外泌体及外泌体miRNA在宫颈癌中的研究进展

宫颈癌作为女性常见恶性肿瘤,近年来其发病情况呈年轻化趋势,且依然是世界范围内危害女性健康的重大问题。外泌体为多囊泡体和细胞膜融合后释放到细胞外的囊泡样小体,可来源于多种细胞,通过运载多种蛋白、脂质、DNA、mRNA和miRNA等生物学功能物质介导细胞-细胞间信息交流。本文主要对外泌体及外泌体miRNA在宫颈癌细胞增殖、转移、诊断和治疗等方面研究进展作一综述,为宫颈癌诊断和治疗提供新思路。     

HPV、HSV和CMV感染与宫颈癌的关系

背景与目的： 探讨宫颈癌前病变和宫颈癌的发生发展与人乳头状瘤病毒及单纯疱疹病毒(Herpes Simplex Virus,HSV)、巨细胞病毒(Cytomegalovirus,CMV)的关系。 材料与方法： 对81例不同宫颈病变组织进行HPV16/18和HPV6/11原位杂交,同时对103例不同宫颈病变组织用DNA扩增法检测HPV、HSV和CMV。 结果: 病毒DNA原位杂交信号的分布与HE染色中挖空细胞的分布一致。 HPV16/18与不同宫颈病变组织原位杂交阳性率平均为51.1 ％,HPV6/11的则为64.7 ％。经PCR检测,HPV16/18 、HPV6/11、HSV、CMV在不同宫颈病变组织中的阳性率分别为21 ％、4 ％、23 ％、0 ％。 结论： HPV感染具有特定的组织学部位,HSV可协同HPV16/18恶性转化宫颈上皮细胞。     

杂合性丢失和HPV在宫颈癌中的研究

在以往宫颈癌与HPV感染相关性研究的基础上,在国内首先应用PCR法检测杂合性丢失(Loss of heterozygosity,LOH),选用p53基因外显子472密码子一对引物对60例宫颈癌组织DNA进行PCR扩增,经B_sH_(1236)Ⅰ内切酶进行RFLP分析,观察到12例有杂合性丢失,占20%(12/60),其中8例是HPV感染阴性组织,4例是HPV感染阳性组织。研究结果表明,在HPV感染阴性组织中,p53基因杂合性丢失率远比HPV感染阳性组织高(89%与7.8%)。在HPV感染阴性的宫颈癌组织中,p53基因杂合性丢失似乎与HPV没有直接关系,可能在其它因素参与下致使p53基因杂合性丢失。     

外泌体microRNAs在卵巢癌诊断和治疗中作用的研究进展

外泌体microRNAs(miRNAs)在卵巢癌进展的各种过程中发挥重要作用,如卵巢癌细胞增殖、凋亡和侵袭。外泌体miRNAs通过各种途径参与基因表达、信使RNA合成、蛋白生成等,有助于对卵巢癌发病机制的理解。由于miRNAs在血浆外泌体中的有效性,miRNAs可作为新兴的癌症早期检测和治疗评估生物标志物。外泌体miRNAs作为一种信使,在肿瘤微环境中起着重要的作用,越来越多的研究也证实了miRNAs作为靶点治疗卵巢癌的可行性。     

p53和HPV—16、18E6蛋白在宫颈癌的表达

目的探讨宫颈癌中抑癌基因p53蛋白与HPV-16、18癌基因E6蛋白的表达及其意义.方法采用SP免疫组织化学方法,检测68例宫颈癌和8例慢性宫颈炎上皮组织中p53和HPV-16、18E6蛋白的表达.结果68例宫颈癌中有17例p53蛋白和60例HPV-16、18E6蛋白呈阳性表达,阳性率分别为25.0%和88.2%.p53蛋白阳性表达与组织学类型有关,其阳性率在宫颈腺癌中为83.3%和宫颈鳞癌中为17.2%,有极显著性差异(P＜0.01);p53蛋白表达也与临床分期相关,该蛋白阳性表达率随着临床分期上升而增高.p53表达同肿瘤分化程度,淋巴结转移无关(P＞0.05).HPV-16、18E6蛋白在宫颈癌组织中的表达同肿瘤分化程度、淋巴结转移、组织学类型和临床分期无关(P＞0.05).在慢性宫颈炎上皮组织中均无p53和HPV-16、18E6蛋白表达.结论p53蛋白阴性和弱阳性表达以及HPV-16、18E6蛋白过度表达与宫颈癌发生有关,但在宫颈腺癌和临床分期升高的宫颈癌组织中,p53蛋白阳性表达的增强可能是p53基因突变的结果,或者与其他细胞蛋白结合,阻止了HPV-16、18E6蛋白对p53蛋白的降解作用,使p53蛋白稳定性增加和阳性表达水平提高.     

