维吾尔族宫颈癌发生与抗原呈递元件基因表达调控的关系研究
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摘要
研究目的：
维吾尔族妇女宫颈癌发病率高,死亡率高,远远超过全国平均水平,是新疆特高发肿瘤。HPV是宫颈癌发生的主要因素,其在维吾尔族妇女宫颈癌的检出率也与国内外宫颈癌高发人群水平相当。利用维吾尔族宫颈癌疾病资源,开展宫颈癌的基础与临床研究,揭示宫颈癌发病发展规律,寻找HPV致病与致癌的生物学本质,建立肿瘤分子标志物体系及临床诊断标准,对新疆宫颈癌的临床早期诊断、基于人群的疫苗预防和临床治疗有重大社会经济意义。
肿瘤细胞的产生与生存标志着肿瘤免疫逃逸的成功,人体免疫监视与清除功能的失败。人类白细胞抗原Ⅰ(human leukocyte antigen class Ⅰ, HLA-Ⅰ)及抗原呈递元件(antigen processing machinery, APM)的正常功能是T细胞介导的免疫监视的前提。HLA-Ⅰ在APM成员的协助下,完成内源性抗原肽的组装、负载和提呈,介导抗肿瘤或病毒的细胞和体液免疫。因此HLA-Ⅰ和APM的正常表达或表达缺陷可能决定肿瘤细胞的免疫清除,或者肿瘤生存和发展。
本研究拟以HLA-Ⅰ和APM(10种基因)为候选基因,利用维吾尔族妇女宫颈病变资源,从基因组表观遗传学修饰(启动子甲基化)、基因转录(mRNA)和蛋白质表达水平等三种基因表达调控层次分析肿瘤进程与候选基因表达水平改变的关系。在实际研究中,我们从蛋白质和mRNA表达水平鉴定入手,第一步筛选具有显著差异的、代表总体趋势的基因种类,淘汰无意义的指标。其次,按照本研究主题思路(表观遗传学),选择肿瘤特异性下调表达或蛋白质缺失的基因,从基因启动子CpG岛异常甲基化水平分析,主要是设计候选基因启动子区富含CpG序列片段特异性引物,通过宫颈癌细胞(细胞株)DNA中特定基因CpG片段的PCR扩增、载体克隆与测序,筛选宫颈癌特异性甲基化的基因。第三步,基于以上结果,依托Sequenom MassARRAY质谱技术平台,对临床宫颈病变组织DNA进行甲基化水平定量分析。同时,分析组织DNA的HPV感染与候选基因甲基化水平的关系。寻求发现宫颈癌病变进程与HLA-Ⅰ及APM基因表达调控的分子机制,提出基于HLA-Ⅰ及APM基因表达水平改变的宫颈癌早期预警指标,从抗原呈递功能角度揭示宫颈癌发病机制。
研究方法
(1)收集维吾尔族妇女宫颈病变患者的石蜡包埋组织和新鲜组织,采用免疫组织化学和半定量RT-PCR方法,鉴定TAP1、TAP2、LMP2、LMP7、calnexin、 calreticulin、ERp57、ERAP1、Tapasin)和HLA-Ⅰ等10种基因的蛋白质和mRNA表达水平。
(2)从Genbank数据库获取基因信息,利用专业软件扫描基因启动子区,设计出CpG岛片段特异性引物,对亚硫酸氢盐修饰的宫颈癌细胞DNA进行PCR扩增、载体克隆和测序分析,获得基因甲基化相关的序列和CpG位点信息。
(3)依托Sequenom MassARRAY技术,选择“第二部分”研究中确认的候选基因CpG岛片段及其特异性引物,对宫颈病变组织DNA进行CpG‘岛片段甲基化水平定量分析,确定不同组织甲基化片段及其CpG位点之差异。利用HPV分型芯片分析组织DNA的HPV阳性及其与候选基因甲基化的依存关系。
结果
(1)免疫组织化学分析显示,随着正常宫颈到CIN和宫颈癌的发病进程,宫颈上皮组织内HLA-Ⅰ、TAP1、TAP2、LMP2、LMP7、ERAP1, Tapasin、calreticulin和ERp57等9种基因的蛋白质表达水平呈现由正常强表达、中度表达到弱表达和或表达缺失的转变,组间差异有统计学意义(P<0.05),而calnexin的变化无统计学意义。RT-PCR结果表明TAP1、TAP2、LMP2、LMP7、Tapasin和ERp57等6种基因以及编码HLA-Ⅰ的HLA-A、HLA-B、HLA-C等三种基因的mRNA表达水平变化趋势与以上蛋白表达水平变化趋势一致,其差异也有统计学意义。分析宫颈癌临床预后参数与候选基因表达水平的关系,发现HLA-Ⅰ、TAP1、LMP7和ERp57蛋白表达水平变化与肿瘤的分化程度存在一定的负相关性,肿瘤组织学级别越高,蛋白表达越少,其蛋白表达在中低分化组低于高分化组,其差异有统计学意义(P<0.05)。HLA-Ⅰ,TAP1,LMP7,Tapasin, calreticulin和ERp57蛋白表达与淋巴结转移也存在一定的负相关性,在淋巴结转移组其蛋白表达明显少于无淋巴结转移组,表达差异有统计学意义(P<0.05)。以FIGO分期为准,低级别组ERp57蛋白表达低于高级别组,差异有统计学意义(P<0.05)。比较分析HLA-Ⅰ与其他候选基因的关联程度,在CIN中HLA-Ⅰ与TAP1,TAP2,LMP7,ERAP1, Tapasin和ERp57表达下调呈正相关,宫颈癌中HLA-Ⅰ与TAP1,TAP2,LMP2、LMP7,ERAP1,ERp57和Tapasin表达下调呈正相关。
