生发展的树模型;而且对鼻咽癌细胞CNE2与NK细胞之间的相互免疫编辑作用关系进行了深入研究。
本研究在研究小组前期工作的基础上,采用GenClip软件初步筛选潜在的鼻咽癌免疫编辑相关基因,再采用SYBR Real-time Q-PCR对所得结果进行初步验证,并且分析了鼻咽癌免疫相关基因所分布的染色体区域特点、这些染色体区域与染色体脆性位点及microRNAs的关系。本研究为了解鼻咽癌发生发展过程中相关的肿瘤免疫机制提供了初步实验证据。实验方法和结果如下:
第一部分鼻咽癌免疫编辑相关基因初步筛选
对实验室已有的鼻咽癌基因芯片结果设立筛选标准,找到在鼻咽癌细胞系高表达而在鼻咽癌组织中低表达的基因7个;在鼻咽癌细胞系低表达而在鼻咽癌组织中高表达的基因183个。采用GO分类方法从上述基因中筛选鼻咽癌免疫相关基因24个。
采用文献挖掘软件GenClip 3.2,将参与肿瘤免疫编辑的11个基因与24个在鼻咽癌细胞系和鼻咽癌组织中差异表达的免疫相关基因一起构建共发生网络,网络中相互关联基因20个(IFNG、IFNA1、PRF1、TRAIL、STAT1、NKG2D、RAG2、RAG1、IL23A、IRF1、CXCL10、IFITM3、INDO、IL1B、CXCL9、CCL2、CD14、CCL18、IL2RG和FAS)。进一步结合文献分析,筛选出6个可能参与鼻咽癌肿瘤免疫编辑过程的免疫相关基因(IFNG、STAT1、INDO、CXCL10、CXCL9和IRF1)。
利用Real-time PCR对6个基因进行初步验证,结果提示:IFNG、STAT1、INDO、CXCL10和IRF1是潜在的鼻咽癌免疫编辑相关基因。
第二部分鼻咽癌免疫相关染色体异常区域初步筛选
结合GO分类方法从本实验室已有的鼻咽癌基因芯片数据中筛选异常表达的免疫相关基因,发现处于扩增区域的表达上调鼻咽癌免疫相关基因14个,其中12个位于1q22-32(FCGR3A、FASLG、FCGR2A、FCER1G、CD1D、CD1E、IFI16、FCGR2C、TNFSF4、MR1、RGS1和CD46),2个位于12q 13-15(STAT6和IFNG);处于缺失区域的表达下调鼻咽癌免疫相关基因5个,其中4个位于14q24-32(IGHM、IGHD、IGHG1和IGHA1)而且位置紧密相邻,另外1个位于16q12-24(CHST4)。
根据基于170例鼻咽癌组织的比较基因组杂交数据构建的鼻咽癌发生发展的树模型提示的三个阶段,探讨了这些基因在鼻咽癌染色体异常区域分布的特点;在鼻咽癌免疫相关基因富集区域(1q22-32和14q24-32)找到3个脆性位点:FRA1G(1q25.1)、FRA1K(1q31)、FRA14C(14q24.1)。
对鼻咽癌染色体异常区域与鼻咽癌脆性位点进行比对,并筛选与这些区域可能相关的人类microRNAs;在这两个区域发现14个人microRNAs,8个位于1q22-32(miR-009-1、miR-29c/miR-102、miR-213S/miR-181b、miR-214/miR-199a-2、miR-205);6个位于14q24-32(miR-127/miR-136、miR-134/miR-154/miR-299、miR-203):这些microRNAs可能与鼻咽癌的发生密切相关。
采用文献挖掘软件GenClip 3.2将得到的各阶段鼻咽癌免疫相关基因一起构建共发生的基因关系网络。筛选出潜在的鼻咽癌免疫编辑相关基因13个(IFNG、CD46、FCGR3A、FASLG、CD1D、CD1E、FCGR2C、FCGR2A、STAT6、MR1、TNFSF4、IGHA1和IFI16)。
本实验采用生物信息学方法从已有的基因芯片数据中筛选鼻咽癌免疫编辑相关基因及鼻咽癌免疫相关染色体异常区域,并进行了初步实验验证。结果提示IFNG、STAT1、INDO、CXCL10和IRF1是潜在的鼻咽癌免疫编辑相关基因;1q22-32和14q24-32是潜在的鼻咽癌免疫相关染色体异常区域。但5个潜在的鼻咽癌免疫编辑相关基因及2个潜在的鼻咽癌免疫相关染色体异常区域在鼻咽癌发生发展过程中的作用机制需更多的体内外实验进行证实。
Nasopharyngeal carcinoma (nasopharyngeal carcinoma, NPC) is a malignancy derived from epithelium with high incidence in Southeast Asia and Southern China. The main treatment modality of NPC patients is radiotherapy. The epidemiological and etiological studies indicate that Epstein-Barr virus (EBV), certain chemical carcinogens and genetic susceptibility are closely associated with its occurrence and development.
