宫颈癌免疫学发病机制研究进展

宫颈癌发病率居妇科恶性肿瘤首位,人乳头瘤病毒(HPV)感染是宫颈癌发生的先决条件,其中高危型HPV持续性感染极大提高了宫颈癌发病风险.HPV感染后,其DNA整合至宿主细胞DNA中,整合过程会导致许多病毒编码的早期和晚期基因缺失,进一步导致宿主细胞周期失控,从而导致宫颈病变发生.同时,HPV通过多种途径使宫颈免疫微环境发...     

HPV16/18基因DNA存在状态与宫颈病变发展的研究

目的:研究人乳头瘤病毒(HPV)16/18两种亚型的DNA在宿主细胞中的存在状态,探讨其与宫颈病变发生发展之间的关系。方法:2016年1月至2018年2月于北京妇产医院行宫颈脱落细胞检查结果为意义不明的不典型鳞状细胞(ASC-US)及以上病变并经快速导流杂交法明确为HPV16/18型感染的宫颈组织共156例。实时定量PCR扩增检测HPV16/18早期基因E2、E6/E7的拷贝数,分析病毒的整合状态。结果:随着宫颈病变级别的增高,HPV16 E2基因的不完整率逐渐增加,但各组比较无统计学差异(OR=0.625,95%CI=0.151~2.586,P>0.05,r=0.113)。HPV18阳性炎症组织中HPV常以游离形式存在(66.7%),全部宫颈癌组织中HPV18均以完全整合状态存在。随着HPV16/18感染的宫颈脱落细胞判读级别的升高,HPV DNA整合率升高(P<0.05)。结论:E2基因的断裂在HPV16/18感染后的早期事件中很常见。HPV16基因整合可能是其持续感染的主要原因,也是其感染导致宫颈癌的一个重要危险因素。HPV18相关病变常很快的经癌前病变的阶段而直接发展为宫颈癌,推断HPV-18感染更具侵袭性。     

HPV整合宫颈上皮细胞机制的研究进展

宫颈癌是常见的妇科恶性肿瘤,持续性高危型HPV感染是宫颈癌发生的必要条件。HPV与宿主细胞染色体的整合是宫颈细胞永生化过程中的重要步骤,是导致宫颈上皮内瘤变向宫颈癌恶性进展的一个重要标志。HPV黏附、穿入宫颈上皮细胞直至癌变是一个漫长而复杂的过程,其如何进入宿主细胞发挥有效感染,具体机制仍不清楚。本文就HPV识别、粘附宫颈上皮细胞、依赖可能转运途径穿膜入胞及进一步整合至宿主细胞染色体的相关机制研究进展作一综述。     

宫颈癌发生过程中的表观遗传异常

表观遗传指DNA序列不发生变化,而基因表达却发生可遗传的改变。在宫颈癌发生过程中,表观遗传改变不仅影响着人乳头瘤病毒（HPV）致癌基因的异常表达,而且可导致宿主细胞多个癌基因激活和抑癌基因的失活。近年发现,表观遗传和微小RNA（miRNA）相互调控异常也与宫颈癌发生密切相关。表观遗传异常可导致具有抑癌作用的miRNA沉默表达,miRNA也可通过DNA甲基化和组蛋白修饰促进病毒的DNA修复、抑癌基因表达沉默。     

HPV相关宫颈癌DNA甲基化的研究进展

宫颈癌是最常见的妇科肿瘤之一，高危型人乳头瘤病毒(hrHPV)持续感染是宫颈恶性肿瘤的重要因素。表观遗传学是指非基因序列改变导致患者基因表达水平改变的一种可遗传现象，其改变形式包括DNA甲基化、染色体失活、基因组印迹、非编码RNA调控等。研究表明，表观遗传修饰影响细胞的生长、分化、凋亡、转化等与肿瘤发生发展相关的生物进程。其中，DNA甲基化是目前研究最清楚、最重要的表观遗传修饰形式。本文重点关注HPV相关宫颈癌中DNA甲基化的改变，对其致癌机制、临床应用的研究进展作一综述，以更好地了解HPV相关宫颈癌的发生发展过程，有助于预防与治疗宫颈癌。     

宫颈癌发生过程中的表观遗传异常

表观遗传指DNA序列不发生变化,而基因表达却发生可遗传的改变.在宫颈癌发生过程中,表观遗传改变不仅影响着人乳头瘤病毒(HPV)致癌基因的异常表达,而且可导致宿主细胞多个癌基因激活和抑癌基因的失活.近年发现,表观遗传和微小RNA(miRNA)相互调控异常也与宫颈癌发生密切相关.表观遗传异常可导致具有抑癌作用的miRNA沉...     

