CN117467771A - 一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其应用 - Google Patents
一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其应用 Download PDFInfo
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Abstract
本发明公开了一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其应用。所述标志物包括牙龈卟啉单胞菌。本发明利用牙龈卟啉单胞菌特异性抗体对90例人宫颈鳞状细胞癌病理切片进行免疫组化染色和荧光原位杂交,检测到牙龈卟啉单胞菌在肿瘤组织中更为富集;发现在宫颈鳞状细胞癌患者中,牙龈卟啉单胞菌感染与远端转移和淋巴结转移相关,与更差的生存预后相关;体外实验发现牙龈卟啉单胞菌选择性的入侵宫颈鳞癌细胞,入侵后的细胞迁移能力显著增强。以上表明牙龈卟啉单胞菌感染可作为预测宫颈鳞状细胞癌转移和预后的新标记物以及治疗靶点。
Description
技术领域
本发明属于生物医药技术领域,涉及一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其应用。
背景技术
宫颈癌是女性生殖系统最常见的一种恶性肿瘤,发病率和致死率排在女性恶性肿瘤的前列,主要发生在40岁至60岁之间,是严重威胁女性生命健康的社会重大公共卫生问题。按组织学不同分为宫颈鳞状细胞癌(cervical squamous cell carcinoma,CSCC)、宫颈腺癌及其他特殊类型宫颈癌,其中CSCC占宫颈癌的75%~80%,是宫颈癌诊治的重点。目前对临床治疗最有意义的标记物为鳞状细胞癌抗原,但其特异性和敏感性仅为60%,对判断是否有淋巴结转移及预后的价值较低。而宫颈癌一旦出现转移,将导致治疗手段受限和治疗效果不佳,预后较差。因此,寻找其他更具有意义的转移和预后的肿瘤标记物仍然是临床上宫颈癌亟待解决的重要问题。
感染人类乳头状瘤病毒(HPV)是宫颈癌发病的必要非充分条件,越来越多的证据表明阴道菌群在HPV感染中及宫颈癌发病中扮演了重要角色。根据近10年的研究报道发现肿瘤组织存在肿瘤特异性的微生物,瘤内微生物是影响预后和个性化诊疗的重要因素。因此,瘤内微生物具有成为肿瘤转移和预后标志物的巨大潜力。在女性生殖道中存在众多的细菌微生物,其数量和种类的动态平衡,是维持生殖道健康的关键。其中生殖道菌群以革兰氏阴性厌氧菌为主,因此其成为重要的机会致病菌。
牙龈卟啉单胞菌是一种非酵解糖的革兰氏阴性厌氧球杆菌,是重要牙周致病菌之一。近来研究报道,牙龈卟啉单胞菌与多种肿瘤的发展转移等恶性化进展相关,如口腔鳞癌、食管癌、结直肠癌、胰腺癌等。在结直肠癌患者中,肿瘤组织中的牙龈卟啉单胞菌富集,且牙龈卟啉单胞菌感染与更差的预后相关。目前流行病学证据表明牙龈卟啉单胞菌感染与先兆子痫、早产、自然流产、妊娠期糖尿病、胎儿生长受限等不良妊娠结局存在关联,但其在宫颈癌的丰度,以及是否与宫颈鳞状细胞癌发展、转移相关,尚未有报道。
综上所述,开发新的更具有临床意义的肿瘤转移和预后标记物,用于有效分析肿瘤得发展、转移及预后,对于为宫颈癌的诊疗具有重要意义。
发明内容
针对现有技术的不足和实际需求,本发明提供一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其应用,本发明深入分析牙龈卟啉单胞菌与宫颈鳞状细胞癌的的关联性,以开发新型预测宫颈鳞状细胞癌转移和预后的新标记物。
为达上述目的,本发明采用以下技术方案:
第一方面,本发明提供一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物,所述标志物包括牙龈卟啉单胞菌。
本发明中,利用牙龈卟啉单胞菌分别与正常宫颈上皮细胞和宫颈鳞癌细胞共培养,牙龈卟啉单胞菌选择性的入侵宫颈鳞癌细胞,并且牙龈卟啉单胞菌入侵后的宫颈鳞癌细胞具有更高的迁移能力。表明牙龈卟啉单胞菌选择性的入侵宫颈鳞癌细胞并与细胞迁移能力增强显著相关。
本发明中,利用牙龈卟啉单胞菌特异性抗体对人宫颈鳞状细胞癌病理切片进行免疫组化染色和荧光原位杂交染色,检测到宫颈鳞状细胞癌肿瘤组织中存在牙龈卟啉单胞菌,与癌旁正常上皮组织相比,牙龈卟啉单胞菌在肿瘤组织中更为富集,对免疫染色结果进行评分,与临床特征信息统计分析,发现在宫颈鳞状细胞癌患者中,牙龈卟啉单胞菌感染与远端转移和淋巴结转移相关,与更差的生存预后相关,表明牙龈卟啉单胞菌感染可作为预测宫颈鳞状细胞癌转移和预后的新标记物。