(2)通过基因启动子区CpG片段甲基化测序,发现宫颈癌细胞基因组的TAP1、TAP2、LMP7、Tapasin和ERp57基因启动子区中选定的CpG位点均有不同程度的甲基化,依次为5／23、8／8、2／22、12／12和18／18。但是,没有发现HLA-B、LMP2和ERAP1等3种基因启动子区发生任何位点甲基化。
(3)根据Sequenom MassARRAY DNA甲基化测试和数据分析,TAP1、LMP7和ERp57基因在宫颈癌组织总甲基化水平高于CIN和正常宫颈组织,两者比较具有统计学意义(P<0.05),但是TAP2和Tapasin的甲基化水平差异无统计学意义(P>0.05)。单点甲基化率分析显示,TAP1、LMP7和ERp57基因的所有CpG位点在不同宫颈病变组织之间具有“单点”差异,其差异也有统计学意义(P<0.05)。比较分析以上基因的目的片段甲基化水平变化与“第一部分”所述的蛋白质水平表达改变,可以看出,TAP1、LMP7和ERp57等三种基因的甲基化水平变化与蛋白质表达变化(阳性)呈负相关。本研究的组织DNA标本中,共检出13种HPV亚型,高危型11种,低危型2种,HPV16感染率构成比达69.8%。分析HPV阳性组织DNA中,HPV16阳性和“非HPV16”与候选基因的目的片段甲基化水平变化的关系,发现HPV16感染组织中ERp57、TAP1和LMP7启动子区甲基化水平明显增加,两者呈正相关(P均<0.05)。
结论
(1)HLA-Ⅰ和抗原呈递元件(APM)基因的转录表达下调或蛋白质表达缺失与维吾尔族妇女宫颈癌病变进程密切相关,可以成为建立肿瘤分子标志物体系重要候选基因。
(2)宫颈癌细胞中TAP1、TAP2、LMP7、Tapasin和ERp57等5种基因的目的CpG岛片段均发生不同程度的CpG位点甲基化,此可能更好地揭示这些基因转录表达下调或蛋白质表达缺失的表观遗传学原因。
(3)TAP1、LMP7和ERp57等三种基因的启动子区甲基化是一种宫颈癌病变特异性改变,其中HPV16感染可能是重要原因之一,也是从表观遗传学层次调节蛋白质表达水平的分子机制。
Aim of the Study:
The prevalence and mortality of cervical cancer in Uighur women has been very high and beyond the average level in China, known as a high incident cancer of Xinjiang. The infection with human papillomavirus (HPV) was believed to be the main cause of cervical cancer development, and indeed HPV was also detectable in Uighur women with cervical cancer at a rate comparable with other populations in and outside China. To promote the cervical cancer research based on clinical practice focusing on the treatment of Uighur women with cervical cancer, reveal the cervical cancer pathogenesis and seek for the nature of HPV induced pathogenesis and carcinogenesis as well as to establish the tumor specific molecular marker profile and clinical diagnostic standard have a great social-economic importance for the early diagnosis, preventive vaccination and clinical treatment of the cancer in Xinjiang.
