食管癌高发区食管鳞癌与HPV、HLA-G和Lin28b的相关性研究
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摘要
研究背景
食管癌是严重威胁人类健康的最常见的胸部恶性肿瘤之一。全世界每年新发食管癌病例大约为40万,死亡病例约为30万,大部分食管癌患者发生在发展中国家。我国是世界上食管癌发病率和死亡率最高的国家和地区之一。20世纪90年代以来,我国食管癌的发病率、死亡率有所下降,但在河南北部地区和广东潮汕地区,食管癌仍居当地各种恶性肿瘤死亡原因的第一位；河南新乡地区、广东潮州地区均属于我国食管癌高发地区。在我国鳞状细胞癌(squamous cell carcinoma)是食管癌最主要的病理组织学类型。对食管癌特别是食管鳞状上皮细胞癌的研究仍是我国胸外科工作者研究的重点领域。食管鳞状上皮细胞癌的发生发展是长时期多因素(霉菌感染、不良饮食习惯、吸烟、饮酒、微量元素缺乏和环境污染等)相互作用、多种相关基因或独立基因(如癌基因、抑癌基因、凋亡抑制因子等)分子改变参与,其先后或同时发生的积累和叠加作用并最终作用于细胞的生长周期,导致细胞周期调控机制的紊乱、细胞增殖失控、基因受损突变导致正常上皮经过各级癌前病变而最终发展为浸润性癌肿。虽然根据目前对肿瘤的发病机制的认识,应用研究出的靶向药物治疗恶性肿瘤取得了一些进展,但是目前肿瘤癌变多阶段演进过程中重要关键性的DNA基因突变及某些分子事件及其相互关系还不十分清楚,寻找、确定肿瘤演进过程中共同的起关键作用的基因、蛋白和环节并将其应用于肿瘤的预防、早期诊断和治疗,最终征服肿瘤,还需要进行大量艰苦的工作。
由于恶性肿瘤的发病机制目前仍未能彻底搞清,所以肿瘤预防和治疗的效果仍很不理想,仍需广大医学工作者继续不断探索、研究肿瘤的发生、发展和有效治疗。近来,除环境、饮食和遗传等因素外,高危基因亚型人乳头状瘤病毒(HPV)感染与肿瘤的关系越来越受到关注。人乳头状瘤病毒属乳多空病毒科A亚群的一种双链环状DNA病毒,为无包膜的20面体对称病毒,直径约45-55nm。现多根据不同基因亚型HPV与恶性肿瘤发生的危险性高低分为低危险型和高危险型HPV。正常细胞DNA由于受到HPV的基因组的整合可能会导致癌基因激活,如Ras等使细胞永生化,经长期传代后激活癌基因。E6和E7癌基因是HPV的主要癌基因。当HPV病毒整合进入宿主细胞的基因组中,既可以逃避宿主免疫系统的免疫监视和免疫杀伤,而且整合的E6、E7癌基因与相邻的基因组共同转录,可以使转录更加稳定；体外研究证实高危型HPV编码产生的E6、E7癌蛋白能有效导致人体细胞发生恶性转化,抑制机体的免疫系统。尤其是高危型HPV16、18基因亚型产生的癌蛋白可抑制p53和Rb等,使其丧失抑制细胞生长的效应,激活端粒酶致,使HPV感染的细胞不断分裂生长,处于异常增殖状态,从而使细胞避免凋亡而永生化,进而发生恶性转化。HPV感染机体细胞在体内持续存在,需要逃避机体免疫系统的攻击,才能发挥重要的致瘤致癌作用。人类白细胞抗原G(HLA-G)属于非经典的HLA-Ⅰb类分子,是一种重要的免疫耐受分子。HLA-G在正常体细胞中不表达,主要在人类正常妊娠母胎界面的绒毛外滋养细胞表达,通过抑制NK细胞和T淋巴细胞等,来保护胚胎免受母体免疫系统的攻击。目前的研究发现HLA-G在乳腺癌、结肠癌、宫颈癌等多种恶性肿瘤中呈高表达,表明HLA-G可能在肿瘤的免疫逃逸机制中发挥着重要的作用。Lin28是AmbrosV等在秀丽隐杆线虫中首先发现的,其具有调节线虫发育的时序性作用的RNA结合蛋白；Lin28通过抑制Let-7在转录后水平发挥调控作用,进而作用于细胞周期,控制细胞的增殖、分裂和分化；是调节胚胎发育的一个重要因子。Lin28在鼠和人胚胎干细胞中呈高表达,并且随着干细胞诱导不断分化其表达逐渐降低；在肿瘤组织中则反常高表达。Lin28b是Lin28的同源异构体,主要在干细胞和某些肿瘤细胞中表达。目前对于HPV感染在食管癌变过程中怎样发挥作用,HLA-G、Lin28b在食管癌发生中是否起作用尚不清楚。HPV与HLA-G、Lin28b在食管癌变过程中的相互关系等尚不可知；本研究拟探讨HLA-G、Lin28b和HPV在食管鳞癌组织中的表达和相互关系。
本文分两章,分别阐释如下：
第一章新乡地区食管鳞癌与HPV、HLA-G和Lin28b的相关性研究
1.目的：
研究人乳头状瘤病毒(HPV)在新乡地区食管鳞状细胞癌组织、癌旁正常食管组织中的感染情况；
研究HLA-G在新乡地区食管鳞状细胞癌组织、癌旁正常食管组织中阳性表达的情况；
研究RNA结合蛋白Lin28b在新乡地区食管鳞状细胞癌、癌旁正常食管组织中阳性表达的情况；
研究新乡地区食管鳞状细胞癌病人的年龄、性别、肿瘤分化程度、肿瘤浸润深度、淋巴结转移与鳞癌组织中感染HPV、HLA-G阳性表达和Lin28b阳性表达之间的关系；
研究新乡地区食管鳞状细胞癌组织感染HPV与HLA-G表达、Lin28b表达之间的关系。
2.方法：
采用基因导流芯片技术,应用潮州凯普生化公司HPV基因分型检测试剂盒(包括13种高危亚型HPV16、18、31、33、35、39、45、51、52、56、58、59和68,5种低危亚型HPV6、11、42、43和44和3种中国人群常见亚型HPV53、66和CP8304),检测114例食管鳞状细胞癌组织及50例癌旁正常食管组织中HPV基因亚型感染的情况,
采用免疫组织化学非生物素二步法检测,用鼠抗人HLA-G单克隆抗体(1：150)和兔抗人Lin28b单克隆抗体(1：100)对114例食管鳞状细胞癌手术切除石蜡标本、50例癌旁正常食管上皮的石蜡标本组织切片进行染色、观察,评定HLA-G和Lin28b阳性表达的情况。
应用统计学软件SPSS13.0进行统计分析。HPV感染、HLA-G、Lin28b在食管鳞癌和正常食管组织中表达的比较、与食管鳞癌组织临床病理参数之间的关系采用χ2检验或Fisher's精确概率法。HPV感染与HLA-G、Lin28b两指标间的关系采用四格表χ2检验、Spearman秩相关。HPV亚型感染与HLA-G、Lin28b两指标间的关系采用列联表χ2检验法。显著性检验水准为α=0.05(双侧),以P<0.05为差别有统计学意义。
3.结果
新乡地区114例食管鳞癌组织及50例癌旁正常食管组织中人乳头状瘤病毒感染阳性率分别为63.2%和6%(72/114,,3/50),差异均有统计学意义(χ2=45.753,P<0.001)；食管鳞癌存在HPV16、18和52三种亚型感染,HPV16感染率最高,HPV52感染率最低,未发现多重HPV基因亚型感染。HPV感染率随食管鳞癌细胞分化程度的降低而增高(χ2=6.793,P=0.009),与患者的年龄、性别、肿瘤浸润的深度和淋巴结转移与否无相关性(P>0.05)。
HLA-G阳性表达产物主要位于细胞质。HLA-G在食管鳞癌及食管正常上皮的阳性表达率分别为51.8%(40/114)和0(0/50),差异有统计学意义(χ2=40.418,P<0.001)。HLA-G蛋白的阳性表达率随食管鳞癌细胞分化程度的降低而增高,差异有统计学意义(χ2=12.131,P<0.001)。HLA-G阳性表达率与食管癌患者的年龄、性别、肿瘤浸润深度和淋巴结转移无相关性(P>0.05)。