宫颈病变中HPV DNA的物理状态和病毒载量的研究进展

宫颈癌是全球危及女性生命的第二高发肿瘤。多因素协同作用促使疾病发生发展,其中人乳头瘤病毒(HPV)感染是导致宫颈癌及癌前病变的必要条件。现就HPV病毒DNA整合状态、整合位点、病毒载量等因素与宫颈癌发生关系的近期研究进展作一综述。     

HPV检测在宫颈癌预警和筛查中的研究

人乳头瘤病毒(HPV)感染与宫颈癌发生密切相关,该病毒感染的检测对宫颈癌的筛查和预警有重要意义.综述近年宫颈癌筛查中HPV DNA的检测方法和HPV感染的病毒学、血清学追踪调查、宫颈癌前、癌变相关分子标志的研究进展,以及HPV检测在宫颈癌筛查中的地位、临床应用前景.     

宫颈HPV感染与端粒改变及端粒酶激活的研究进展

近年 ,宫颈HPV感染呈上升趋势 ,研究表明 ,高危HPV感染与宫颈癌的发生密切相关。高危HPV转化基因E6和E7整合于宫颈细胞DNA中 ,可通过激活端粒酶 ,影响端粒而改变宿主细胞的生长模式。现就宫颈HPV感染与端粒改变及端粒酶激活研究的最新进展作一综述 ,旨在加深对HPV致癌机制的了解     

自噬在HPV持续感染中的研究进展

自噬是双膜囊泡包裹胞内受损蛋白质及异常细胞器等组分并运输至溶酶体降解的生物过程,将降解内容物再利用以维持细胞内稳态。人乳头瘤病毒(HPV)持续感染是宫颈癌发生和发展的主要因素。研究发现,HPV内吞过程可抑制细胞自噬,促进病毒感染,同时还可能通过调节自噬反应影响先天免疫应答和DNA损伤修复等途径维持病毒持续状态。现就自噬与HPV感染及病毒持续状态之间的研究进展作一综述,为探讨HPV持续状态的发生机制及建立新的治疗方案提供思路。     

Humane Papillomaviren

Human papillomaviruses (HPV) are the most important cause of cervical cancer and other carcinomas. The course and outcome of HPV infections depend on the HPV subtype, the anatomy of the infection site and the differentiation status of the host cells. Approximately 30 HPV types, which are divided into low-risk and high-risk types, are specialized for infecting the skin and mucous membranes in the anogenital region. A genital HPV infection often occurs even at the first sexual contact. The HPV prevalence varies in different population groups, depending on age, social class and cultural background. Generally, the immune system can overcome an HPV infection within 2 years; however, recovery from an infection with an HPV type does not result in lifelong immunity. Persistent or parallel infections with different HPV types increase the risk of developing cervical cancer. Malignant transformation of an infected epithelial cell requires the overexpression of the viral oncogenes E6 and E7. For complete malignant transformation of the host cell, the HPV DNA must be integrated into the host genome. During this process gene sections of the viral DNA are destroyed, frequently involving the E2, E1 or L1 genes. Current vaccines can only immunize against some of the 18 high-risk HPV and only provide limited protection against cervical carcinoma; therefore, even vaccinated women should attend regular screening checks by a gynecologist. State of the art PCR-based tests for detection of HPV are established in the clinical routine and allow infections to be detected objectively, sensitively and at an early stage but the quality of the results significantly varies between tests.     

阴道微环境与人乳头瘤病毒感染相关性的研究进展

人乳头瘤病毒(HPV)感染是唯一可以明确的导致宫颈癌的致病因子,但HPV感染并不等于已是宫颈癌或者宫颈癌前病变,而提示有一种向宫颈病变发展的可能性。因此,有效的筛查和预防是降低HPV感染及宫颈病变发生的有效措施。宫颈阴道部处于阴道微环境中,正常阴道微环境是由阴道解剖结构、微生物菌群、局部免疫及机体的内分泌调节功能组成,他们之间相互影响,始终处于动态平衡的状态。而当阴道菌群、pH值、局部免疫、雌孕激素水平发生变化,可导致机体对HPV易感性增加,清除力降低。鉴于阴道微环境与HPV感染关系十分密切,本文就HPV感染与阴道微环境相关性进行综述。     

HPV detection and genotyping as an earlier approach in cervical cancer screening of the female genital tract