The formation and survival of a tumor cell is a sign of a successful immune escape and the failure of host in immune surveillance and elimination. The normal function of human leukocyte antigen class Ⅰ (HLA-Ⅰ) and antigen processing machinery (APM) is the prerequisite for the T cell-mediated immune surveillance. HLA-Ⅰ works together with the members of APM in the assembling, loading and presentation of endogenous antigenic peptide, mediates anti-tumor or anti-viral cellular and humoral immunity. Thus, the elimination of tumor cells by immune system or the tumor survival and development may greatly be depended on the normal or abnormal expression of APM and HLA-Ⅰ.
In this study, we will focus on10candidate genes belong to the HLA-Ⅰ and APM family and clinical resources from the treatment of cervical cancer, analyze the relationship between cancer development and the alteration of candidate gene expression at three different levels of gene expression control including epigenomic modification (gene promoter methylation), transcription (mRNA) and protein expression. In the practical approach, we will start with the detection at protein and mRNA expression levels, as a first step to identify genes significantly different and representing the overall trend of changes, and abandon the genes without significance. In the second step, in accordance with the main topic of this study (epigenetic research), we will focus on genes that were tumor-specific down-regulated or loss of protein expression and analyze the aberrant methylation of CpG islands at promoter regions such as to design primers of candidate genes specific to promoter regions rich in CpG islands, to screen cervical cancer specific methylated genes by amplification of cervical cancer cell DNA, cloning and sequencing of target CpG fragments of corresponding genes.
In the third step, we will analyze tissue DNA generated from clinical samples for the quantitative difference of methylation by mass spectrometry approach (Sequenom MassARRAY) and the dependence on HPV infection, to find out the molecular mechanism of the relationship between cervical carcinogenesis and HLA-I and APM expression regulation, provide with early diagnostic markers based on the alteration of HLA-I and APM gene expression, and to understand the cervical cancer pathogenesis related to the function of antigen presentation.
Methods:
(1) Paraffin-embedded and/or fresh tissue specimens of Uighur women with cervical disease were collected for the detection of protein and semi-quantitative mRNA expression level of TAP1、TAP2、LMP2、LMP7、calnexin、calreticulin、ERp57、ERAP1、 tapasin and HLA-Ⅰ genes by immunohistochemistry (IHC) and RT-PCR.
(2) CpG island fragment specific primers were designed by scanning gene promoter region using specialized software based on genetic information obtained from the Genbank database online, and bisulphate treated DNA of cervical cancer cells was amplified with PCR followed by cloning into vector and sequencing to identify CpG sites related to gene promoter methylation.
(3) By DNA Sequenom MassARRAY approach for quantitative detection of methylated DNA, we analyzed the cervical tissue DNA for CpG content of candidate genes provided by the analysis in "Part II" of this study using gene specific primer pairs to compare methylation level of target fragments and CpG sites among different tissues. The dependence of candidate gene methylation on HPV infection was analyzed by detection of HPV positivity and genotypes of tissue DNA by HPV typing chips.
Results:
(1) Immunohistochemical analysis showed that with the development of cervical lesions from normal uterine cervix to cervical intraepithelial neoplasia (CIN) or cervical squamous cell carcinoma (CSCC), the protein expression level of nine genes, including HLA-Ⅰ、TAP1、TAP2、LMP2、IMP7、ERAP1, Tapasn、CRT and ERp57, was altered from normal expression to partial loss or total loss of expression, with statistically significance except for calnexin (P<0.05). RT-PCR results suggested that the change in mRNA expression level of TAP1, TAP2, LMP2, LMP7, ERAP1, Tapasin, CRT and ERp57as well as the HLA-A, HLA-B and HLA-C genes coding for HLA-Ⅰ was also significant among cervical lesions, and correlated with the protein expression described above. From the analysis of the association of clinical prognostic parameters for cervical cancer with candidate gene expression, we found a reverse correlation of the downregulation of HLA-Ⅰ, TAP1, and LMP7and ERp57protein expression with tumor differentiation state (P<0.05) as well as the down regulation of HLA-Ⅰ, TAP1, LMP7, Tapasin, CRT and ERp57with lymphnode metastasis, both with a statistically significance (P<0.05). From the FIGO stage point of view, the ERp57protein expression was significantly lower in low stage cancer than in high stage. The downregulation of TAP1, TAP2, LMP7, ERAP1, Tapasin and ERp57protein expression was positively associated with HLA in CIN lesions, whereas TAP1, TAP2, LMP2, LMP7, ERAP1, ERp57and Tapasin was positively associated with HLA-Ⅰ in the cancer.