Lin28b的阳性表达产物主要位于细胞质。Lin28b在新乡地区114例食管鳞癌组织中的阳性表达率显著高于癌旁正常食管组织66.7%vs2%(40/114,1/50),差异有统计学意义(χ2=62.121,P<0.001)；Lin28b的阳性表达率随食管鳞癌细胞分化程度的降低而增高,差异有统计学意义(χ2=11.225,P=0.001)；Lin28b的阳性表达率随肿瘤浸润深度的进展而增高,差异有统计学意义(χ2=4.342,P=0.037)；Lin28b的阳性表达率随淋巴结转移而增高,差异有统计学意义(χ2=21.658,P<0.001)。Lin28b阳性表达率与患者的年龄、性别无相关性(P>0.05)。
在食管鳞状细胞癌组织中HPV阳性组中HLA-G阳性率显著高于HPV阴性组(χ2=11.525,P=0.001)。HPV与HLA-G存在一定正相关关系,但不密切(rs=0.318)。
在食管鳞状细胞癌组织中HPV阳性组中Lin28b阳性表达率显著高于HPV阴性组(χ2=13.741,P<0.001)。HPV与Lin28b存在一定正相关关系,但不密切(rs=0.347)。
第二章新乡和潮州地区食管鳞癌与人乳头状瘤病毒基因亚型感染的相关性研究
1.目的：
研究人乳头状瘤病毒(HPV)基因亚型在潮州地区食管鳞状细胞癌组织、癌旁正常食管组织中的感染情况；人乳头状瘤病毒基因亚型在新乡和潮州两地区食管鳞状细胞癌组织中的感染情况是否有差异。
2.方法：
采用基因导流芯片技术,应用潮州凯普生化公司HPV基因分型检测试剂盒(包括13种高危亚型HPV16、18、31、33、35、39、45、51、52、56、58、59和68,5种低危亚型HPV6、11、42、43和44以及3种中国人群常见亚型HPV53、66和CP8304)分别对新乡地区114例和潮州地区105例食管鳞癌组织、各50例癌旁正常食管组织(均已经福尔马林固定石蜡包埋处理)进行HPV亚型检测。
应用统计学软件SPSS13.0进行统计学分析。HPV感染与食管鳞癌组织、临床病理参数之间的关系采用χ2检验或Fisher's精确概率法。两个独立样本均数的比较采用t检验。显著性检验水准为a=0.05(双侧),以P<0.05为差异有统计学意义。
3.结果：
在新乡和潮州两地区219例食管鳞癌组织中,HPV感染的总阳性率为49.8%；新乡地区114例食管鳞癌组织及50例癌旁食管正常组织中HPV感染的阳性率分别为63.2%和6%(72/114,3/50),差异均有统计学意义(χ2=45.753,P<0.001)；潮州地区食管鳞癌组织中的HPV阳性感染率显著高于正常食管粘膜组织35.2%vs4%(37/105,2/50),差异有统计学意义(χ2=17.552,P<0.001)。新乡地区食管鳞癌组织HPV的阳性检出率高于潮州地区(63.2%vs35.2%),差别有统计学意义(χ2=17.043,P<0.001)。在新乡和潮州地区食管鳞癌组织中HPV16的阳性率分别为34.2%和23.8%,HPV18的阳性率分别为16.7%和11.4%,HPV52的阳性率分别为12.3%、0。未检出其它HPV基因亚型感染及多重基因亚型感染。
新乡地区HPV感染率随食管鳞癌细胞分化程度的降低而增高(χ2=6.793,P=0.009),HPV感染率与患者年龄、性别、肿瘤浸润深度和淋巴结转移无相关性(P>0.05)；潮州地区HPV感染率与患者年龄、性别、肿瘤分化、浸润深度和淋巴结转移无相关性(P>0.05)。
结论
1.新乡和潮州地区食管鳞癌组织中都存在人乳头状瘤病毒感染；新乡地区HPV感染为HPV16、18和52基因亚型,而潮州地区为18基因亚型；不同食管鳞癌高发区感染HPV基因亚型可能不同。
2.HLA-G阳性表达产物主要位于食管鳞癌细胞的细胞质；HLA-G蛋白的阳性表达率与食管鳞癌细胞的分化程度有关。
3.Lin28b阳性表达产物主要位于食管鳞癌细胞的细胞质；Lin28b的阳性表达率与食管癌患者肿瘤的分化程度、浸润深度和淋巴结转移有关。
4.食管鳞癌感染HPV与Lin28b、HLA-G存在一定正相关关系。
5.HPV、HLA-G与Lin28b可能在食管鳞癌的发生、发展中起重要作用,但其在食管鳞癌恶变过程中的作用机制仍需进一步研究。
6.联合检测到HPV、HLA-G与Lin28b的阳性表达可能对研究食管鳞癌发生的分子机制具有一定的参考价值。
Esophageal squamous cell carcinoma (ESCC) is one of the most common chest cancer, with about400,000new cases and300,000deaths all over the world. Most of esophageal cancers occur mainly in the developing countries. China is one region of the highest incidence and mortality of esophageal cancer in the world. Since1990s, the incidence and mortality rate of esophageal cancer declined. ESCC continued to hold the first cause of death in the northern part of Henan province. Xinxiang region in Henan Province is the place with the highest ESCC. In our country, esophageal squamous cell carcinoma is the common types. Research on ESCC is still the key areas of researches of our country. Because the mechanism of carcinoma is not clear, there is still a very long road to go. The development from normal epithelium to ESCC needs a long time. There are a few factors of fungal infection, poor diet, smoking, micronutrient deficiencies, environmental pollution and other factors to be related with ESCC. From normal epithelium to invasive carcinoma, it needs a variety of related genes or independent genes or molecular changes to involve in the mechanism. Although based on the current understanding of the mechanism of carcinoma, the application of targeted drug has made some progress. It is needed that much work and time be put into researchs of this tumor by a lot of researchers.