第二方面,本发明提供第一方面所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其检测试剂在制备预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的产品中的应用。
优选地,所述检测试剂包括通过测序技术、核酸杂交技术、核酸扩增技术或蛋白免疫技术等检测牙龈卟啉单胞菌丰度的试剂。
第三方面,本发明提供一种预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的产品,所述产品包括检测第一方面所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物的试剂和/或设备。
优选地,所述产品包括制剂、核酸膜条、芯片或试剂盒。
第四方面,本发明提供第一方面所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物在制备预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的装置中的应用。
第五方面,本发明提供一种预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的装置,所述装置包括检测单元和分析单元,所述检测单元用于执行包括:检测待测样本中牙龈卟啉单胞菌的丰度;所述分析单元用于执行包括:根据检测单元获得的牙龈卟啉单胞菌的水平预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后。
优选地,所述预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的标准为牙龈卟啉单胞菌丰度的高低。
优选地,所述待测样本包括宫颈鳞状细胞癌活检组织病理切片、宫颈鳞状细胞癌锥切组织病理切片。
第六方面,本发明提供第一方面所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物作为治疗靶点在制备或筛选治疗宫颈鳞状细胞癌的药物中的应用。
与现有技术相比,本发明具有以下有益效果:
本发明利用牙龈卟啉单胞菌特异性抗体对人宫颈鳞状细胞癌病理切片进行免疫组化染色,检测到宫颈鳞状细胞癌肿瘤组织中存在牙龈卟啉单胞菌,与癌旁正常上皮组织相比,牙龈卟啉单胞菌在肿瘤组织中更为富集,对免疫染色结果进行评分,与临床特征信息统计分析,发现在宫颈鳞状细胞癌患者中,牙龈卟啉单胞菌感染与远端转移和淋巴结转移相关,与更差的生存预后相关,表明牙龈卟啉单胞菌感染可作为预测宫颈鳞状细胞癌转移和预后的新标记物以及治疗靶点。
附图说明
图1为宫颈鳞状细胞癌肿瘤组织及癌旁组织免疫组化染色图;
图2为宫颈鳞状细胞癌肿瘤组织及癌旁组织荧光原位杂交染色图;
图3为牙龈卟啉单胞菌丰度与宫颈鳞状细胞癌预后关系图;
图4A为牙龈卟啉单胞菌选择性入侵宫颈鳞癌荧光检测图;
图4B为为牙龈卟啉单胞菌选择性入侵宫颈鳞癌荧光检测结果统计图;
图5A为牙龈卟啉单胞菌选择性入侵宫颈鳞癌细胞Transwell结果图;
图5B为牙龈卟啉单胞菌选择性入侵宫颈鳞癌细胞Transwell结果统计图。
具体实施方式
为进一步阐述本发明所采取的技术手段及其效果,以下结合实施例和附图对本发明作进一步地说明。可以理解的是,此处所描述的具体实施方式仅仅用于解释本发明,而非对本发明的限定。
实施例中未注明具体技术或条件者,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购获得的常规产品。
实施例1
本实施例进行病例收集。
收集2016年09月至2021年12月在广东省珠海市中山大学附属第五医院接受宫颈癌手术治疗的90例患者的福尔马林固定石蜡包埋组织标本。病理入组标准:1.年龄25-80岁之间;2.接受子宫颈锥形切除术和子宫广泛根治性切除术;3.术后病理证实为宫颈鳞状细胞癌。肿瘤的TNM分期根据第8版AJCC分期手册进行评估,肿瘤的分化程度由中山大学附属第五医院病理科资深病理医生评估。
实施例2
本实施例进行免疫组化染色及统计分析。
将实施例1收集病理切片从4℃冰箱中放入65℃烘箱中30min,按以下程序进行脱蜡复水:二甲苯I:10min、二甲苯II:10min、无水乙醇:10min95%乙醇:3min、80%乙醇:3min、70%乙醇:3min、50%乙醇:3min。将柠檬酸钠抗原修复液(pH=9.0)加入修复盒中,放于微波炉加热10min,使温度接近100℃,将复水后的切片放于修复液中,在微波炉中低火力加热10min(温度维持在95℃至100℃),然后自然冷却至25℃,用免疫组化笔沿组织周围封闭画圈,滴加试剂盒中的过氧化物酶去除剂5min,用PBS洗2遍,每遍3min。
