ROMA在卵巢上皮性癌早期诊断中的研究进展

卵巢上皮性癌（Epithelial ovarian cancer,EOC）死亡率居妇科恶性肿瘤首位,早期诊断可明显改善患者预后。人附睾上皮分泌蛋白（human epididymis protein 4,HE4）对早期EOC的检测敏感性高,有助于对EOC高危患者的筛选,与CA125可互补,增加盆腔包块患者中EOC早期诊断力度。HE4与CA125联合检测及结合绝经状态预测盆腔包块患者中卵巢恶性肿瘤的发病风险模型（Risk of Ovarian Malignancy Algorithm,ROMA）,能成功预测盆腔包块患者中EOC高风险个体,对卵巢良恶性肿瘤的鉴别预测更为准确且更易被接受,有较大的临床应用价值。     

血清HE4、FS、SMRP及CA125在卵巢癌患者中的表达及临床意义

目的:探讨血清人附睾蛋白4(HE4)、卵泡抑素(FS)、可溶性间皮素相关蛋白(SMRP)、糖类抗原125(CA125)在卵巢癌患者中的表达水平及临床意义。方法:选取2014年6月-2017年9月我院收治的卵巢癌患者60例作为卵巢癌组,另选取同期收治的卵巢良性肿瘤患者32例作为良性组,选取同期健康体检妇女40例作为对照组,检测三组受试者血清HE4、FS、SMRP、CA125水平,对比三组HE4、FS、SMRP、CA125阳性表达率,并分析血清HE4、FS、SMRP、CA125对卵巢癌的诊断价值。结果:三组受试者的HE4、FS、SMRP、CA125水平整体对比有统计学意义(P0.05),其中卵巢癌组与良性组HE4、FS、SMRP、CA125水平高于对照组,且卵巢癌组高于良性组,差异有统计学意义(P0.05)。三组受试者的HE4、FS、SMRP、CA125阳性表达率整体对比有统计学意义(P0.05),卵巢癌组与良性组HE4、FS、SMRP、CA125阳性表达率高于对照组,且卵巢癌组高于良性组,差异有统计学意义(P0.05)。联合检测的灵敏度高于FS、SMRP单项检测,差异有统计学意义(P0.05),联合检测的特异度高于HE4、FS、SMRP、CA125单项检测,但差异无统计学意义(P0.05)。结论:卵巢癌患者血清HE4、FS、SMRP、CA125水平及阳性表达率均较高,四项指标联合检测可提高诊断卵巢癌的灵敏度及特异度。     

卵巢癌患者血清HE4、CA125、CA72-4及炎性因子水平检测的临床价值评估

目的:探讨血清人附睾蛋白4(HE4)、糖类抗原125(CA125)、糖类抗原72-4(CA72-4)及炎性因子IL-6、IL-8、IL-17水平检测对卵巢癌患者的临床价值。方法:选取2015年2月至2017年2月我院收治的卵巢肿瘤患者81例,包括卵巢恶性肿瘤组39例及卵巢良性肿瘤组42例,另选42例健康人作正常对照组,比较各组及临床不同分期卵巢癌患者血清HE4、CA125、CA72-4、IL-6、IL-8、IL-17水平的差异。结果:卵巢恶性肿瘤组血清HE4、CA125、CA72-4、IL-6、IL-8及IL-17水平均显著高于对照组(P0.05),而卵巢良性肿瘤组与对照组以上指标比较差异并无统计学意义(P0.05);随卵巢癌分期增加,患者血清HE4、CA125、CA72-4、IL-6、IL-8及IL-17水平呈上升趋势,以血清HE4、CA125及IL-17增加较为显著(P0.05),而Ⅰ期、Ⅱ期及Ⅲ期卵巢癌患者血清CA72-4、IL-6及IL-8在增加并不明显(P0.05)。结论:卵巢癌患者血清HE4、CA125、CA72-4、IL-6、IL-8及IL-17水平较高,且随临床分期增加呈上升趋势,以上指标可能有助于卵巢癌的诊断、治疗及病情评估。     