Human papillomavirus (HPV) infection is the leading risk factor for cervical intraepithelial neoplasia (CIN) and cervical cancer. More than 100 virus genotypes have been identified so far, some of them strongly associated with the development of neoplasia. The aim of this study was to evaluate the prevalence of the different HPV genotypes in women presenting no cytological alterations in cervical cells, in women presenting light alterations, and in women presenting severe alterations at routine gynecological examination. We retrospectively analyzed 97 HPV results of women submitted to cervical cancer screening compared to their Papanicolaou and colposcopy examinations. Data were analyzed individually and within groups to correlate the HPV genotypes identified by polymerase chain reaction (PCR) and the respective alterations in cervical cells. Among the nine cases diagnosed as CIN I (9.3%), two were positive for low-risk HPV genotypes (22%), and the other seven were negative for HPV by PCR (78%). CIN II or CIN III diagnoses were associated with positive HPV results by PCR in four cases (36%), for high-risk as well as low-risk genotypes. There were two patients with severe cytological alterations in cervical cells, but with an indeterminate HPV genotype (18%), and one case with a negative HPV result (9%). Among the 57 cases without cytological alterations, seven were positive for low-risk HPV (12%) and two for high-risk HPV genotypes (3.5%). In the 48 remaining cases, we observed one with an indeterminate HPV genotype (2%), and the other 47 were negative for HPV by PCR (47%). Our study demonstrates an important prevalence of high- and low-risk HPV genotypes in our population, including those not present in the commercially available vaccine, even in patients with no evidence of cytological alterations in cervical cells. These results highlight the usefulness of HPV detection and typing as an early approach for cervical cancer screening and prevention.     

TLRs在宫颈HPV16持续性感染及宫颈病变中的作用研究

目的:探讨Toll样受体(TLRs)在宫颈人乳头瘤病毒(HPV)16持续性感染及宫颈病变中的作用。方法:以PCR法检测宫颈脱落细胞中TLR3、TLR7、TLR8、TLR9及干扰素β(IFN-β)基因在宫颈HPV16持续性感染及宫颈病变中的表达,并分为HPV16持续感染组与HPV16非持续感染组及宫颈炎症及CINⅠ组、高级别CIN和原位癌组、宫颈浸润癌组进行比较分析。结果:1在HPV16持续感染组与HPV16非持续感染组中,TLR3 DNA表达量分别为0.622±0.160、0.696±0.155,干扰素β(IFN-β)DNA表达量分别为0.640±0.169、0.735±0.151,TLR3、IFN-βDNA在HPV16持续感染组表达量低于HPV16非持续感染组(t=6.574,P=0.011;t=4.378,P=0.038);TLR3 DNA与IFN-βDNA呈正相关(r=0.693,P0.001),TLR 9DNA与IFN-βDNA呈负相关(r=-0.384,P0.001)。2在宫颈炎症及CINⅠ组、高级别CIN和原位癌组、宫颈浸润癌组中,TLR3DNA表达量分别为0.661±0.159、0.606±0.143、0.507±0.160,IFN-β表达量分别为0.722±0.169、0.659±0.144、0.483±0.143,TLR7DNA表达量为0.737±0.198、0.754±0.206、0.864±0.167,TLR9DNA表达量为0.531±0.172、0.606±0.192、0.701±0.200。TLR3、IFN-βDNA表达量随宫颈病变进展而逐渐下降(F=7.983,P0.001;F=12.163,P0.001),而TLR7、TLR9 DNA表达量则随宫颈病变进展而逐渐增高(F=3.647,P=0.028;F=9.415,P0.001)。结论:TLRs可能参与宫颈局部免疫系统对HPV16的清除过程,TLR3表达减低可能通过下调IFN-β表达而影响宫颈局部免疫功能,从而导致HPV16持续性感染。TLR3、TLR7、TLR9异常表达在宫颈病变发生及进展中可能发挥重要作用。     

阴道微生物与人乳头瘤病毒感染及宫颈上皮内肿瘤相关性研究进展

人乳头瘤病毒（HPV）感染是宫颈癌前病变或宫颈癌发生的必要条件,阴道微生物多样性的改变可能是造成HPV持续感染继而发生宫颈病变的伴随因素。正常女性阴道微生物多样性较低,仅由少数几种乳酸杆菌（Lactobacillus）构成主要菌群。随着对细菌16SrRNA基因高通量测序技术的应用,越来越多的研究证实阴道菌群中非乳酸杆菌属微生物的多样性增加与HPV感染及宫颈病变存在密切联系。标志性的阴道微生物可能通过多种分子机制与宿主细胞及HPV相互作用,导致阴道局部免疫抑制、慢性炎症的状态,从而造成HPV持续感染及宫颈病变。重建阴道微生态平衡状态尤其是乳酸杆菌为主的阴道菌群是未来HPV感染及相关宫颈病变治疗的新途径。本文就阴道微生物多样性改变与HPV感染及宫颈病变发生的研究观点进行总结归纳。     