Nowadays, besides of the environmental, dietary, genetic and other factors, it has become a heated topic that Human papillomavirus is suspected of causing cancers, including cancer of colon cancer, cervix cancer. Human papillomavirus (HPV), a double-stranded DNA virus, has a diameter of about40-50nm. HPV infection can make its genome into normal cells DNA, and may activate oncogenes and inactivate anti-oncogene. When HPV integrates host cells, its can evade the host immune system and activate telomerase and make replication. As some progression has made on research, it is known that the oncoproteins E6and E7produced by high-risk HPV genotypes (especially HPV16,18) are necessary for malignant transformation of human cells. These oncoproteins of human papillomavirus can bind to P53, Rb and cell cycle regulatory proteins, then make human cells to produce abnormal proliferation state and malignant transformation. Human leukocyte antigen-G (HLA-G) is a non-classical MHC molecule expressed in human immune-privileged sites. HLA-G is an essential immune tolerance. It does not expressed in normal somatic cells. It can play an important role in the development of maternal tolerance to different fetal tissues. HLA-G can protect the embry from maternal immune system attack through the inhibition of NK cells and T lymphocyte cells. The expression of it was reported in colon cancer, breast and lung cancer, et al. HLA-G may play an important role in immune escape of carcinoma. Lin28is a kind of RNA-binding protein, which was firstly characterized by Ambros V in the nematode Caenorhabditis elegans as an essential regulator of developmental timing. The mammalian homologs of Lin28and Lin28b can bind to let-7and inhibit let-7to regulate micro RNAs at the post-transcriptional level. Then they may control cell proliferation, separatism, differentiation in embryonic stem cells.
At present, little is known on the correlation between high risk HPV infection with HLA-G and Lin28b expression in esophageal squamous cell carcinomas. The aim of the study was to investigate the possible roles of HLA-G and Lin28b in tumorigenesis among HPV genotypes positive ESCC.
This paper consist of2chapters, as follows: Chapterl:Correlation of high risk HPV infection, HLA-G and Lin28b expression in esophageal squamous cell carcinomas.
1. Objective:
To investigate the infection risk of human papillomavirus (HPV) genotypes in esophageal squamous cell carcinomas (ESCC) and paracancerous normal tissue. The aim of this study was to investigate the expression of HLA-G and Lin28b in esophageal squamous cell carcinomas and paracancerous normal tissue.