使用牙龈卟啉单胞菌特异性抗体对90例人宫颈鳞状细胞癌病理切片进行免疫组化染色,按抗体说明书配置一抗,滴加一抗,放于湿盒4℃冰箱过夜。将切片经PBS润洗3次,每次5min。滴加二抗,放于湿盒中,25℃孵育1h。孵育后用PBS洗2遍,每遍3min。配制DAB显色液,滴加显色液,待染色至合适深度即可用PBS洗去终止染色。将切片浸于苏木精染液中10min,浸泡在1%的盐酸乙醇溶液中5s,然后放入PBS中返蓝10min。然后按以下流程进行脱水:50%乙醇3min,70%乙醇3min,80%乙醇3min,90%乙醇3min,95%乙醇3min,无水乙醇10min;二甲苯I10min,二甲苯II 10min。在组织上滴加中性树脂,将盖玻片轻轻盖上,放于通风橱过夜,用3D Histech病理切片扫描系统扫片。由两位经验丰富的病理医师对组织切片的染色情况进行评估。
使用GraphPad Prism软件(9.3.0版,美国)进行统计分析。Welch校正的非配对t检验用于两组间比较,临床数据一般特征用平均数(mean)±标准差(SD)表示,其他统计结果用或平均数±标准差(standard error ofmean)表示,P值小于0.05被认为差异具有统计学意义。
实施例3
本实施例进行荧光原位杂交染色及统计分析。
1.探针变性:将探针在75℃恒温水浴中温育5min,立即置0℃,8min,使双链DNA探针变性。
2.标本变性:将制备好的染色体玻片标本于50℃培养箱中烤片3h。取出玻片标本,将其浸在73℃的体积分数70%甲酰胺/2×SSC的变性液中变性2min。立即按顺序将标本经体积分数70%、体积分数90%和体积分数100%冰乙醇系列脱水,每次5min,然后空气干燥。本实施案例中pg的绿色荧光探针和标记细菌的EUB338红色荧光探针。
3.杂交反应:将已变性或预退火的DNA探针10μL滴于已变性并脱水的玻片标本上,盖上18×18盖玻片,用Parafilm封片,置于潮湿暗盒中37℃杂交过夜(约15~17h)。
4.洗涤:进行多次的洗涤步骤,以去除未与待测DNA配对的自由探针。
5.反应可视化:通过荧光显微镜观察样品。荧光标记的探针会发出荧光信号,标记出待测序列的位置和数量。详细操作步骤参照实施例2。
实施例4
本实施例进行牙龈卟啉单胞菌分别与正常宫颈上皮细胞以及宫颈鳞癌细胞共培养。
1.在体外对宫颈鳞癌上皮细胞系SiHa和正常宫颈上皮细胞HCEC进行细胞爬片,根据MOI=50与P.gingivalis共培养。
2.鬼笔环肽染色:细胞爬片用4%PFA中固定10分钟,用PBS清洗2次。使用鬼笔环肽染色(Phalloidin-iFluor 594),加入DAPI染核(20ug/uL)15分钟。抗荧光淬灭剂封片,使用激光共聚焦显微镜进行图像采集。
实施例5
本实施例进行牙龈卟啉单胞菌与宫颈鳞癌细胞共培养前后细胞迁移能力检测和分析。
在体外对宫颈鳞癌上皮细胞系SiHa进行饥饿,然后与P.gingivalis共培养通过transwell实验检测对肿瘤细胞迁移能力的强弱。Transwell的上室加入无血清培养基重悬的细胞+P.gingivalis,下室加入完全培养基。在相应的时间点收取transwell小室,通过统计迁移细胞的数目来比较细胞迁移能力的强弱。
Transwell迁移实验具体操作步骤如下:将处于生长对数期的细胞消化下来,用无胎牛血清的基础培养基重悬细胞,细胞计数为2×105个/孔。取出transwell小室,将细胞悬液均匀铺在小室上层,上层加入37℃预热的无胎牛血清培养基200μL,下层加入37℃预热的700μL含10%胎牛血清、1%青霉素/链霉素的完全培养基。将培养板放置于5%CO2、37℃培养箱中培养,待24h后收集小室,吸去上下层的培养基,用PBS轻柔清洗小室。加入4%多聚甲醛固定15min,加结晶紫染液染色10min,用自来水清洗多余染液,再用棉签擦去小室内的细胞和小室外的水,烘干后倒置显微镜观察并拍照记录。使用image J软件通过图像分析计数染色细胞个数,并使用GraphPadprism 8.0软件进行统计分析。结果显示(图4A和图4B,HCEC:正常宫颈上皮细胞,SiHa:CSCC细胞):在MOI:50和100的P.gingivalis刺激下,食管上皮细胞系表现出显著的小室迁移能力(图5A和图5B)。