人附睾蛋白4与血清CA125联合检测在卵巢癌诊断中的应用价值

目的：探讨人附睾蛋白4（HE4）和CA125联合检测在上皮性卵巢癌临床诊断中的应用价值。方法：用化学发光法测定51例卵巢癌患者、64例卵巢良性疾病患者和50例健康对照者血清中的HE4和CA125水平,并对结果进行比较分析。结果：卵巢癌组血清中HE4和CA125水平均显著高于卵巢良性肿瘤组和健康对照组,差异有统计学意义（P〈0．05）,卵巢良性肿瘤组与健康对照组比较无显著性差异;HE4在早期卵巢癌中的阳性率高于CA125,两者联合检测可提高卯巢癌诊断的阳性率;卵巢癌组联合检测ROC曲线下面积大于单项检测曲线下面积。结论：联合检测HE4和CA125有助于卵巢癌的早期诊断。     

Validation of LRG1 as a Potential Biomarker for Detection of Epithelial Ovarian Cancer by a Blinded Study

Background

Leucine-rich alpha-2-glycoprotein (LRG1) was found to be differentially expressed in sera from patients with Epithelial Ovarian Cancer (EOC). The aim of this study is to investigate the performance of LRG1 for detection of EOC, including early stage EOC, and to evaluate if LRG1 can complement CA125 in order to improve EOC detection using two independent blinded sample sets.

Methods and Results

Serum LRG1 and CA125 were measured by immunoassays. All assays were performed blinded to clinical data. Using the two independent sample sets (156 participants for sample set 1, and 233 for sample set 2), LRG1 was differentially expressed in EOC cases as compared to healthy, surgical, and benign controls, and its performance was not affected by the conditions of blood collection. The areas under the ROC curve (AUC) for LRG1 in differentiating EOC cases from non-cases were 0.797 and 0.786 for sample set 1 and 2. For differentiating EOC cases from healthy controls, the AUC values for LRG1 were 0.792 and 0.794. At a fixed specificity of 95%, LRG1 detects 52%, and 53.5% of EOC cases from healthy controls for sample set 1 and 2. When combining LRG1 and CA125, the AUC value increased to 0.927, which was improved compared to CA125 (AUC=0.916) (p=0.008) alone in distinguishing EOC cases from non-cases. More importantly, LRG1 also showed potential performance in differentiating early stage EOC from non-cases with an AUC of 0.715 for sample set 1, and 0.690 for sample set 2. The combination of LRG1 and CA125 resulted in an AUC of 0.838, which outperforms CA125 (AUC=0.785) (p=0.018) in detecting early stage EOC cases from non-cases using the larger sample set.

Conclusions

LRG1 could be a useful biomarker alone or in combination with CA125 for the diagnosis of ovarian cancer.     

人附睾蛋白4在卵巢癌中的应用进展

卵巢癌是妇科常见的恶性肿瘤,其死亡率居妇科恶性肿瘤之首,早期发现有助于提高患者的五年生存率。人附睾蛋白(HE4)属于蛋白酶抑制剂家族,是一种新的卵巢癌肿瘤标志物。HE4在卵巢癌组织中及患者血清中处于高表达状态。研究表明在早期诊断方面HE4比糖类抗原125(CA125)有更高的灵敏度和特异度,在疾病的治疗过程中可以预测肿瘤细胞减灭术的满意度及患者对铂类的反应,在卵巢癌的复发及预后的监测中HE4也有很大的临床应用价值。     

HE4和HE4/CA125并联诊断卵巢癌的系统评价

目的:通过Meta分析方法系统评价血清人附睾蛋白4(HE4)及HE4并联糖类抗原125(CA125)诊断卵巢癌的价值。方法:中国知网期刊数据库(CNKI)、中文科技期刊数据库(中国万方数据库)、中文电子期刊数据库及维普网等数据库检索2005年1月至2015年3月的相关文献,使用Meta-Disc软件进行Meta分析,分析异质性及处理后选择适当效应模型合并效应量,得出合并敏感性、合并特异性及合并似然比,制作SROC曲线并计算曲线下面积(AUC)。对HE4及HE4/CA125并联检测诊断卵巢癌的AUC应用Z检验进行比较。采用STATA13.0软件应用Egger检验法进行发表偏倚检测。结果:16篇文献符合纳入标准,将对照组分为健康人群和良性疾病组,经Meta分析后得出:以健康人群为对照,HE4和HE4/CA125并联检测卵巢癌的AUC分别为0.8611±0.0399、0.8959±0.0237,差异无统计学意义(Z值=0.749871,P0.05)。以良性疾病组为对照,HE4和HE4/CA125并联检测卵巢癌的AUC分别为0.9443±0.0153、0.9328±0.0132,差异无统计学意义(Z值=0.569105,P0.05)。结论:HE4/CA125并联检测提高了卵巢癌检测的灵敏度,而单独检测HE4有良好的特异度,两者对卵巢癌诊断均有较高的AUC,但HE4与HE4/CA125并联检测的诊断价值差异并无统计学意义。     