To investigate the relationship between different human papillomavirus (HPV) genotypes, HLA-G and Lin28b with age, gender, differentiation, infiltration depth and lymph node in esophageal squamous cell carcinomas. The aim of this study was to investigate the relationship between different human papillomavirus (HPV) genotypes and the expression of HLA-G and Lin28b in esophageal squamous cell carcinomas and paracancerous normal tissue.
2. Methods:
HPV typing was carried out by gene chip (high risk HPV genotype of16,18,31,33,35,39,45,51,52,56,58,59and68, low risk HPV genotype of6.11,42,43and44, and Chinese genotype of HPV53,66and CP8304) in114cases of formalin-fixed and paraffin-embedded esophageal squamous cell carcinomas specimens and50cases of paracancerous normal tissue from Xinxiang. A totle of114cases of esophageal carcinomas and50cases of paracancerous normal tissue were assayed for expression of HLA-G and Lin28b by immunohistochemistry.
SPSS13.0for windows software was used to analyse the data. Difference of the ratio between groups were calculated by χ2test or Fisher's exact test. Correlation between HPV infection with HLA-G and Lin28b expression was analyased by R×C χ2test and Spearman test. The significant difference was considered when the P value was less than0.05.
3. Results:
Overall, HPV prevalence were63.2%,6%among the esophageal carcinomas and paracancerous normal tissue in this study (x2=45.753, P<0.001). HPV-16,18and52were detected by34.2%.16.7%and12.3%in the tumors. HPV infection was positively correlated with tumor differentiation degree (χ2=6.793, P=0.009).
HLA-G was mainly expressed in the cytoplasm. The positive expression rate in normal epithelium and ESCC were63.2%,6%,(χ2=45.753, P=0.000); Lin28b was mainly expressed in the cytoplasm. Lin28b prevalence were63.2%、6%and66.7%,2%among the esophageal carcinomas and paracancerous normal tissue (χ2=62.121, P<0.001). HLA-G protein expression was correlated with tumor differentiation degree (χ2=12.131, P<0.001). Lin28b protein expression was correlated with tumor differentiation degree (χ2=11.225, P=0.001), tumor infiltration depth (χ2=4.342, P=0.037), lymph node metastasis (χ2=21.658, P<0.001).
HPV infection was correlated with HLA-G in esophageal squamous cell carcinomas (rs=0.318). HPV infection was correlated with Lin28b in esophageal squamous cell carcinomas (rs=0.347)
Chpter2:The research between human papillomavirus infection and esophageal carcinoma in Xinxiang and Chaozhou regions.
1. Objective:
To investigate the infection risk of human papillomavirus (HPV) genotypes between esophageal squamous cell carcinomas (ESCC) and paracancerous normal tissue in Xinxiang and Chaozhou regions.
To examine the difference of human papillomavirus (HPV) genotype in esophageal squamous cell carcinoma (ESCC) specimens collected from Xinxiang and Chaozhou regions, respectively.
2. Methods:
HPV and its genotype was detected using gene chip technology to examine114and105formalin-fixed and paraffin-embedded ESCC specimens from Xinxiang and Chaozhou regions, respectively. HPV and its genotype was detected using gene chip in50cases of paracancerous normal tissue from Xinxiang and Chaozhou regions, too.
SPSS13.0for windows software was used to analyse the data. Difference of the ratio between groups were calculated by χ2test or Fisher's exact test. Correlation was analyased by χ2test between HPV and HLA-G or Lin28b. The significant difference was considered when the P value was less than0.05.
3. Results:
HPV prevalence were63.2%、6%among the esophageal carcinomas and paracancerous normal tissue in Xinxiang region(χ2=45.753, P<0.001), HPV-16,18and52were detected34.2%,16.7%and12.3%in ESCC. HPV prevalence were35.2%and4%among the esophageal carcinomas and normal esophageal tissue in ChaoZhoug region (χ2=17.552, P<0.001, HPV16and18were detected by23.8%and11.4%in ESCC. HPV was detected in219ESCC specimens (49.8%). ESCC cases from Xinxiang had a higher prevalance of HPV than in Chaozhou (63.2%vs35.2%) with stastical significance (χ2=17.043, P<0.001).
HPV infection was positively correlated with differentiation degree of tumor in XinXiang region (χ2=6.793, P=0.009). HPV infection was not correlated with differentiation degree of tumor in Chaozhou region (P>0.05).
Conclusion
1. There is HPV infection in ESCC specimens collected from Xinxiang and Chaozhou regions. HPV16,18and52genotypes can be found in ESCC specimens collected from Xinxiang region; HPV16and18genotypes can be found in ESCC specimens collected from Chaozhou region.
2. HLA-G was mainly expressed in the cytoplasm. HLA-G protein expression was correlated with tumor differentiation degree.
3. Lin28b was mainly expressed in the cytoplasm. Lin28b protein expression was correlated with tumor differentiation degree, tumor infiltration depth, lymph node metastasis.
4. HPV was correlated with HLA-G and Lin28b in esophageal squamous cell carcinomas.
5. It supports the hypothesis that HPV, HLA-G and Lin28b may play important roles in the activation of carcinogenesis and malignant transformation of esophageal neoplasia. But their exact mechanism in cancerization of paracancerous normal tissue need to be furtherly studied.
6. Combinative detecting the infection of HPV genotype and expression of HLA-G and Lin28b may provide some information in the research of cancerization mechanism of paracancerous normal tissue.