(2) By sequencing of the CpG fragment methylation at gene promoter region, we identified the target CpG site methylation to various extents at promoter regions of TAP1, TAP2, LMP7, Tapasin and ERp57, with the ratio5/23,8/8,2/22,12/12and18/18representing methylated CpG sites in total CpG sites. However, no methylation was found for HLA-B, LMP2and ERAP1.
(3) According to the data generated by Sequenom Mass ARRAY DNA detection, total methylation level of target fragments of TAP1, LMP7, and ERp57genes tissues was higher in cervical cancer than CIN and normal tissues with statistical significance (P<0.05), but no difference was found for TAP2and Tapasin. The single-site methylation level analysis showed that the single-site methylation was significant for almost all CpG sites of TAP1, LMP7and ERp57genes in cervical cancer tissues compared to CIN and the normal. Comparative analysis of target fragment methylation and the data of altered protein expression described in "part Ⅰ" of this study, we found a reverse correlation of TAP1, LMP7and ERp57gene methylation level with the protein expression. We detected13HPV genotypes in tissue DNA samples, including11high-risk and2low-risk types, with infection rate of52/78(69.8%). Comparative analysis of methylation level of target gene fragments between HPV positive and negative cases, we found a significant increase of promoter methylation of ERp57, TAP1and LMP7genes in HPV positive tissues.
Conclusion:
(1) The transcription downregulation and loss of protein expression of HLA-Ⅰ and antigen processing machinery (AMP) was closely associated with development of cervical cancer in Uighur women, and may become important candidates for the establishment of tumor molecular marker profile.
(2) The target CpG fragments of TAP1, TAP2, LMP7, Tapasin and ERp57were CpG site methylated at various degrees in cervical cancer cells, may most probably the cause of the transcription downregulation or protein loss expression regulated at epigenetic level.
(3) The promoter methylation of TAP1, LMP7and ERp57genes was a change specific to cervical carcinogenesis caused by HPV16infection, and an epigenetic regulation mechanism of protein expression too.
维吾尔族妇女宫颈癌发病率高,死亡率高,远远超过全国平均水平,是新疆特高发肿瘤。HPV是宫颈癌发生的主要因素,其在维吾尔族妇女宫颈癌的检出率也与国内外宫颈癌高发人群水平相当。利用维吾尔族宫颈癌疾病资源,开展宫颈癌的基础与临床研究,揭示宫颈癌发病发展规律,寻找HPV致病与致癌的生物学本质,建立肿瘤分子标志物体系及临床诊断标准,对新疆宫颈癌的临床早期诊断、基于人群的疫苗预防和临床治疗有重大社会经济意义。
肿瘤细胞的产生与生存标志着肿瘤免疫逃逸的成功,人体免疫监视与清除功能的失败。人类白细胞抗原Ⅰ(human leukocyte antigen class Ⅰ, HLA-Ⅰ)及抗原呈递元件(antigen processing machinery, APM)的正常功能是T细胞介导的免疫监视的前提。HLA-Ⅰ在APM成员的协助下,完成内源性抗原肽的组装、负载和提呈,介导抗肿瘤或病毒的细胞和体液免疫。因此HLA-Ⅰ和APM的正常表达或表达缺陷可能决定肿瘤细胞的免疫清除,或者肿瘤生存和发展。
本研究拟以HLA-Ⅰ和APM(10种基因)为候选基因,利用维吾尔族妇女宫颈病变资源,从基因组表观遗传学修饰(启动子甲基化)、基因转录(mRNA)和蛋白质表达水平等三种基因表达调控层次分析肿瘤进程与候选基因表达水平改变的关系。在实际研究中,我们从蛋白质和mRNA表达水平鉴定入手,第一步筛选具有显著差异的、代表总体趋势的基因种类,淘汰无意义的指标。其次,按照本研究主题思路(表观遗传学),选择肿瘤特异性下调表达或蛋白质缺失的基因,从基因启动子CpG岛异常甲基化水平分析,主要是设计候选基因启动子区富含CpG序列片段特异性引物,通过宫颈癌细胞(细胞株)DNA中特定基因CpG片段的PCR扩增、载体克隆与测序,筛选宫颈癌特异性甲基化的基因。第三步,基于以上结果,依托Sequenom MassARRAY质谱技术平台,对临床宫颈病变组织DNA进行甲基化水平定量分析。同时,分析组织DNA的HPV感染与候选基因甲基化水平的关系。寻求发现宫颈癌病变进程与HLA-Ⅰ及APM基因表达调控的分子机制,提出基于HLA-Ⅰ及APM基因表达水平改变的宫颈癌早期预警指标,从抗原呈递功能角度揭示宫颈癌发病机制。