血清OPN、HE4和CA125检测对卵巢癌的临床意义

目的：探讨联合检测血清OPN、HE4和CA125对卵巢癌的临床意义。方法：选择2010年6月-2012年7月西安市中心医院妇科及陕西省肿瘤医院妇瘤科收治的35例卵巢癌患者、73例卵巢良性肿瘤患者及40例同期体检的健康妇女为研究对象,应用ELISA法检测患者手术前后血清OPN、HE4水平,电化学发光法检测患者手术前后血清CA125水平,计算3种肿瘤标志物单项以及联合检测在卵巢癌诊断中的敏感性及特异性。结果：（1）卵巢癌患者术前血清OPN、HE4和CA125水平分别为94.6±61.06ng/mL、412.3±278.62 pmol/mL和398.64±220.91 U/mL,与卵巢良性肿瘤组及正常对照组比较差异有统计学意义（P〈0.05）;（2）卵巢癌患者手术前与术后1月血清OPN、HE4和CA125水平比较,差异均有统计学意义（P〈0.05）;（3）血清OPN、HE4和CA125水平联合检测诊断卵巢癌的敏感性（94.3%）显著高于血清OPN、HE4和CA125单项指标检测（分别为37.1%、71.4%和77.1%）,联合检测与单项指标检测比较差异均有统计学意义（P〈0.05）,而血清OPN、HE4和CA125联合检测诊断卵巢癌的特异性（78.8%）稍低于血清OPN、HE4和CA125单项指标检测（分别为87.6%、100%和80.5%）,联合检测与单项指标检测的特异性比较差异无统计学意义（P〉0.05）。血清HE4单项指标检测的特异性高达100%。结论：联合检测卵巢癌患者血清OPN、HE4和CA125水平可作为诊断和评估卵巢癌预后的参考指标。     

肿瘤标志物在卵巢恶性肿瘤早期误诊预防中的价值

目的:探讨糖类抗原CA125、CEA与CA199联合检测对卵巢癌有一定的鉴别诊断价值。方法:应用化学发光免疫法对126例经病理查证实的卵巢癌患者(试验组)、104例良性肿瘤患者(对照组)进行血清CA125、CEA与CA199检测。结果:试验组血清检测结果和阳性率均明显高于对照组(P<0.01),联合检测阳性率高于单项检测(P<0.01)。结论:应用检验医学进行CA125、CEA与CA199联合检测对卵巢癌有一定的鉴别诊断价值。可降低误诊率。     

超声造影联合HE4、CA125、CA153在子宫内膜癌诊断中的价值研究

摘要 目的：为提高对子宫内膜癌的早期诊断,本研究对超声造影联合肿瘤标志物人附睾蛋白4（human epididymis protein-4,HE4）血清糖类抗原125（carbohydrate antigen 125,CA125）及153（CA153）在子宫内膜癌中的诊断价值进行研究。方法：以80例疑似子宫内膜癌患者为研究组,另以80例于本院体检的健康女性为对照组。对患者进行超声造影检查,比较两组血清HE4、CA125以及CA153水平,考察超声造影联合HE4、CA125及CA153对子宫内膜癌的诊断作用。结果：本研究中80例疑似患者中,子宫内膜癌患者有49例,子宫内膜良性病变患者31例,而超声造影检查显示子宫内膜癌患者有41例,良性病变39例,与金标准检查结果有一定的差异,单纯的超声造影检查对子宫内膜癌的诊断有局限性。子宫内膜癌和良性病变患者的病变区灌注的时间、增强强度以及增强均度都有显著差异（P<0.05）。对照组血清HE4、CA125及CA153水平分别为82.31±15.45 pmol/mL、22.31±6.21 U/mL、16.45±4.91 U/mL,研究组血清HE4、CA125及CA153水平分别为159.28±24.01 pmol/mL、42.88±5.73 U/mL、28.30±3.76 U/mL,经统计,研究组各项指标均显著高于对照组（P<0.05）。超声造影的灵敏度为79.3 %、特异度为67.34 %、阳性似然比为2.54、阴性似然比为0.25、阳性预测值为84.63 %、阴性预测值为60.51 %及符合率为72.19 %;联合检测的灵敏度为86.58 %、特异度为78.92 %、阳性似然比为3.11、阴性似然比为0.23、阳性预测值为93.19 %、阴性预测值为67.42 %及符合率为77.90 %。结论：超声造影联合HE4、CA125及CA153检测对子宫内膜癌诊断价值更高,HE4、CA125及CA153能辅助提高超声造影的诊断效果。     