食管癌是严重威胁人类健康的最常见的胸部恶性肿瘤之一。全世界每年新发食管癌病例大约为40万,死亡病例约为30万,大部分食管癌患者发生在发展中国家。我国是世界上食管癌发病率和死亡率最高的国家和地区之一。20世纪90年代以来,我国食管癌的发病率、死亡率有所下降,但在河南北部地区和广东潮汕地区,食管癌仍居当地各种恶性肿瘤死亡原因的第一位；河南新乡地区、广东潮州地区均属于我国食管癌高发地区。在我国鳞状细胞癌(squamous cell carcinoma)是食管癌最主要的病理组织学类型。对食管癌特别是食管鳞状上皮细胞癌的研究仍是我国胸外科工作者研究的重点领域。食管鳞状上皮细胞癌的发生发展是长时期多因素(霉菌感染、不良饮食习惯、吸烟、饮酒、微量元素缺乏和环境污染等)相互作用、多种相关基因或独立基因(如癌基因、抑癌基因、凋亡抑制因子等)分子改变参与,其先后或同时发生的积累和叠加作用并最终作用于细胞的生长周期,导致细胞周期调控机制的紊乱、细胞增殖失控、基因受损突变导致正常上皮经过各级癌前病变而最终发展为浸润性癌肿。虽然根据目前对肿瘤的发病机制的认识,应用研究出的靶向药物治疗恶性肿瘤取得了一些进展,但是目前肿瘤癌变多阶段演进过程中重要关键性的DNA基因突变及某些分子事件及其相互关系还不十分清楚,寻找、确定肿瘤演进过程中共同的起关键作用的基因、蛋白和环节并将其应用于肿瘤的预防、早期诊断和治疗,最终征服肿瘤,还需要进行大量艰苦的工作。
由于恶性肿瘤的发病机制目前仍未能彻底搞清,所以肿瘤预防和治疗的效果仍很不理想,仍需广大医学工作者继续不断探索、研究肿瘤的发生、发展和有效治疗。近来,除环境、饮食和遗传等因素外,高危基因亚型人乳头状瘤病毒(HPV)感染与肿瘤的关系越来越受到关注。人乳头状瘤病毒属乳多空病毒科A亚群的一种双链环状DNA病毒,为无包膜的20面体对称病毒,直径约45-55nm。现多根据不同基因亚型HPV与恶性肿瘤发生的危险性高低分为低危险型和高危险型HPV。正常细胞DNA由于受到HPV的基因组的整合可能会导致癌基因激活,如Ras等使细胞永生化,经长期传代后激活癌基因。E6和E7癌基因是HPV的主要癌基因。当HPV病毒整合进入宿主细胞的基因组中,既可以逃避宿主免疫系统的免疫监视和免疫杀伤,而且整合的E6、E7癌基因与相邻的基因组共同转录,可以使转录更加稳定；体外研究证实高危型HPV编码产生的E6、E7癌蛋白能有效导致人体细胞发生恶性转化,抑制机体的免疫系统。尤其是高危型HPV16、18基因亚型产生的癌蛋白可抑制p53和Rb等,使其丧失抑制细胞生长的效应,激活端粒酶致,使HPV感染的细胞不断分裂生长,处于异常增殖状态,从而使细胞避免凋亡而永生化,进而发生恶性转化。HPV感染机体细胞在体内持续存在,需要逃避机体免疫系统的攻击,才能发挥重要的致瘤致癌作用。人类白细胞抗原G(HLA-G)属于非经典的HLA-Ⅰb类分子,是一种重要的免疫耐受分子。HLA-G在正常体细胞中不表达,主要在人类正常妊娠母胎界面的绒毛外滋养细胞表达,通过抑制NK细胞和T淋巴细胞等,来保护胚胎免受母体免疫系统的攻击。目前的研究发现HLA-G在乳腺癌、结肠癌、宫颈癌等多种恶性肿瘤中呈高表达,表明HLA-G可能在肿瘤的免疫逃逸机制中发挥着重要的作用。Lin28是AmbrosV等在秀丽隐杆线虫中首先发现的,其具有调节线虫发育的时序性作用的RNA结合蛋白；Lin28通过抑制Let-7在转录后水平发挥调控作用,进而作用于细胞周期,控制细胞的增殖、分裂和分化；是调节胚胎发育的一个重要因子。Lin28在鼠和人胚胎干细胞中呈高表达,并且随着干细胞诱导不断分化其表达逐渐降低；在肿瘤组织中则反常高表达。Lin28b是Lin28的同源异构体,主要在干细胞和某些肿瘤细胞中表达。目前对于HPV感染在食管癌变过程中怎样发挥作用,HLA-G、Lin28b在食管癌发生中是否起作用尚不清楚。HPV与HLA-G、Lin28b在食管癌变过程中的相互关系等尚不可知；本研究拟探讨HLA-G、Lin28b和HPV在食管鳞癌组织中的表达和相互关系。
本文分两章,分别阐释如下：
第一章新乡地区食管鳞癌与HPV、HLA-G和Lin28b的相关性研究
1.目的：
研究人乳头状瘤病毒(HPV)在新乡地区食管鳞状细胞癌组织、癌旁正常食管组织中的感染情况；
研究HLA-G在新乡地区食管鳞状细胞癌组织、癌旁正常食管组织中阳性表达的情况；
研究RNA结合蛋白Lin28b在新乡地区食管鳞状细胞癌、癌旁正常食管组织中阳性表达的情况；
研究新乡地区食管鳞状细胞癌病人的年龄、性别、肿瘤分化程度、肿瘤浸润深度、淋巴结转移与鳞癌组织中感染HPV、HLA-G阳性表达和Lin28b阳性表达之间的关系；
研究新乡地区食管鳞状细胞癌组织感染HPV与HLA-G表达、Lin28b表达之间的关系。
2.方法：
采用基因导流芯片技术,应用潮州凯普生化公司HPV基因分型检测试剂盒(包括13种高危亚型HPV16、18、31、33、35、39、45、51、52、56、58、59和68,5种低危亚型HPV6、11、42、43和44和3种中国人群常见亚型HPV53、66和CP8304),检测114例食管鳞状细胞癌组织及50例癌旁正常食管组织中HPV基因亚型感染的情况,
采用免疫组织化学非生物素二步法检测,用鼠抗人HLA-G单克隆抗体(1：150)和兔抗人Lin28b单克隆抗体(1：100)对114例食管鳞状细胞癌手术切除石蜡标本、50例癌旁正常食管上皮的石蜡标本组织切片进行染色、观察,评定HLA-G和Lin28b阳性表达的情况。
应用统计学软件SPSS13.0进行统计分析。HPV感染、HLA-G、Lin28b在食管鳞癌和正常食管组织中表达的比较、与食管鳞癌组织临床病理参数之间的关系采用χ2检验或Fisher's精确概率法。HPV感染与HLA-G、Lin28b两指标间的关系采用四格表χ2检验、Spearman秩相关。HPV亚型感染与HLA-G、Lin28b两指标间的关系采用列联表χ2检验法。显著性检验水准为α=0.05(双侧),以P<0.05为差别有统计学意义。
3.结果
新乡地区114例食管鳞癌组织及50例癌旁正常食管组织中人乳头状瘤病毒感染阳性率分别为63.2%和6%(72/114,,3/50),差异均有统计学意义(χ2=45.753,P<0.001)；食管鳞癌存在HPV16、18和52三种亚型感染,HPV16感染率最高,HPV52感染率最低,未发现多重HPV基因亚型感染。HPV感染率随食管鳞癌细胞分化程度的降低而增高(χ2=6.793,P=0.009),与患者的年龄、性别、肿瘤浸润的深度和淋巴结转移与否无相关性(P>0.05)。
HLA-G阳性表达产物主要位于细胞质。HLA-G在食管鳞癌及食管正常上皮的阳性表达率分别为51.8%(40/114)和0(0/50),差异有统计学意义(χ2=40.418,P<0.001)。HLA-G蛋白的阳性表达率随食管鳞癌细胞分化程度的降低而增高,差异有统计学意义(χ2=12.131,P<0.001)。HLA-G阳性表达率与食管癌患者的年龄、性别、肿瘤浸润深度和淋巴结转移无相关性(P>0.05)。