研究方法
(1)收集维吾尔族妇女宫颈病变患者的石蜡包埋组织和新鲜组织,采用免疫组织化学和半定量RT-PCR方法,鉴定TAP1、TAP2、LMP2、LMP7、calnexin、 calreticulin、ERp57、ERAP1、Tapasin)和HLA-Ⅰ等10种基因的蛋白质和mRNA表达水平。
(2)从Genbank数据库获取基因信息,利用专业软件扫描基因启动子区,设计出CpG岛片段特异性引物,对亚硫酸氢盐修饰的宫颈癌细胞DNA进行PCR扩增、载体克隆和测序分析,获得基因甲基化相关的序列和CpG位点信息。
(3)依托Sequenom MassARRAY技术,选择“第二部分”研究中确认的候选基因CpG岛片段及其特异性引物,对宫颈病变组织DNA进行CpG‘岛片段甲基化水平定量分析,确定不同组织甲基化片段及其CpG位点之差异。利用HPV分型芯片分析组织DNA的HPV阳性及其与候选基因甲基化的依存关系。
结果
(1)免疫组织化学分析显示,随着正常宫颈到CIN和宫颈癌的发病进程,宫颈上皮组织内HLA-Ⅰ、TAP1、TAP2、LMP2、LMP7、ERAP1, Tapasin、calreticulin和ERp57等9种基因的蛋白质表达水平呈现由正常强表达、中度表达到弱表达和或表达缺失的转变,组间差异有统计学意义(P<0.05),而calnexin的变化无统计学意义。RT-PCR结果表明TAP1、TAP2、LMP2、LMP7、Tapasin和ERp57等6种基因以及编码HLA-Ⅰ的HLA-A、HLA-B、HLA-C等三种基因的mRNA表达水平变化趋势与以上蛋白表达水平变化趋势一致,其差异也有统计学意义。分析宫颈癌临床预后参数与候选基因表达水平的关系,发现HLA-Ⅰ、TAP1、LMP7和ERp57蛋白表达水平变化与肿瘤的分化程度存在一定的负相关性,肿瘤组织学级别越高,蛋白表达越少,其蛋白表达在中低分化组低于高分化组,其差异有统计学意义(P<0.05)。HLA-Ⅰ,TAP1,LMP7,Tapasin, calreticulin和ERp57蛋白表达与淋巴结转移也存在一定的负相关性,在淋巴结转移组其蛋白表达明显少于无淋巴结转移组,表达差异有统计学意义(P<0.05)。以FIGO分期为准,低级别组ERp57蛋白表达低于高级别组,差异有统计学意义(P<0.05)。比较分析HLA-Ⅰ与其他候选基因的关联程度,在CIN中HLA-Ⅰ与TAP1,TAP2,LMP7,ERAP1, Tapasin和ERp57表达下调呈正相关,宫颈癌中HLA-Ⅰ与TAP1,TAP2,LMP2、LMP7,ERAP1,ERp57和Tapasin表达下调呈正相关。
(2)通过基因启动子区CpG片段甲基化测序,发现宫颈癌细胞基因组的TAP1、TAP2、LMP7、Tapasin和ERp57基因启动子区中选定的CpG位点均有不同程度的甲基化,依次为5／23、8／8、2／22、12／12和18／18。但是,没有发现HLA-B、LMP2和ERAP1等3种基因启动子区发生任何位点甲基化。
(3)根据Sequenom MassARRAY DNA甲基化测试和数据分析,TAP1、LMP7和ERp57基因在宫颈癌组织总甲基化水平高于CIN和正常宫颈组织,两者比较具有统计学意义(P<0.05),但是TAP2和Tapasin的甲基化水平差异无统计学意义(P>0.05)。单点甲基化率分析显示,TAP1、LMP7和ERp57基因的所有CpG位点在不同宫颈病变组织之间具有“单点”差异,其差异也有统计学意义(P<0.05)。比较分析以上基因的目的片段甲基化水平变化与“第一部分”所述的蛋白质水平表达改变,可以看出,TAP1、LMP7和ERp57等三种基因的甲基化水平变化与蛋白质表达变化(阳性)呈负相关。本研究的组织DNA标本中,共检出13种HPV亚型,高危型11种,低危型2种,HPV16感染率构成比达69.8%。分析HPV阳性组织DNA中,HPV16阳性和“非HPV16”与候选基因的目的片段甲基化水平变化的关系,发现HPV16感染组织中ERp57、TAP1和LMP7启动子区甲基化水平明显增加,两者呈正相关(P均<0.05)。
结论
(1)HLA-Ⅰ和抗原呈递元件(APM)基因的转录表达下调或蛋白质表达缺失与维吾尔族妇女宫颈癌病变进程密切相关,可以成为建立肿瘤分子标志物体系重要候选基因。
(2)宫颈癌细胞中TAP1、TAP2、LMP7、Tapasin和ERp57等5种基因的目的CpG岛片段均发生不同程度的CpG位点甲基化,此可能更好地揭示这些基因转录表达下调或蛋白质表达缺失的表观遗传学原因。
(3)TAP1、LMP7和ERp57等三种基因的启动子区甲基化是一种宫颈癌病变特异性改变,其中HPV16感染可能是重要原因之一,也是从表观遗传学层次调节蛋白质表达水平的分子机制。
Aim of the Study:
The prevalence and mortality of cervical cancer in Uighur women has been very high and beyond the average level in China, known as a high incident cancer of Xinjiang. The infection with human papillomavirus (HPV) was believed to be the main cause of cervical cancer development, and indeed HPV was also detectable in Uighur women with cervical cancer at a rate comparable with other populations in and outside China. To promote the cervical cancer research based on clinical practice focusing on the treatment of Uighur women with cervical cancer, reveal the cervical cancer pathogenesis and seek for the nature of HPV induced pathogenesis and carcinogenesis as well as to establish the tumor specific molecular marker profile and clinical diagnostic standard have a great social-economic importance for the early diagnosis, preventive vaccination and clinical treatment of the cancer in Xinjiang.