图1和图2为宫颈鳞状细胞癌肿瘤组织及癌旁组织免疫组化染色图和荧光原位杂交染色图,表明在宫颈鳞状细胞癌肿瘤组织中存在牙龈卟啉单胞菌,与癌旁正常上皮组织相比,牙龈卟啉单胞菌在肿瘤组织中更为富集;对免疫染色结果进行评分,与临床特征信息统计分析,发现在宫颈鳞状细胞癌患者中,牙龈卟啉单胞菌感染与远端转移和淋巴结转移相关(表1),与更差的生存预后相关(图3),表明牙龈卟啉单胞菌感染可作为预测宫颈鳞状细胞癌转移和预后的新标记物。
其中详细的评分标准如下:1)阳性着色强度:无色为0分,淡黄色为1分,棕黄色为2分,棕褐色为3分。2)阳性着色细胞数:每张切片上观察正常组织和肿瘤组织染色情况,按阳性结果计算面积,所得结果少于5%,0分;5%-25%,1分;26%-50%,2分;51%-75%,3分;大于75%,4分。3)二者计数相乘为阳性等级,0分为阴性(-),1-4分为阳性(+),5-8分为中阳性(++),大于9分为强阳性(+++)。免疫组化的阴性(-)和阳性(+)定义为低细菌丰度;将中阳性(++)和强阳性(+++)定义为高细菌丰度。
图4A和图4B表示牙龈卟啉单胞菌分别与宫颈正常上皮细胞和宫颈鳞癌细胞共培养,牙龈卟啉单胞菌选择性粘附/入侵宫颈鳞癌细胞结果。图5A和图5B表示牙龈卟啉单胞菌入侵宫颈鳞癌细胞前后细胞迁移能力变化结果,表明牙龈卟啉单胞菌促进宫颈鳞癌细胞迁移。
表1
综上所述,本发明利用牙龈卟啉单胞菌特异性抗体和CD151抗体对90例人宫颈鳞状细胞癌病理切片进行免疫组化染色,检测到在宫颈鳞状细胞癌肿瘤组织中存在牙龈卟啉单胞菌,与癌旁正常上皮组织相比,牙龈卟啉单胞菌在肿瘤组织中更为富集;对免疫染色结果进行评分,与临床特征信息统计分析,发现在宫颈鳞状细胞癌患者中,牙龈卟啉单胞菌感染与远端转移和淋巴结转移相关,与更差的生存预后相关,表明牙龈卟啉单胞菌感染可作为预测宫颈鳞状细胞癌转移和预后的新标记物。
申请人声明,本发明通过上述实施例来说明本发明的详细方法,但本发明并不局限于上述详细方法,即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物,其特征在于,所述标志物包括牙龈卟啉单胞菌。
2.权利要求1所述的一种与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物,其特征在于,所述标志物为牙龈卟啉单胞菌的丰度。
3.权利要求1所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物及其检测试剂在制备预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的产品中的应用。
4.根据权利要求3所述的应用,其特征在于,所述检测试剂包括通过测序技术、核酸杂交技术、核酸扩增技术或蛋白免疫技术检测牙龈卟啉单胞菌丰度的试剂。
5.一种预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的产品,其特征在于,所述产品包括检测权利要求1所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物的试剂和/或设备。
6.根据权利要求5所述的预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的产品,其特征在于,所述产品包括制剂、核酸膜条、芯片或试剂盒。
7.权利要求1所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物在制备预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的装置中的应用。
8.一种预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后的装置,其特征在于,所述装置包括检测单元和分析单元;
所述检测单元用于执行包括:
检测待测样本中牙龈卟啉单胞菌的细胞丰度;
所述分析单元用于执行包括:
根据检测单元获得的牙龈卟啉单胞菌的水平预测宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后。
9.根据权利要求8所述的装置,其特征在于,所述待测样本包括宫颈鳞状细胞癌活检组织病理切片、宫颈鳞状细胞癌锥切组织病理切片。
10.权利要求1所述的与宫颈鳞状细胞癌的淋巴结转移、远端转移和生存预后相关的标志物作为治疗靶点在制备或筛选治疗宫颈鳞状细胞癌的药物中的应用。
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