CN114480657A - 一种卵巢癌的标志物及其应用 - Google Patents
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Abstract
本发明属于医药生物技术领域,具体涉及一种卵巢癌的标志物及其应用。本发明首次提出PRPF6在卵巢癌中表达水平与FIGO分期密切相关,与年龄、分化程度和淋巴结转移无关。通过PCR、免疫组织化学等方法检测卵巢癌耐药细胞/组织中PRPF6基因及其编码蛋白的表达水平,发现PRPF6在耐药细胞/组织中高表达,明确了PRPF6可以作为卵巢癌紫杉醇耐药标志物。而抑制PRPF6的表达水平,可以抑制紫杉醇耐药性,减少卵巢癌细胞的侵袭和迁移,诱导细胞凋亡,抑制肿瘤生长,提示PRPF6抑制剂可作为卵巢癌紫杉醇化疗耐药治疗的潜在靶点,为临床上对化疗药物耐药型卵巢癌的诊断及治疗提供参考依据,具有广阔的应用前景和巨大的潜在社会效益。
Description
技术领域
本发明属于医药生物技术领域,具体涉及一种卵巢癌的标志物及其应用。
背景技术
卵巢癌(Ovarian Cancer,OC)是全球发病率和死亡率较高的女性恶性肿瘤之一。由于卵巢癌患者早期临床表现无明显特异性,在我国早期诊断率较低,就诊的卵巢癌患者大多数已属于晚期,尽管细胞减压术联合放化疗,5年生存率很低。紫杉醇(Paclitaxel)是目前具有广泛使用的抗肿瘤的化疗药物。然而,长期治疗可以使肿瘤细胞对其产生耐药性,这是导致化学治疗失败的主要原因。因此,对卵巢癌化疗耐药展开深入的研究,寻找有效的、可靠的耐药性标志物,开发逆转耐药性的相关药物,对于提高卵巢癌患者预后,降低死亡率具有重要意义。
前体RNA加工因子6(pre-mRNA pressing factor,PRPF6)作为一种RNA结合蛋白,介导多种癌症中可变剪切的调节,增加具有癌基因功能的亚型的表达,促进肿瘤的增殖和转移。说明抑制PRPF6有助于抑制多种癌症的发生发展。PRPF6在结直肠癌、前列腺癌和肝细胞癌中充当癌基因。PRPF6的功能在包括卵巢癌在内的其他癌症中未见报道。而进一步研究其在卵巢癌发生发展中的作用,对于卵巢癌的早起诊断以及预后都具有非常重要的帮助。
发明内容
针对上述问题,本发明提供一种卵巢癌的标志物及其应用。通过本发明的研究,明确了PRPF6可以作为卵巢癌紫杉醇耐药标志物,敲低PRPF6抑制紫杉醇耐药性,而高表达PRPF6促进紫杉醇耐药性,说明PRPF6可能作为卵巢癌治疗的潜在治疗策略。
为了实现上述目的,本发明提供了如下技术方案。
本发明提供了一种PRPF6基因及其编码的蛋白的表达水平的检测试剂在制备辅助诊断化疗药物耐药/敏感型卵巢癌的产品中的应用。
进一步地,所述化疗药物为紫杉醇。
进一步地,所述产品通过逆转录PCR、实时定量PCR、免疫组织化学染色或酶联免疫吸附检测样本中PRPF6基因及其编码的蛋白的表达水平。
进一步地,所述产品中含有扩增PRPF6的特异性引物、与PRPF6核苷酸序列杂交的探针或与其蛋白特异性结合的抗体。
优选地,扩增PRPF6的特异性引物序列如序列表SEQ ID NO.1-2所示;所述抗体为单克隆抗体或多克隆抗体。
本发明还提供了PRPF6基因的表达水平的抑制剂在制备治疗化疗药物耐药型的卵巢癌的药物中的应用。
进一步地,所述药物通过抑制PRPF6基因的表达水平抑制化疗药物耐药型卵巢癌细胞的侵袭、迁移、生长。
进一步地,所述PRPF6的表达抑制剂包括特异性siRNA,所述siRNA的序列如SEQ IDNO.3所示。
进一步地,所述化疗药物为紫杉醇。
进一步地,所述药物与紫杉醇联合用药。
与现有技术相比本发明的有益效果。