外泌体miRNAs在乳腺癌肿瘤微环境中的研究进展

乳腺癌是全球女性最常发生的恶性肿瘤,患者死亡的主要原因是复发、转移和耐药性的出现.研究已经证明,外泌体介导癌细胞与肿瘤微环境之间的信息交流,外泌体携带的miRNAs通过差异表达于乳腺癌细胞,在微环境中影响癌基因表达的调控,介导乳腺癌细胞的信号通路,调节癌细胞周期进程以及重塑肿瘤相关成纤维细胞等,从而促进乳腺癌的发生、发...     

cobas 4800 HPV检测在宫颈癌筛查中的应用价值

  目的  评价cobas 4800 HPV检测技术在宫颈癌及癌前病变筛查中的可行性及应用价值。  方法  对河南省新密市856例年龄 > 21岁有性生活的妇女进行宫颈癌筛查。每位妇女均接受了cobas 4800 HPV检测、高危型HPV第二代杂交捕获试验(hy brid capture 2 technology, HC2)检测、ThinPrep液基细胞学和阴道镜检查。阴道镜下在可见病变处直接取活检; 任意筛查结果阳性但无可见病变时, 于宫颈外口鳞柱交界处行四象限随机活检和宫颈管搔刮术(endocervical curettage, ECC)。  结果  cobas 4800HPV检测与HC2检测对宫颈上皮内瘤变(cervical intraepithelial neoplasia, CIN)2级以上(CIN2、CIN3及宫颈癌)患者的灵敏度均为94.4%(34/36), 特异度分别为63.2%(516/817)和63.9%(522/817);一致率为83.4%(711/853), 两者具有高度一致性(Kappa=0.65)。cobas 4800 HPV检测对于液基细胞学检查漏诊的患者具有100%检出率。cobas 4800 HPV16及18分型检测对于CIN2以上患者的阳性预测值21.9%为HC2检测10.3%的2.13倍。妇女感染HPV16及18型患CIN2以上病变的年龄比感染其他类型平均小5.4岁。  结论  cobas 4800 HPV检测与HC2检测具有相似的准确性和良好的一致性, 比ThinPrep液基细胞学检查更为灵敏, 并且能鉴别HPV16及18两种高风险类型HPV感染, 利于医生更有针对性地随访宫颈病变中的高危病例。      

维吾尔族妇女宫颈癌发生与EBV及HPV感染的关系

目的:探讨维吾尔族妇女宫颈癌发生过程中EB病毒(Ebstein-Barr virus,EBV)及人乳头瘤病毒(human papillomavirus,HPV)感染的作用及其意义。方法:收集维吾尔族妇女宫颈炎、宫颈内上皮瘤样病变(cervical intraepithelial neoplasja,CIN)Ⅰ/Ⅱ/Ⅲ和宫颈鳞癌患者福尔马林浸泡与石蜡包埋组织标本共178例,提取DNA并采用PCR方法对EBV和HPV DNA进行检测;用免疫组织化学方法检测宫颈癌EBV蛋白表达。结果:病毒DNA检测结果显示,宫颈炎、CINⅠ、CINⅡ～Ⅲ和宫颈癌患者各组HPVDNA检出率依次足2.5%、12.5%、68.0%、96.4%,EBV DNA为0、3.1%、28.0%和69.6%,其中宫颈炎组与CINⅡ～Ⅲ和宫颈癌组问的差异具有统计学意义(P均0.05),但宫颈炎与CINI组间的差异无统计学意义(P0.05)。宫颈病变病理进程不仅伴随着HPV及EBVDNA阳性检出率梯度上升,而且与HPV和EBV双重感染检出率增高呈正相关(r=0.46,X~2=82.50,P0.001)。对宫颈癌组织进行免疫组织化学分析,发现EBV DNA检测阳性标本中EBV蛋白阳性表达检出率为89.7%(34/39),而阴性标本中蛋白表达阳性率为6%(1/17)。结论:维吾尔族妇女宫颈癌的发生与发展可能与HPV和EBV双重感染密切相关。     