The formation and survival of a tumor cell is a sign of a successful immune escape and the failure of host in immune surveillance and elimination. The normal function of human leukocyte antigen class Ⅰ (HLA-Ⅰ) and antigen processing machinery (APM) is the prerequisite for the T cell-mediated immune surveillance. HLA-Ⅰ works together with the members of APM in the assembling, loading and presentation of endogenous antigenic peptide, mediates anti-tumor or anti-viral cellular and humoral immunity. Thus, the elimination of tumor cells by immune system or the tumor survival and development may greatly be depended on the normal or abnormal expression of APM and HLA-Ⅰ.
In this study, we will focus on10candidate genes belong to the HLA-Ⅰ and APM family and clinical resources from the treatment of cervical cancer, analyze the relationship between cancer development and the alteration of candidate gene expression at three different levels of gene expression control including epigenomic modification (gene promoter methylation), transcription (mRNA) and protein expression. In the practical approach, we will start with the detection at protein and mRNA expression levels, as a first step to identify genes significantly different and representing the overall trend of changes, and abandon the genes without significance. In the second step, in accordance with the main topic of this study (epigenetic research), we will focus on genes that were tumor-specific down-regulated or loss of protein expression and analyze the aberrant methylation of CpG islands at promoter regions such as to design primers of candidate genes specific to promoter regions rich in CpG islands, to screen cervical cancer specific methylated genes by amplification of cervical cancer cell DNA, cloning and sequencing of target CpG fragments of corresponding genes.
In the third step, we will analyze tissue DNA generated from clinical samples for the quantitative difference of methylation by mass spectrometry approach (Sequenom MassARRAY) and the dependence on HPV infection, to find out the molecular mechanism of the relationship between cervical carcinogenesis and HLA-I and APM expression regulation, provide with early diagnostic markers based on the alteration of HLA-I and APM gene expression, and to understand the cervical cancer pathogenesis related to the function of antigen presentation.
Methods:
(1) Paraffin-embedded and/or fresh tissue specimens of Uighur women with cervical disease were collected for the detection of protein and semi-quantitative mRNA expression level of TAP1、TAP2、LMP2、LMP7、calnexin、calreticulin、ERp57、ERAP1、 tapasin and HLA-Ⅰ genes by immunohistochemistry (IHC) and RT-PCR.