本发明提供了一种PRPF6的新用途,具体将PRPF6应用于卵巢癌紫杉醇化疗耐药检测。本发明首次提出PRPF6在卵巢癌耐药组织中上调,并与FIGO分期密切相关。PRPF6在体内外可促进卵巢癌细胞的进展、转移、上皮间质转化和紫杉醇抗性。
附图说明
图1. PRPF6在化疗耐药组织中表达情况研究。A为PRPF6在SKOV3和SKOV3-TR30细胞中表达情况。B为化疗耐药/敏感卵巢癌组织中表达情况。
图2.PRPF6在卵巢癌细胞中和体内促进肿瘤发生、上皮间质转化和紫杉醇抗性。A为CCK8显示敲低PRPF6和过表达PRPF6对SKOV3和SKOV3-TR30细胞的影响。B为克隆实验结果。C为Transwell分析敲低PRPF6和过表达PRPF6对细胞侵袭和迁移的影响。D为药物敏感性分析敲低PRPF6和过表达PRPF6对紫杉醇耐药性的影响。E为流式细胞仪显示敲低PRPF6和过表达PRPF6对细胞凋亡的影响。F为敲低PRPF6对荷瘤鼠模型肿瘤生长的影响。G为敲低PRPF6对肿瘤生长的影响。H为敲低PRPF6对肿瘤重量的影响。I为敲低PRPF6对GATA3、N-cadherin、Vimentin 、β-tubulin III 和E-cadherin的影响。
具体实施方式
下面结合具体实施例对本发明做详细的说明,但这些实施例仅为了对本发明加以说明,本发明并不限于这些内容。
一、实验方法。
1. 研究中使用的所有组织均来自2017年至2020年在中国医科大学盛京医院妇产科治疗的132名卵巢癌患者。本实验方案经中国医科大学盛京医院伦理委员会批准。
2.人卵巢癌细胞系SKOV3是从中国医学科学院肿瘤细胞库(北京)获得的。人卵巢癌紫杉醇耐药细胞SKOV3-TR30由浙江大学附属妇产科医院(杭州)提供。细胞使用RPMI-1640培养基加入10%胎牛血清,1%青霉素链霉素双抗于37℃恒温和5%CO2培养。SKOV3-TR30培养基中加入20nM的紫杉醇。耐药细胞于实验前1周停止加药培养,选取对数期细胞进行后续实验。
3. Real-Time PCR:使用TRIzol试剂从细胞中提取RNA。mRNA用gDNA EraserPrimeScriptTM RT Reagent Kit逆转录为cDNA。利用SYBR Premix Ex Taq 将cDNA添加到20μL系统中。采用TB Green Premix Ex Taq II试剂盒 (Takara)进行实时定量PCR。将mRNA表达归一化至β-Actin,β-Actin的引物序列如序列表SEQ ID NO.4-5所示),通过计算2-ΔΔCt进行相对定量。所有实验重复三次。
4. 细胞转染:将待转染的细胞均有铺至6孔板内,密度为30-50%。培养24小时后显微镜观察细胞状态至细胞融合度达到50-70%,更换培养基为无血清无双抗的培养基。向新1.5mL离心管内加入200μL jetPRIME buffer,2μg质粒DNA溶液或25nM siRNA溶液,4μLjetPRIME转染试剂。混合均匀后室温静置10分钟。将混合液转移至6孔板中,补充无血清无双抗培养基至终体积为1mL。4-6小时后更换为含血清培养基。
5. Transwell实验:将小室放于24孔板中,向上室内加入50000个细胞/200μL无血清培养基,下室加入600μL含10%血清的培养基,孵育48小时。取出小室,PBS冲洗3次,甲醇固定5min。PBS清洗3次,1%结晶紫染色5分钟。PBS清洗3次后,用棉签擦去上室内细胞。将小室膜切下,放置于载玻片上,外室面朝上,中性树胶封片。显微镜下随机任取5个视野拍照并计数细胞。
6. 细胞侵袭实验:向上室内预先加入50μL Matrigel胶(Matrigel胶与无血清培养基1:10比例配置)。37℃孵育2-4小时后,基质胶凝固后,余下步骤同细胞迁移实验。
