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。     

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、发展和转移;另外外泌体介导中和、药物外排和免疫系统抑制三种主要机制导致耐药性。未来,各种类型乳腺癌中差异表达的miRNAs有望成为临床诊断和预后的相关生物标志物,及抗肿瘤治疗的新靶点。     

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.     

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。      

外泌体在肺癌中的研究进展

外泌体（exosomes）是由多种细胞分泌的具有脂质双分子层结构的纳米级膜囊小泡,其内含有蛋白质、脂质、核酸等大量生物活性物质。研究表明,外泌体在肺癌的发生发展过程中发挥着重要作用,尤其是在肺癌的早期诊断、侵袭和转移、预后评估以及治疗等方面的作用成为目前研究的热点。因此,关于外泌体的研究将在转化医学的研究模式下,为肺癌临床早期诊断、治疗及预后评估带来新的契机。本文对外泌体在肺癌中的研究进展作一综述。     

外泌体在黑色素瘤中的研究进展

黑色素瘤是一种具有高侵袭性及死亡率的恶性肿瘤性疾病,早期诊断并通过手术切除后预后较好,发生转移后由于缺乏有效的治疗手段,生存率急剧降低。外泌体是由多种类型细胞分泌的一种细胞外囊泡,通过其载体作用将内容物从分泌细胞转移到受体细胞以实现细胞间的交流通信。最近的一系列研究表明外泌体参与黑色素瘤的进展、转移、细胞免疫等过程,且在黑色素瘤诊断、治疗、预后评价等方面发挥着重要作用,本文针对外泌体在该方面的研究进展情况进行综述。     

Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review

Cervical cancer (CC) is the fourth most common cause of cancer death in women. The most important risk factor for the development of CC is cervical infection with human papilloma virus (HPV). Inflammation is a protective strategy that is triggered by the host against pathogens such as viral infections that acts rapidly to activate the innate immune response. Inflammation is beneficial if it is brief and well controlled; however, if the inflammation is excessive or it becomes of chronic duration, it can produce detrimental effects. HPV proteins are involved, both directly and indirectly, in the development of chronic inflammation, which is a causal factor in the development of CC. However, other factors may also have a potential role in stimulating chronic inflammation. MicroRNAs (miRNAs) (a class of noncoding RNAs) are strong regulators of gene expression. They have emerged as key players in several biological processes, including inflammatory pathways. Abnormal expression of miRNAs may be linked to the induction of inflammation that occurs in CC. Exosomes are a subset of extracellular vesicles shed by almost all types of cells, which can function as cargo transfer vehicles. Exosomes contain proteins and genetic material (including miRNAs) derived from their parent cells and can potentially affect recipient cells. Exosomes have recently been recognized to be involved in inflammatory processes and can also affect the immune response. In this review, we discuss the role of HPV proteins, miRNAs and exosomes in the inflammation associated with CC.     

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。     

人乳头瘤病毒与人类宫颈癌

鉴于人乳头瘤病毒（HPV）与人类宫颈上皮内瘤样病变以至宫颈癌的发病有密切的关系，为此作者复习相关文献，就HPV的结构、女性生殖道HPV感染的流行病学、HPV感染与宫颈癌的关系等方面加以扼要的综述。     

子宫颈癌与HPV感染关系的临床研究

目的分析子宫颈癌组织HPV检测的结果及相关临床资料,探讨HPV与子宫颈癌的临床生物学行为之间关系。方法收集200例有完整临床病历资料的子宫颈癌患者病灶组织,采用HPV分型基因芯片检测系统,进行HPV阳性率及其亚型的检测并对相关资料加以分析。结果HPV检出率94．0％,其中HPV16阳性率65．6％;HPV18阳性率15．5％。HPV阳性率与子宫颈癌临床分期、病理分级无相关性（P=0．25、P=0．75）;HPV阳性率与肿瘤的盆腔淋巴结转移、肿瘤的治疗后复发亦无相关性（P=0．29、P=0．47）;鳞状细胞癌的HPV检出率明显高于腺癌（P〈0．005）。结论子宫颈癌组织中的HPV阳性率很高,主要为16、18型。HPV感染与鳞状上皮恶变的关系更密切;HPV与宫颈癌的临床期别、病理分级、盆腔淋巴结转移、肿瘤的复发无明显相关性。     