Nasopharyngeal carcinogenesis is a multistage, multifactor and multipathway process involving multiple gene alterations. But research on immunological mechanism of NPC is scarce. Cancer immunoediting was put forward by Schreiber and Dunn in 2002, which based on the development of modern immunology and experimental evidence. It is also called "three E's hypothesis", which explains three continuous immunological kinetic phases (elimination, equilibrium and escape) presented during the process of tumor development. This hypothesis has profound influence on the strategy to elucidate the mechanism of tumor occurrence and development as well as to explore cancer immunodiagno-sis and immunotherapy.
Through gene chips study on NPC tissues and NPC cell lines, we have revealed the roles of many genes in the development of NPC. Based on comparative genomic hybridization (CGH) results from several laboratories, we have set up a tree model for explaining the pathogenesis of NPC. Furthermore, we have also explored the immunoediting events between CNE2 cells and NK cells recently.
In this study, potential immunoediting related genes of NPC were screened by GenClip software, and the results were validated by SYBR real-time q-PCR. Moreover, we analyzed the positional feature of immuno-related genes in chromosomal regions of NPC, the relation among these chromosomal regions and fragile sites and microRNAs. This study provides the preliminary experimental evidence for immunological mechanism in the development of NPC. The experimental methods and results are as follows:
I . Preliminary screening for immunoediting related genes in NPC
Differential expression criteria were set up for screening NPC gene chip data of our laboratory. 7 genes were found that they were up-regulated in NPC cell lines but down-regulated in NPC tissues, and 183 genes were found to be down-regulated in NPC cell lines but up-regulated in NPC tissues. According to gene ontology classification, 24 immuno-related genes of NPC were screened out from above-mentioned genes.
A relational network of gene co-occurrences was constructed by using 11 genes that participating in the process of cancer immunoediting and 24 above-mentioned genes with the literature-mining software GenClip 3.2. There are 20 genes (IFNG, IFNA1, PRF1, TRAIL, STAT1, NKG2D, RAG2, RAG1, IL23A, IRF1, CXCL10, IFITM3, INDO, IL1B, CXCL9, CCL2, CDM, CCL18, IL2RG and FAS) in this relational network. Based on detailed analysis of literature, 6 genes were found to probably participated in the process of NPC immunoediting, which included IFNG, STAT1, INDO, CXCL10, CXCL9 and IRF1.
Real-time PCR was performed to analyze these 6 genes, the results further suggests that IFNG, STAT1, INDO, CXCL10 and IRF1 are potential immunoediting related genes of NPC.
II. Preliminary screening of immuno-related abnormal chromosome regions in NPC
According to gene ontology classification, abnormal expression of immuno-related genes were found from the NPC gene chip data of our laboratory. 14 up-regulated immuno-related genes were discovered in NPC chromosomal amplification regions, in which 12 genes locate at the lq22-32 region (FCGR3A, FCGR2A, FCER1G, CD1D, CD1E, IFI16, FCGR2C, TNFSF4, MR1, RGS1 and CD46) , and 2 others locate at the 12q13-15 region (STAT6 and IFNG) , meanwhile, 5 down-regulated immuno-related genes are discovered in NPC chromosomal deletion regions, among them 4 locate at the 14q24-32 region (IGHM, IGHD, IGHG1 and IGHA1) , they are closely adjacent to each other, CHST4 at the 16q12-24 region.
The positional features of immuno-related genes in the NPC chromosomal regions were studied according to the three stages suggested by in the tree model for pathogenesis of NPC which was constructed by 170 comparative genomic hybridization (CGH) samples, and related or nearby fragile sites were also searched out. We found 3 fragile sites in the immuno-related gene enriched area (lq22-32 and 14q24-32 region), such as FRA1G (1q25.1), FRA1K (1q31) and FRA14C (14q24.1).
Human microRNAs probably related with the 1q22-32 and 14q24-32 regions were screened. We found 14 human microRNAs at two above mentioned regions, among which 8 microRNAs locate in 1q22-32 region ( including miR-009-1, miR-29c/miR-102, miR-213S/miR-181b, miR-214/miR-199a-2 and miR-205) , and the other 6 microRNAs locate at 14q24-32 region (including miR-127 / miR-136, miR-134 / miR-154 / miR-299 and miR-203) , We infer that these microRNAs are closely related to NPC.
A relational network of genes was constructed by NPC immuno-related genes screened from all stages with the literature-mining software GenClip 3.2, and we screened 13 potential genes that are related to NPC immunoediting genes (IFNG, CD46, FCGR3A, FASLG, CD1D, CD1E, FCGR2C, FCGR2A, STAT6, MR1, TNFSF4, IGHA1 and IFI16).
In summary, based on previous work of our laboratory, potential immunoediting related genes and immuno-related potential abnormal regions of chromosomes in NPC were screened by using bioinformatics method, and these data were validated preliminarily. The results suggest that IFNG, STAT1, INDO, CXCL10 and IRF1 are potential immunoediting related genes of NPC, and lq22-32 and 14q24-32 regions are potential immuno-related abnormal regions of chromosomes in NPC. The role of these genes in the pathogenesis of NPC remains to be elucidated.
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