Lin28b的阳性表达产物主要位于细胞质。Lin28b在新乡地区114例食管鳞癌组织中的阳性表达率显著高于癌旁正常食管组织66.7%vs2%(40/114,1/50),差异有统计学意义(χ2=62.121,P<0.001)；Lin28b的阳性表达率随食管鳞癌细胞分化程度的降低而增高,差异有统计学意义(χ2=11.225,P=0.001)；Lin28b的阳性表达率随肿瘤浸润深度的进展而增高,差异有统计学意义(χ2=4.342,P=0.037)；Lin28b的阳性表达率随淋巴结转移而增高,差异有统计学意义(χ2=21.658,P<0.001)。Lin28b阳性表达率与患者的年龄、性别无相关性(P>0.05)。
在食管鳞状细胞癌组织中HPV阳性组中HLA-G阳性率显著高于HPV阴性组(χ2=11.525,P=0.001)。HPV与HLA-G存在一定正相关关系,但不密切(rs=0.318)。
在食管鳞状细胞癌组织中HPV阳性组中Lin28b阳性表达率显著高于HPV阴性组(χ2=13.741,P<0.001)。HPV与Lin28b存在一定正相关关系,但不密切(rs=0.347)。
第二章新乡和潮州地区食管鳞癌与人乳头状瘤病毒基因亚型感染的相关性研究
1.目的：
研究人乳头状瘤病毒(HPV)基因亚型在潮州地区食管鳞状细胞癌组织、癌旁正常食管组织中的感染情况；人乳头状瘤病毒基因亚型在新乡和潮州两地区食管鳞状细胞癌组织中的感染情况是否有差异。
2.方法：
采用基因导流芯片技术,应用潮州凯普生化公司HPV基因分型检测试剂盒(包括13种高危亚型HPV16、18、31、33、35、39、45、51、52、56、58、59和68,5种低危亚型HPV6、11、42、43和44以及3种中国人群常见亚型HPV53、66和CP8304)分别对新乡地区114例和潮州地区105例食管鳞癌组织、各50例癌旁正常食管组织(均已经福尔马林固定石蜡包埋处理)进行HPV亚型检测。
应用统计学软件SPSS13.0进行统计学分析。HPV感染与食管鳞癌组织、临床病理参数之间的关系采用χ2检验或Fisher's精确概率法。两个独立样本均数的比较采用t检验。显著性检验水准为a=0.05(双侧),以P<0.05为差异有统计学意义。
3.结果：
在新乡和潮州两地区219例食管鳞癌组织中,HPV感染的总阳性率为49.8%；新乡地区114例食管鳞癌组织及50例癌旁食管正常组织中HPV感染的阳性率分别为63.2%和6%(72/114,3/50),差异均有统计学意义(χ2=45.753,P<0.001)；潮州地区食管鳞癌组织中的HPV阳性感染率显著高于正常食管粘膜组织35.2%vs4%(37/105,2/50),差异有统计学意义(χ2=17.552,P<0.001)。新乡地区食管鳞癌组织HPV的阳性检出率高于潮州地区(63.2%vs35.2%),差别有统计学意义(χ2=17.043,P<0.001)。在新乡和潮州地区食管鳞癌组织中HPV16的阳性率分别为34.2%和23.8%,HPV18的阳性率分别为16.7%和11.4%,HPV52的阳性率分别为12.3%、0。未检出其它HPV基因亚型感染及多重基因亚型感染。
新乡地区HPV感染率随食管鳞癌细胞分化程度的降低而增高(χ2=6.793,P=0.009),HPV感染率与患者年龄、性别、肿瘤浸润深度和淋巴结转移无相关性(P>0.05)；潮州地区HPV感染率与患者年龄、性别、肿瘤分化、浸润深度和淋巴结转移无相关性(P>0.05)。
结论
1.新乡和潮州地区食管鳞癌组织中都存在人乳头状瘤病毒感染；新乡地区HPV感染为HPV16、18和52基因亚型,而潮州地区为18基因亚型；不同食管鳞癌高发区感染HPV基因亚型可能不同。
2.HLA-G阳性表达产物主要位于食管鳞癌细胞的细胞质；HLA-G蛋白的阳性表达率与食管鳞癌细胞的分化程度有关。
3.Lin28b阳性表达产物主要位于食管鳞癌细胞的细胞质；Lin28b的阳性表达率与食管癌患者肿瘤的分化程度、浸润深度和淋巴结转移有关。
4.食管鳞癌感染HPV与Lin28b、HLA-G存在一定正相关关系。
5.HPV、HLA-G与Lin28b可能在食管鳞癌的发生、发展中起重要作用,但其在食管鳞癌恶变过程中的作用机制仍需进一步研究。
6.联合检测到HPV、HLA-G与Lin28b的阳性表达可能对研究食管鳞癌发生的分子机制具有一定的参考价值。
Esophageal squamous cell carcinoma (ESCC) is one of the most common chest cancer, with about400,000new cases and300,000deaths all over the world. Most of esophageal cancers occur mainly in the developing countries. China is one region of the highest incidence and mortality of esophageal cancer in the world. Since1990s, the incidence and mortality rate of esophageal cancer declined. ESCC continued to hold the first cause of death in the northern part of Henan province. Xinxiang region in Henan Province is the place with the highest ESCC. In our country, esophageal squamous cell carcinoma is the common types. Research on ESCC is still the key areas of researches of our country. Because the mechanism of carcinoma is not clear, there is still a very long road to go. The development from normal epithelium to ESCC needs a long time. There are a few factors of fungal infection, poor diet, smoking, micronutrient deficiencies, environmental pollution and other factors to be related with ESCC. From normal epithelium to invasive carcinoma, it needs a variety of related genes or independent genes or molecular changes to involve in the mechanism. Although based on the current understanding of the mechanism of carcinoma, the application of targeted drug has made some progress. It is needed that much work and time be put into researchs of this tumor by a lot of researchers.