环氧合酶-2在宫颈癌中的表达及其与HPV16感染的关系

目的：探讨环氧合酶-2(COX-2)在宫颈癌发生发展中的作用，分析COX-2与宫颈癌中HPV16感染之间的关系。方法：收集46例宫颈癌组织作为实验组，31例健康的宫颈组织作为对照组。用免疫组化方法检测各组的COX-2表达水平。用PCK方法检测宫颈癌组的HPV16DNA。结果：COX-2在宫颈癌组织中有较高表达；COX-2在宫颈癌组织中表达与年龄、临床分期、组织分化程度、浸润深度之间均无相关性。而与淋巴结转移有显著相关性；宫颈癌组织中HPV16DNA阳性率为5652％(26/46)。在COX-2表达阳性的宫颈癌组织中，HPV16DNA阳性组的染色分值明显高于HPV16DNA阴性组。结论：宫颈癌的发生发展中有COX-2的参与。并且COX-2与宫颈癌的转移密切相关。宫颈癌中COX-2高表达与HPV16感染可能有一定的相关性。     

HPV vaccines and the prevention of cervical cancer

Cervical cancer is the second commonest causes of cancer death among women worldwide. Uniquely amongst human cancers, it is entirely attributable to infection. Persisting infection of anogenital epithelium with one of a limited subset of human papillomaviruses (HPVs) is necessary for the development of cervical cancer. Several recent large clinical trials have shown that prophylactic vaccines, based on PV virus particles produced using recombinant DNA technology, provide long lasting immunity against infection with the incorporated PV genotypes, and against premalignant conditions caused by these infections. Effective deployment of these vaccines, which have excellent safety and efficacy profiles, could eventually reduce the global burden of cervical cancer by up to 70% through universal immunisation of preadolescent girls. Vaccine use will supplement rather than replace cervical cancer screening programs, where these programs already exist.     

新疆维吾尔族女性人乳头瘤病毒感染与宫颈癌相关性的流行病学调查

目的　了解新疆维吾尔族女性人乳头瘤病毒（ＨＰＶ）感染及宫颈癌的发病状况,为新疆宫颈癌预防和筛查提供数据。方法　于２００６年采用整群抽样方法选择新疆于田县有性生活、１６～５９岁维吾尔族女性,按年龄分层入组,依次行宫颈液基细胞学检查和ＨＰＶ检测。意义不明的不典型鳞状细胞（ＡＳＣＵＳ）以上或ＨＰＶ阳性者行阴道镜检查及必要的宫颈活检。结果　新疆维吾尔族妇女高危型、低危型和总体ＨＰＶ感染率分别为７.２５％、１.５９％和８.２７％。ＣＩＮⅡ级以上病变和宫颈癌现患率分别为１.９３％和０.２３％。高危型ＨＰＶ在细胞学ＡＳＣＵＳ、鳞状上皮内低度病变（ＬＳＩＬ）和鳞状上皮内高度病变（ＨＳＩＬ）中的比例分别为１３.４６％、６４.７１％和９０.００％;高危型ＨＰＶ在ＣＩＮⅠ、ＣＩＮⅡ、ＣＩＮⅢ和ＩＣＣ的比例分别为６６.６７％、８３.３３％、１００.００％和１００.００％。ＨＰＶ感染率随宫颈病变级别增加有增高趋势,但在ＣＩＮⅡ级以上病变中无统计学差异。结论　新疆维吾尔族女性ＨＰＶ感染率低于我国汉族女性,但宫颈癌现患率高于我国城市汉族女性,低于一些农村汉族女性。新疆维吾尔族女性ＨＰＶ感染率在不同级别宫颈上皮内瘤变中的分布趋势与中国其他地区相似,但同时具有自身民族特征。     

Does pretreatment HPV viral load correlate with prognosis in patients with early stage cervical carcinoma?