(2) CpG island fragment specific primers were designed by scanning gene promoter region using specialized software based on genetic information obtained from the Genbank database online, and bisulphate treated DNA of cervical cancer cells was amplified with PCR followed by cloning into vector and sequencing to identify CpG sites related to gene promoter methylation.
(3) By DNA Sequenom MassARRAY approach for quantitative detection of methylated DNA, we analyzed the cervical tissue DNA for CpG content of candidate genes provided by the analysis in "Part II" of this study using gene specific primer pairs to compare methylation level of target fragments and CpG sites among different tissues. The dependence of candidate gene methylation on HPV infection was analyzed by detection of HPV positivity and genotypes of tissue DNA by HPV typing chips.
Results:
(1) Immunohistochemical analysis showed that with the development of cervical lesions from normal uterine cervix to cervical intraepithelial neoplasia (CIN) or cervical squamous cell carcinoma (CSCC), the protein expression level of nine genes, including HLA-Ⅰ、TAP1、TAP2、LMP2、IMP7、ERAP1, Tapasn、CRT and ERp57, was altered from normal expression to partial loss or total loss of expression, with statistically significance except for calnexin (P<0.05). RT-PCR results suggested that the change in mRNA expression level of TAP1, TAP2, LMP2, LMP7, ERAP1, Tapasin, CRT and ERp57as well as the HLA-A, HLA-B and HLA-C genes coding for HLA-Ⅰ was also significant among cervical lesions, and correlated with the protein expression described above. From the analysis of the association of clinical prognostic parameters for cervical cancer with candidate gene expression, we found a reverse correlation of the downregulation of HLA-Ⅰ, TAP1, and LMP7and ERp57protein expression with tumor differentiation state (P<0.05) as well as the down regulation of HLA-Ⅰ, TAP1, LMP7, Tapasin, CRT and ERp57with lymphnode metastasis, both with a statistically significance (P<0.05). From the FIGO stage point of view, the ERp57protein expression was significantly lower in low stage cancer than in high stage. The downregulation of TAP1, TAP2, LMP7, ERAP1, Tapasin and ERp57protein expression was positively associated with HLA in CIN lesions, whereas TAP1, TAP2, LMP2, LMP7, ERAP1, ERp57and Tapasin was positively associated with HLA-Ⅰ in the cancer.
(2) By sequencing of the CpG fragment methylation at gene promoter region, we identified the target CpG site methylation to various extents at promoter regions of TAP1, TAP2, LMP7, Tapasin and ERp57, with the ratio5/23,8/8,2/22,12/12and18/18representing methylated CpG sites in total CpG sites. However, no methylation was found for HLA-B, LMP2and ERAP1.
(3) According to the data generated by Sequenom Mass ARRAY DNA detection, total methylation level of target fragments of TAP1, LMP7, and ERp57genes tissues was higher in cervical cancer than CIN and normal tissues with statistical significance (P<0.05), but no difference was found for TAP2and Tapasin. The single-site methylation level analysis showed that the single-site methylation was significant for almost all CpG sites of TAP1, LMP7and ERp57genes in cervical cancer tissues compared to CIN and the normal. Comparative analysis of target fragment methylation and the data of altered protein expression described in "part Ⅰ" of this study, we found a reverse correlation of TAP1, LMP7and ERp57gene methylation level with the protein expression. We detected13HPV genotypes in tissue DNA samples, including11high-risk and2low-risk types, with infection rate of52/78(69.8%). Comparative analysis of methylation level of target gene fragments between HPV positive and negative cases, we found a significant increase of promoter methylation of ERp57, TAP1and LMP7genes in HPV positive tissues.
Conclusion:
(1) The transcription downregulation and loss of protein expression of HLA-Ⅰ and antigen processing machinery (AMP) was closely associated with development of cervical cancer in Uighur women, and may become important candidates for the establishment of tumor molecular marker profile.
(2) The target CpG fragments of TAP1, TAP2, LMP7, Tapasin and ERp57were CpG site methylated at various degrees in cervical cancer cells, may most probably the cause of the transcription downregulation or protein loss expression regulated at epigenetic level.
(3) The promoter methylation of TAP1, LMP7and ERp57genes was a change specific to cervical carcinogenesis caused by HPV16infection, and an epigenetic regulation mechanism of protein expression too.
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