Nowadays, besides of the environmental, dietary, genetic and other factors, it has become a heated topic that Human papillomavirus is suspected of causing cancers, including cancer of colon cancer, cervix cancer. Human papillomavirus (HPV), a double-stranded DNA virus, has a diameter of about40-50nm. HPV infection can make its genome into normal cells DNA, and may activate oncogenes and inactivate anti-oncogene. When HPV integrates host cells, its can evade the host immune system and activate telomerase and make replication. As some progression has made on research, it is known that the oncoproteins E6and E7produced by high-risk HPV genotypes (especially HPV16,18) are necessary for malignant transformation of human cells. These oncoproteins of human papillomavirus can bind to P53, Rb and cell cycle regulatory proteins, then make human cells to produce abnormal proliferation state and malignant transformation. Human leukocyte antigen-G (HLA-G) is a non-classical MHC molecule expressed in human immune-privileged sites. HLA-G is an essential immune tolerance. It does not expressed in normal somatic cells. It can play an important role in the development of maternal tolerance to different fetal tissues. HLA-G can protect the embry from maternal immune system attack through the inhibition of NK cells and T lymphocyte cells. The expression of it was reported in colon cancer, breast and lung cancer, et al. HLA-G may play an important role in immune escape of carcinoma. Lin28is a kind of RNA-binding protein, which was firstly characterized by Ambros V in the nematode Caenorhabditis elegans as an essential regulator of developmental timing. The mammalian homologs of Lin28and Lin28b can bind to let-7and inhibit let-7to regulate micro RNAs at the post-transcriptional level. Then they may control cell proliferation, separatism, differentiation in embryonic stem cells.
At present, little is known on the correlation between high risk HPV infection with HLA-G and Lin28b expression in esophageal squamous cell carcinomas. The aim of the study was to investigate the possible roles of HLA-G and Lin28b in tumorigenesis among HPV genotypes positive ESCC.
This paper consist of2chapters, as follows: Chapterl:Correlation of high risk HPV infection, HLA-G and Lin28b expression in esophageal squamous cell carcinomas.
1. Objective:
To investigate the infection risk of human papillomavirus (HPV) genotypes in esophageal squamous cell carcinomas (ESCC) and paracancerous normal tissue. The aim of this study was to investigate the expression of HLA-G and Lin28b in esophageal squamous cell carcinomas and paracancerous normal tissue.