Epidemiology and natural history of genital infection by human papillomavirus

Human papillomavirus genital infection is a very common sexual transmitted disease, probably the most common of them. On one hand, this infection is more often than not transient and asymptomatic and induces an effective immunity which allows the infection cure; on the other hand it can be responsible for an intraepithelial lesion which can progress to an invasive cancer. In spite of the decrease of cervical cancer incidence thanks to Pap smear screening, it remains a real preoccupation for clinicians. If HPV is not sufficient for cervical carcinogenesis, it represents however a necessary factor. Near 100% of cervical cancers are indeed positive in HPV DNA. HPV infection is very frequent in young people aged less than 25 years and viral clearance average is 8 months. This clearance is the consequence of host immunity intervention which leads to spontaneous regression of infection and of the overwhelming majority of low grade squamous intraepithelial lesions (more than 80% within a period of two years). The major factor which permits the progression to high grade squamous intraepithelial lesions is the persistent feature of HPV infection. Cervical cancer is clearly the first viral-induced solid tumor discovered in human species. Furthermore it represents a woman death cause that can be avoided.     

妊娠合并宫颈疾病诊治进展

妊娠期宫颈可发生炎性疾病,人乳头瘤病毒(HPV)感染,宫颈上皮内瘤样病变(CIN)甚至宫颈浸润癌。近年来,对妊娠期宫颈疾病的关注度逐渐上升。妊娠合并宫颈疾病可通过细胞学检查、HPV-DNA检测、P16/Ki67双联染色、阴道镜、活检和宫颈锥切等进行诊断。治疗方面妊娠合并HPV感染没有特别治疗;CIN患者排除宫颈浸润癌后可行细胞学及阴道镜随访至分娩;妊娠合并宫颈癌的处理较为复杂,需要考虑到肿瘤治疗与胎儿安全之间的平衡,治疗需综合考虑肿瘤大小、淋巴结转移情况及患者继续妊娠的意愿。分娩时机及分娩方式方面,合并宫颈感染性疾病及CIN的妊娠患者均按照产科处理;Ⅰa1期、间质浸润深度3 mm并且切缘阴性宫颈癌患者可妊娠至足月阴道试产,对于更高期别患者建议胎儿成熟后剖宫产终止妊娠。     

高危型人乳头瘤病毒阳性患者宫颈病变风险预测方法及进展

宫颈癌的主要致病机制与高危型人乳头瘤病毒（HR-HPV）的持续性感染密切相关。HR-HPV检测已成为宫颈病变筛查的一个主要手段，其敏感度高、特异度差。因此，对持续性HR-HPV阳性患者的病变风险评估及分流判读尤为重要。随着对宫颈病变机制研究的深入，许多新兴分流手段逐步应用于临床：HR-HPV载量检测可以除外一些一过性感染患者；P16/Ki67细胞学双染使细胞学检查更为客观；HPV DNA甲基化、宿主DNA甲基化和微小RNA（miRNA）宫颈癌筛查不仅敏感度、特异度相对较高，同时使患者自采样成为可能；免疫微环境可以反映宫颈病变程度及免疫状态。这些新型检查手段在提供HR-HPV患者阴道镜分流的同时，对于宫颈病变风险预测均有很好的临床应用价值。现综述HPV阳性后除细胞学检测外新的检测分流手段，为临床HPV阳性后的进一步检查及风险预测提供参考。     

Human papillomavirus

Human papillomaviruses are ancient small DNA viruses and represent the most common sexually transmitted infection in the world. In the majority, HPV infection is cleared by an incompletely understood immune response. HPV is a necessary but not sufficient cause of cervical cancer, and responsible for a proportion of other anogenital cancers including vulval, vaginal, anal and oropharyngeal. Oncogenesis is likely mediated through viral proteins which hijack host-cell machinery in epithelial keratinocytes and disrupt host tumour-suppressor proteins. Much work has been undertaken to further characterise the natural history of HPV infection and cervical disease. Such efforts have been translated to important public health interventions like the introduction of HPV tests in cervical screening. HPV vaccination programmes are expected to further reduce the incidence of high-risk HPV infections and resultantly HPV-related disease.