子宫内膜癌患者血浆溶血磷脂酸、血清癌抗原125及人附睾蛋白4的表达及临床意义

目的:探讨子宫内膜癌患者血浆溶血磷脂酸(LPA)、血清癌抗原125(CA125)及人附睾蛋白4(HE4)的表达及与临床病理特征的关系。方法:选取2014年3月到2016年6月在同济大学附属第一妇婴保健院进行治疗的子宫内膜癌患者76例作为观察组,另选取我院同期收治的子宫内膜增生症患者50例作为良性病变组,再选取同期在我院体检结果为健康的志愿者50例作为对照组。比较三组受试者血浆LPA、血清CA125以及HE4水平。以病理检测结果为金标准,计算血浆LPA、血清CA125、HE4诊断子宫内膜癌的灵敏度、特异度、阳性预测值、阴性预测值。分析子宫内膜癌患者血浆LPA、血清CA125以及HE4水平与临床病理特征的关系。结果:观察组的血浆LPA、血清CA125以及HE4水平均高于对照组和良性病变组(P0.05),良性病变组的血浆中CA125水平高于对照组(P0.05)。血浆LPA、血清CA125以及HE4诊断子宫内膜癌的灵敏度、特异度、阳性预测值、阴性预测值比较无统计学差异(P0.05)。子宫内膜癌患者LPA水平与年龄、肿瘤直径无关(P0.05),与淋巴结转移、临床分期、分化程度、疾病类型有关(P0.05);CA125、HE4水平与年龄、疾病类型无关(P0.05),与淋巴结转移、临床分期、肿瘤直径、分化程度有关(P0.05)。结论:子宫内膜癌患者血浆LPA、血清CA125以及HE4水平偏高,LPA、CA125、HE4与部分临床病理参数相关,三指标对子宫内膜癌均有较高的诊断价值。     

Effects of adiponectin,plasma D-dimer,inflammation and tumor markers on clinical characteristics and prognosis of patients with ovarian cancer

BackgroundTo investigate the effects of adiponectin (ADPN), plasma D-dimer (D-D), inflammation, and tumour markers on clinical characteristics and prognosis of patients with ovarian cancer.MethodsA total of 80 patients with ovarian cancer treated in our hospital from April 2017 to November 2019 were enrolled as study subjects and evenly divided into an observation group (patients with ovarian cancer) and a control group (patients with the benign ovarian tumour) based on the results of the postoperative pathological biopsy. The levels of ADPN, plasma D-D, inflammatory factors, and serum tumour markers carbohydrate antigen 125 (CA125), human epididymis protein 4 (HE4), and risk of ovarian malignancy algorithm (ROMA) were compared between the two groups. The diagnostic value of serum tumour markers CA125, HE4, and ROMA in ovarian cancer was explored. The correlations of ROMA changes with the changes in the levels of ADPN, plasma D-D, high-sensitivity C-reactive protein (hs-CRP), CA125, and HE4 were analysed. Additionally, the related risk factors affecting the development of ovarian cancer were subjected to univariate and multivariate logistic regression analyses.ResultsIn comparison with the control group, the observation group exhibited a lowered ADPN level (p<0.05), notably raised levels of plasma D-D, inflammatory factors hs-CRP and interleukin-6 (IL-6) and serum tumour markers CA125 and HE4 and an evidently increased ROMA (p<0.05). Besides, the detection of serum ROMA showed the highest specificity and sensitivity and low false-positive rate and false-negative rate. The changes of ROMA were positively correlated with the changes in the levels of plasma D-D, hs-CRP, CA125, and HE4 (p<0.05) and negatively associated with the changes in ADPN level (p<0.05). The results of the univariate analysis showed that abnormal ADPN, D-D, hs-CRP, IL-6, CA125, and HE4 levels were related to risk factors affecting the development of ovarian cancer. It was found through multivariate logistic regression analysis that decreased ADPN level and increased D-D, hsCRP, IL-6, CA125, and HE4 levels were independent risk factors affecting the development of ovarian cancer.ConclusionsIn the case of ovarian cancer, the ADPN level declines, while the levels of plasma D-D, inflammatory factors, and serum tumour markers CA125, HE4, and ROMA rise obviously. Besides, the ROMA level displays a positive relation to the content of CA125, HE4, plasma D-D, and inflammatory factors and a negative association with the ADPN level.     