To investigate the relationship between different human papillomavirus (HPV) genotypes, HLA-G and Lin28b with age, gender, differentiation, infiltration depth and lymph node in esophageal squamous cell carcinomas. The aim of this study was to investigate the relationship between different human papillomavirus (HPV) genotypes and the expression of HLA-G and Lin28b in esophageal squamous cell carcinomas and paracancerous normal tissue.
2. Methods:
HPV typing was carried out by gene chip (high risk HPV genotype of16,18,31,33,35,39,45,51,52,56,58,59and68, low risk HPV genotype of6.11,42,43and44, and Chinese genotype of HPV53,66and CP8304) in114cases of formalin-fixed and paraffin-embedded esophageal squamous cell carcinomas specimens and50cases of paracancerous normal tissue from Xinxiang. A totle of114cases of esophageal carcinomas and50cases of paracancerous normal tissue were assayed for expression of HLA-G and Lin28b by immunohistochemistry.
SPSS13.0for windows software was used to analyse the data. Difference of the ratio between groups were calculated by χ2test or Fisher's exact test. Correlation between HPV infection with HLA-G and Lin28b expression was analyased by R×C χ2test and Spearman test. The significant difference was considered when the P value was less than0.05.
3. Results:
Overall, HPV prevalence were63.2%,6%among the esophageal carcinomas and paracancerous normal tissue in this study (x2=45.753, P<0.001). HPV-16,18and52were detected by34.2%.16.7%and12.3%in the tumors. HPV infection was positively correlated with tumor differentiation degree (χ2=6.793, P=0.009).
HLA-G was mainly expressed in the cytoplasm. The positive expression rate in normal epithelium and ESCC were63.2%,6%,(χ2=45.753, P=0.000); Lin28b was mainly expressed in the cytoplasm. Lin28b prevalence were63.2%、6%and66.7%,2%among the esophageal carcinomas and paracancerous normal tissue (χ2=62.121, P<0.001). HLA-G protein expression was correlated with tumor differentiation degree (χ2=12.131, P<0.001). Lin28b protein expression was correlated with tumor differentiation degree (χ2=11.225, P=0.001), tumor infiltration depth (χ2=4.342, P=0.037), lymph node metastasis (χ2=21.658, P<0.001).
HPV infection was correlated with HLA-G in esophageal squamous cell carcinomas (rs=0.318). HPV infection was correlated with Lin28b in esophageal squamous cell carcinomas (rs=0.347)
Chpter2:The research between human papillomavirus infection and esophageal carcinoma in Xinxiang and Chaozhou regions.
1. Objective:
To investigate the infection risk of human papillomavirus (HPV) genotypes between esophageal squamous cell carcinomas (ESCC) and paracancerous normal tissue in Xinxiang and Chaozhou regions.
To examine the difference of human papillomavirus (HPV) genotype in esophageal squamous cell carcinoma (ESCC) specimens collected from Xinxiang and Chaozhou regions, respectively.
2. Methods:
HPV and its genotype was detected using gene chip technology to examine114and105formalin-fixed and paraffin-embedded ESCC specimens from Xinxiang and Chaozhou regions, respectively. HPV and its genotype was detected using gene chip in50cases of paracancerous normal tissue from Xinxiang and Chaozhou regions, too.
SPSS13.0for windows software was used to analyse the data. Difference of the ratio between groups were calculated by χ2test or Fisher's exact test. Correlation was analyased by χ2test between HPV and HLA-G or Lin28b. The significant difference was considered when the P value was less than0.05.
3. Results:
HPV prevalence were63.2%、6%among the esophageal carcinomas and paracancerous normal tissue in Xinxiang region(χ2=45.753, P<0.001), HPV-16,18and52were detected34.2%,16.7%and12.3%in ESCC. HPV prevalence were35.2%and4%among the esophageal carcinomas and normal esophageal tissue in ChaoZhoug region (χ2=17.552, P<0.001, HPV16and18were detected by23.8%and11.4%in ESCC. HPV was detected in219ESCC specimens (49.8%). ESCC cases from Xinxiang had a higher prevalance of HPV than in Chaozhou (63.2%vs35.2%) with stastical significance (χ2=17.043, P<0.001).
HPV infection was positively correlated with differentiation degree of tumor in XinXiang region (χ2=6.793, P=0.009). HPV infection was not correlated with differentiation degree of tumor in Chaozhou region (P>0.05).
Conclusion
1. There is HPV infection in ESCC specimens collected from Xinxiang and Chaozhou regions. HPV16,18and52genotypes can be found in ESCC specimens collected from Xinxiang region; HPV16and18genotypes can be found in ESCC specimens collected from Chaozhou region.
2. HLA-G was mainly expressed in the cytoplasm. HLA-G protein expression was correlated with tumor differentiation degree.
3. Lin28b was mainly expressed in the cytoplasm. Lin28b protein expression was correlated with tumor differentiation degree, tumor infiltration depth, lymph node metastasis.
4. HPV was correlated with HLA-G and Lin28b in esophageal squamous cell carcinomas.
5. It supports the hypothesis that HPV, HLA-G and Lin28b may play important roles in the activation of carcinogenesis and malignant transformation of esophageal neoplasia. But their exact mechanism in cancerization of paracancerous normal tissue need to be furtherly studied.
6. Combinative detecting the infection of HPV genotype and expression of HLA-G and Lin28b may provide some information in the research of cancerization mechanism of paracancerous normal tissue.
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