海南地区宫颈癌病例的HPV感染状况

 目的　分析本地区宫颈癌患者的HPV感染情况。方法　收集 10 1例治疗前病例的颈管分泌物 ,用PCR荧光定量方法进行HPV6、11、16、18的检测。结果　HPV阳性者 4 4例 ,阳性率 4 3.6 % ,在 <4 0岁、4 0～ 5 0岁、>5 0岁 3个年龄段 ,HPV阳性率分别为 5 9.5 %、35 .9%、2 5 % (P <0 .0 5 )。近 2年与 2年前病例HPV感染率分别是 5 0 %、33.3%。宫颈鳞癌的HPV阳性率明显高于腺癌、腺鳞癌 (P <0 .0 1)。结论　HPV感染是宫颈癌的重要致病因素 ;鳞癌的发生与HPV感染的关系较腺癌更密切 ;在本地区极可能存在除上述 4型以外的已定或未定亚型的感染     

Awareness of cervical cancer and HPV vaccination and its affordability among rural folks in Penang Malaysia

Introduction: As the second most common cancer in women worldwide, cervical cancer causes major health and economic burdens. Recent introduction of HPV immunization program locally has been encouraging but vaccine uptake remains poor. In addition, no study has been conducted to explore the people’s awareness and knowledge on cervical cancer, HPV and its vaccine in a rural setting in Malaysia after the inception of the HPV vaccination program. Objective: This study was conducted to determine the awareness of cervical cancer, HPV vaccination and its affordability among people in a rural area in Malaysia. Method: A cross-sectional study was conducted among 116 participants in a village in Penang. All consenting female villagers aged 13 years and above, and males who were married were interviewed using a questionnaire. Results: Most participants (88.8%) had heard of cervical cancer, however only 29.3% and 42.2% of them had heard of HPV and HPV vaccination respectively. Only 5.2% knew the actual market price for the vaccine. They were willing to pay an average of RM 96.7 (USD $27.7) for the full course of vaccination if it is not given to them for free, whereas the market price is RM1200 (USD $342.85). Conclusion: Awareness among the Malaysian population in a rural setting on HPV and HPV vaccination is low. Educating the public on the infection can help control the illness. Cost of the HPV vaccine is a serious barrier to the success of the vaccination program in Malaysia.     

miRNA与宫颈癌发病机制的研究进展

微小核糖核酸(microRNA,miRNA）是在调节基因表达过程中发挥作用的一类非编码的内源RNA。宫颈癌是常见的妇科恶性肿瘤。随着科研水平的提高,人们对miRNA研究的深入,大量的研究证实miRNA与宫颈癌的发病机制相关,本文就近年来与宫颈癌发病机制相关的miRNA作一综述。     

High risk HPV types in southern Iranian patients with cervical cancer

This study was undertaken to assess the rate of HPV infection in cervical carcinoma among southern Iranian patients. 101 archival cervical carcinoma tissue samples of a 10 year period were studied for the presence of HPV DNA in southern Iran by a polymerase chain reaction method. In addition, the presence of high risk HPV-16 and HPV-18 genotypes was investigated. In total, 88 (87.1%) of the samples were HPV DNA positive, of which 83 were squamous cell carcinomas and 5 were adenocarcinomas. HPV-16 genotype was detected in 26.7% of HPV positive cervical carcinomas; however, none of the samples were positive for the existence of HPV-18 genotype. Collectively, these results suggest that HPV-16 and HPV-18 are not the frequent high risk HPV types in our patients and circulating HPV types in southern Iranian population are different from many other populations.     

Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin

The present study further investigated the mode of action of methyl jasmonate (MJ) in different cervical cancer cell lines. We show that in addition to the short term cytotoxicity, MJ effectively reduced the survival of cervical cancer cells (clonogenicity assays). MJ induced apoptosis in all cervical cancer cells. In some cell lines, MJ caused elevation of the mitochondrial superoxide anion, notably, in HeLa and CaSki. Changes in the expression of p53 and bax were variable, yet, downregulation of survivin was common to all cervical cancer cells. MJ significantly reduced the levels of the human papillomavirus (HPV) E6 and E7 proteins without alteration of the mRNA levels. Moreover, ectopic expression of E6, E7 or both in cervical cancer cells that lack HPV (C33A), did not alter significantly their response to MJ. Our studies point to MJ as an effective anticancer agent against a variety of cervical cancer cells acting through shared and different pathways to induce cell death regardless of the presence of HPV.