术前HE4、FOLR1、NLR联合监测在上皮性卵巢癌术后复发中的临床应用价值

摘要 目的：探讨术前人附睾蛋白4（HE4）、叶酸受体1（FOLR1）、中性粒细胞淋巴细胞比值（NLR）联合监测在上皮性卵巢癌（EOC）术后复发中的临床应用价值,并分析EOC术后复发的危险因素。方法：选取2018年4月~2019年9月期间广东医科大学附属第二医院收治的114例EOC患者纳为EOC组,EOC组根据术后有无复发分为未复发组（n=42）和复发组（n=72）,选择同期在广东医科大学附属第二医院住院治疗的100例卵巢上皮良性肿瘤患者作为卵巢良性疾病组,另选广东医科大学附属第二医院体检中心的健康女性志愿者95例作为对照组。对比EOC组和卵巢良性疾病组术前、对照组体检当日的HE4、FOLR1、NLR。对比未复发组、复发组术前的HE4、FOLR1、NLR及其他临床资料。采用多因素Logistic回归分析EOC术后复发的危险因素,通过绘制受试者工作特征（ROC）曲线分析HE4、FOLR1、NLR单独或联合应用对EOC术后复发的预测价值。结果：EOC组、卵巢良性疾病组的HE4、FOLR1、NLR高于对照组,且EOC组高于卵巢良性疾病组（P<0.05）。复发组的HE4、FOLR1、NLR均高于未复发组（P<0.05）。复发组、未复发组在病理类型、临床分期、术中腹水细胞学检查结果、化疗周期、清扫淋巴结、组织分化程度、术后残留大小方面对比差异有统计学意义（P<0.05）。HE4偏高、FOLR1偏高、NLR偏高、临床分期Ⅲ ~ Ⅳ期、组织分化程度为低分化、病理类型为浆液性、术后残留大小>1 cm、术中腹水细胞学检查结果为阴性、未清扫淋巴结均为EOC术后复发的危险因素（P<0.05）。HE4、FOLR1、NLR这三项指标术前联合检测预测术后复发的曲线下面积（AUC）为0.911均高于各指标单独检测的0.777、0.782、0.770。结论：EOC患者术前HE4、FOLR1、NLR处于高水平,且术前联合检测HE4、FOLR1、NLR对于EOC术后复发具有一定的预测价值,同时应关注临床分期Ⅲ ~ Ⅳ期、组织分化程度为低分化、病理类型为浆液性、术后残留大小>1cm、术中腹水细胞学检查结果为阴性、未清扫淋巴结的EOC患者,给予相关干预,以降低术后复发几率。     