Objective

Recent data suggest that pretreatment HPV (Human papillomavirus) viral load is useful to predict the severity of intraepithelial lesions of the uterine cervix and formulate a treatment plan. However, the relationship between initial HPV viral load and prognosis of cervical cancer patients has not yet been clearly defined. The objective of this study was to determine whether HPV viral load has prognostic significance in patients with early stage cervical carcinoma treated by surgery.

Methods

A retrospective review of all patients with early stage cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy at our institution from August 2003 to December 2007 was conducted. Patients were included only if they had pretreatment Hybrid Capture II test for HPV DNA detection.

Results

We identified 34 patients who met the inclusion criteria. Two groups were identified: patients who had low HPV viral load (≤100 RLU) versus those who had high viral load (>100 RLU). There were no differences in age, FIGO stage, histology, pathologic risk factors - tumor size, deep stromal invasion, lymph-vascular space invasion, parametrial extensions, vaginal margin involvement, and lymph node metastasis - and adjuvant CCRT. There was no significant difference of disease-free survival regard to pretreatment HPV viral load (p=0.7756).

Conclusion

In our study, survival was not significantly different between early stage cervical cancer patients who had low and high pretreatment HPV viral load. It seems that pretreatment HPV viral load may not be of help to predict disease prognosis.     

消除子宫颈癌 关注一级预防

子宫颈癌是严重威胁女性生命健康的恶性肿瘤之一。因已有成熟的三级预防措施,世界卫生组织（WHO）在2020年提出《加速消除宫颈癌的全球战略》,其中一级预防除了进行健康教育外,最重要的是人乳头瘤病毒（HPV）预防性疫苗的接种。目前我国已有五种HPV疫苗上市,并有完整的中国人群应用的研究数据。本文将探讨HPV疫苗在我国的应用及其应用中关注的问题。     

Burden of Disease Associated with Cervical Cancer in Malaysia and Potential Costs and Consequences of HPV Vaccination

Background: An estimated 70% of cervical cancers worldwide are attributable to persistent infection withhuman papillomaviruses (HPV) 16 and 18. Vaccination against HPV 16/18 has been shown to dramatically reducethe incidence of associated precancerous and cancerous lesions. The aims of the present analyses were, firstly, toestimate the clinical and economic burden of disease attributable to HPV in Malaysia and secondly, to estimatelong-term outcomes associated with HPV vaccination using a prevalence-based modeling approach. Methods:In the first part of the analysis costs attributable to cervical cancer and precancerous lesions were estimated;epidemiologic data were sourced from the WHO GLOBOCAN database and Malaysian national data sources.In the second part, a prevalence-based model was used to estimate the potential annual number of cases ofcervical cancer and precancerous lesions that could be prevented and subsequent HPV-related treatment costsaverted with the bivalent (HPV 16/18) and the quadrivalent (HPV 16/18/6/11) vaccines, at the population level, atsteady state. A vaccine efficacy of 98% was assumed against HPV types included in both vaccines. Effectivenessagainst other oncogenic HPV types was based on the latest results from each vaccine’s respective clinical trials.Results: In Malaysia there are an estimated 4,696 prevalent cases of cervical cancer annually and 1,372 prevalentcases of precancerous lesions, which are associated with a total direct cost of RM 39.2 million with a furtherRM 12.4 million in indirect costs owing to lost productivity. At steady state, vaccination with the bivalent vaccinewas estimated to prevent 4,199 cervical cancer cases per year versus 3,804 cases for the quadrivalent vaccine.Vaccination with the quadrivalent vaccine was projected to prevent 1,721 cases of genital warts annually, whereasthe annual number of cases remained unchanged with the bivalent vaccine. Furthermore, vaccination with thebivalent vaccine was estimated to avert RM 45.4 million in annual HPV-related treatment costs (direct+indirect)compared with RM 42.9 million for the quadrivalent vaccine. Conclusion: This analysis showed that vaccinationagainst HPV 16/18 can reduce the clinical and economic burden of cervical cancer and precancerous lesions inMalaysia. The greatest potential economic benefit was observed using the bivalent vaccine in preference to thequadrivalent vaccine.