联合检测血清糖类抗原标志物在女性绝经前后卵巢浆液性癌诊断中的价值

目的:探讨联合检测血清糖类抗原标志物在女性绝经前后卵巢浆液性癌诊断中的价值。方法:采用回顾性研究方法,选择2016年8月到至2018年2月在我院肿瘤科进行检测的绝经前后卵巢浆液性癌患者60例(癌变组)与绝经前后健康体检者60例(健康对照组),检测其血清癌胚抗原(carcino-embryonic antigen,CEA)、人附睾蛋白4(human epididymis protein 4,HE4)和糖链抗原125(carbohydrate antigen 125,CA125)的水平,并分析其与患者的临床病理特征与随访预后的相关性。结果:癌变组血清CEA、HE4、CA125水平及阳性表达率都均显著高于健康对照组(P0.05)。在癌变组60例患者中,随着病理分期增加、分化程度的减少、淋巴结转移与死亡情况的发生,血清CEA、HE4、CA125的阳性表达率显著升高,对比差异有统计学意义(P0.05)。同时在120例人群中,联合诊断为卵巢浆液性癌者54例,联合诊断的敏感性与特异性分别为90.0%和100.0%。结论:绝经前后女性卵巢浆液性癌患者血清糖类抗原标志物-CEA、HE4、CA12水平均呈现高表达,可能作为绝经前后女性卵巢浆液性癌诊断与预后预测的参考指标。     

血清和胸水中CA125在结核性和癌性胸水中的表达及临床意义

目的:探讨血清和胸水中CA125在结核性和癌性胸水中的表达及鉴别诊断意义。方法:抽选我院确诊的结核性胸水病人85例(结核组)和癌性胸水病人71例(癌症组),检测两组患者血清和胸水中CA125表达,并以胸水/血清中CA125比值10(p-CA125/s-CA12510)为临界值,观察其对癌性胸水的鉴别特异度、灵敏度及准确性。结果:癌症组胸水中CA125表达及p-CA125/s-CA125比值均显著高于结核组(P0.05);但血清中两组CA125表达比较差异无显著性(P0.05);两组胸水中,以35U/ml为临界值,两组患者阳性率92.9%(79/85)、100%(71/71)比较差异无显著性(X2=7.0718,P=0.0078)。癌症组中p-CA125/sCA125比值10的比率(84.5%VS 17.6%)明显高于结核组(X2=66.6244,P=0.0000);并以其为诊断癌性胸水的临界值,鉴别诊断特异度、灵敏度及准确性分别为82.3%、84.5%、83.3%。结论:血清和胸水中CA125表达对于鉴别结核性或者是癌性胸水的临床意义不大,但是p-CA125/s-CA125比值对于鉴别结核性和癌性胸水具有一定临床价值。     

Anti-MUC1 monoclonal antibody (C595) and docetaxel markedly reduce tumor burden and ascites, and prolong survival in an in vivo ovarian cancer model

MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. We previously reported that anti-MUC1 monoclonal antibody C595 (MAb C595) plus docetaxel (DTX) increased efficacy of DTX alone and caused cultured human epithelial ovarian cancer (EOC) cells to undergo apoptosis. To further study the mechanisms of this combination-mediated apoptosis, we investigated the effectiveness of this combination therapy in vivo in an intraperitoneal (i.p.) EOC mouse model. OVCAR-3 cells were implanted intraperitoneally in female athymic nude mice and allowed to grow tumor and ascites. Mice were then treated with single MAb C595, DTX, combination test (MAb C595 and DTX), combination control (negative MAb IgG(3) and DTX) or vehicle control i.p. for 3 weeks. Treated mice were killed 4 weeks post-treatment. Ascites volume, tumor weight, CA125 levels from ascites and survival of animals were assessed. The expression of MUC1, CD31, Ki-67, TUNEL and apoptotic proteins in tumor xenografts was evaluated by immunohistochemistry. MAb C595 alone inhibited i.p. tumor growth and ascites production in a dose-dependent manner but did not obviously prevent tumor development. However, combination test significantly reduced ascites volume, tumor growth and metastases, CA125 levels in ascites and improved survival of treated mice compared with single agent-treated mice, combination control or vehicle control-treated mice (P<0.05). The data was in a good agreement with that from cultured cells in vitro. The mechanisms behind the observed effects could be through targeting MUC1 antigens, inhibition of tumor angiogenesis, and induction of apoptosis. Our results suggest that this combination approach can effectively reduce tumor burden and ascites, prolong survival of animals through induction of tumor apoptosis and necrosis, and may provide a potential therapy for advanced metastatic EOC.     

人附睾蛋白4在卵巢癌中的研究进展

卵巢癌是严重威胁女性健康的恶性疾病之一。糖类抗原125（carbohydrate antigen125,CA125）是目前临床上广泛用于诊断卵巢上皮性癌的肿瘤标记物,然而其缺乏敏感性和特异性,因此,迫切需要寻找一种新的标志物来提高卵巢癌的诊断。人附睾蛋白4（human epididymis protein4,HE4）是近年发现的肿瘤标志物,其在良性肿瘤和正常组织中含量极低,但在卵巢癌中高表达。本文就HE4在卵巢癌中的诊断,动态监测等方面的进展做一综述。     

Role of DNA repair and cell cycle control genes in ovarian cancer susceptibility

Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different cancer diseases. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40 % of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. The aim of the present study was to evaluate the role of SNPs in three genes, XRCC2 (R188H), ERCC2 (K751Q) and CDKN1B (V109G) which are with moderate risk for ovarian cancer susceptibility in Egyptian women. We further investigated the potential combined effect of these genes variants on ovarian cancer risk. The three genes polymorphisms were characterized in 100 ovarian cancer Egyptian females and 100 healthy women by (RFLP–PCR) method in a case control study. Our results revealed that the frequencies of AC genotypes of ERCC2 (K751Q), and GG genotypes of CDKN1B (V109G) polymorphisms were significantly higher in EOC patients than in normal individual (P = 0.007, 0.02 respectively). The frequencies of AA genotype of XRCC2 (R188H) and CC genotype of ERCC2 (K751Q) were higher in EOC patients than in normal individual but without significance (P = 0.06, 0.38 respectively). Also, no association between any one of the three studied genes polymorphisms and the clinical characteristics of disease. The combination of GA (XRCC2) + AC (ERCC2) + GG (CDKN1B) was significantly associated with increased EOC risk. Also, the combination for GA (XRCC2) + AC (ERCC2) and the combination of AA (XRCC2) + CC (ERCC2) were significantly associated with increased EOC risk. There was significant difference in CA125 values between EOC and control Group (P < 0.001). Our results suggested that, XRCC2, ERCC2 and CDKN1B genes are important candidate genes for susceptibility to EOC. Also, gene–gene interaction between GA (XRCC2) + AC (ERCC2) + GG (CDKN1B) polymorphism may be associated with increased risk of EOCC in Egyptian women.     

人附睾蛋白4 在卵巢癌中的研究进展

卵巢癌是严重威胁女性健康的恶性疾病之一。糖类抗原125(carbohydrate antigen125,CA125)是目前临床上广泛用于诊断卵巢上皮性癌的肿瘤标记物,然而其缺乏敏感性和特异性,因此,迫切需要寻找一种新的标志物来提高卵巢癌的诊断。人附睾蛋白4(human epididymis protein 4,HE4)是近年发现的肿瘤标志物,其在良性肿瘤和正常组织中含量极低,但在卵巢癌中高表达。本文就HE4在卵巢癌中的诊断,动态监测等方面的进展做一综述。     

Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility

Human epididymis protein 4 (HE4) is a novel and specific biomarker for epithelial ovarian cancer (EOC). We previously demonstrated that serum HE4 levels were significantly elevated in the majority of EOC patients but not in subjects with benign disease or healthy controls. However, the precise mechanism of HE4 protein function is unknown. In this study, we generated HE4-overexpressing SKOV3 cells and found that stably transduced cells promoted cell adhesion and migration. Knockdown of HE4 expression was achieved by stable transfection of SKOV3 cells with a construct encoding a short hairpin DNA directed against the HE4 gene. Correspondingly, the proliferation and spreading ability of HE4-expressed cells were inhibited by HE4 suppression. Mechanistically, impaired EGFR and Erk1/2 phosphorylation were observed in cells with HE4 knockdown. The phosphorylation was restored when the knockdown cells were cultured in conditioned medium containing HE4. Moreover, in vivo tumorigenicity showed that HE4 suppression markedly inhibited the growth of tumors. This suggests that expression of HE4 is associated with cancer cell adhesion, migration and tumor growth, which can be related to its effects on the EGFR-MAPK signaling pathway. Our results provide evidence of the cellular and molecular mechanisms that may underlie the motility-promoting role of HE4 in EOC progression. The role of HE4 as a target for gene-based therapy might be considered in future studies.