7.CCk8细胞活力的检测:收集各组细胞,在1640培养基中重悬。将细胞添加到96孔板上,密度为2000个/孔,置于37℃,5% CO2的培养箱中培养。分别在0、24、48、72 和 96小时测定细胞活力。不同浓度的紫杉醇组和未处理组分别设置5个复孔。每孔加入10微升CCK8试剂,37℃孵育2小时。用酶标仪测量在450nm下的吸光度。
8. 克隆形成实验:取对数期细胞,胰酶消化细胞,收集细胞后2000rpm离心5分钟,弃上清。用培养基重悬细胞并计数,在6孔板每孔加入1000个细胞。37℃,5%CO2条件下培养2-3周,直至培养皿中出现肉眼可见的克隆时,终止培养。弃去旧培养基,PBS清洗2-3次。4%多聚甲醛室温固定15分钟。去除固定液后,加入1%结晶紫染液染色10分钟。PBS洗去染色液后室温晾干。培养皿拍照后使用Image J计数克隆。
9. 细胞凋亡检测:收集各组细胞,预冷PBS洗涤2次,500µL缓冲液重悬。采用凋亡检测试剂盒检测细胞凋亡情况。加入Annexin V-FITC或Annexin PE,孵育15分钟后加入PI或7-AAD染料。孵育10分钟后,用流式细胞仪检测细胞凋亡率。
10. Western Blot实验:用RIPA裂解缓冲液和磷酸酶抑制剂收获细胞和组织蛋白。采用BCA蛋白检测试剂盒测定蛋白浓度。将37.5µg蛋白和5X加载缓冲液的混合物添加到15% SDS-聚丙烯酰胺凝胶中进行电泳。通过上述工艺将其转移到PVDF膜上。将膜在5%脱脂乳TBST缓冲液中室温封闭1小时,然后与一抗在4˚C孵育过夜。用TBST缓冲液冲洗膜3次后,将其与相应的山羊抗小鼠IgG抗体或山羊抗兔IgG抗体在室温下结合1小时。采用ImageJ软件用密度法测定蛋白质相对量。多克隆兔抗β-actin抗体作为负载对照。
11. 免疫组织化学(IHC):石蜡切片进行脱蜡,通过加入柠檬酸盐缓冲液(pH 6.1)进行抗原回收。然后将切片与在5%牛血清白蛋白稀释的PRPF6抗体一起孵育,然后进行DAB染色和显微镜下观察。
12. 裸鼠成瘤实验:用含有siPRPF6序列的慢病毒感染SKOV3-TR30细胞,获得稳定转染的细胞。4周龄雌性BALB/cA-nu小鼠(3只/组)购自中国北京华阜康。小鼠被随机分为四组。小鼠背部皮下接种稳定转染细胞悬液(5×106 细胞)观察肿瘤生长。1周后,当肿瘤大小达到80-100mm 3时,每3天向肿瘤内注射紫杉醇(20 mg/kg)或生理盐水,持续3周。
13. 数据采用SPSS 24.0软件进行统计分析,以均属±标准差描述数据,两独立样本数据的统计学差异使用T检验分析,单因素方差分析用于比较多项组间数据的统计学差异,四格表类型计数资料采用卡方检验。使用GraphPad Prism 9进行统计图片的绘制。*P<0.05,**P<0.01,***P<0.001,有统计学差异。
实施例1 PRPF6在化疗耐药组织中上调,与卵巢癌的FIGO期有关。
为探讨PRPF6在化疗耐药组织中的表达差异,我们分析了PRPF6在化疗敏感型卵巢癌细胞系SKOV3和化疗耐药细胞系SKOV3-TR30中有差异表达。通过PCR检测发现,与SKOV3相比,PRPF6在SKOV3-TR30中相对上调(图1A)。IHC用于检测原发性癌组织中PRPF6的表达。PRPF6在化疗耐药卵巢癌组织(N=20)中相对高于化疗敏感组织(N=32,图1B)。然后,我们研究了PRPF6表达与临床病理特征的关系。结果表明,PRPF6与FIGO分期密切相关,与年龄、分化程度和淋巴结转移无关(表1)。
表1. PRPF6与FIGO、年龄、分化程度和淋巴结转移相关性分析
实施例2PRPF6在卵巢癌细胞中和体内促进肿瘤发生、上皮间质转化和紫杉醇抗性。
PRPF6的siRNA转染入SKOV3-TR30细胞,并将过表达质粒PC-DNA3.1-PRF6稳定转染入SKOV3细胞。CCK结果显示敲低PRPF6和过表达PRPF6分别显著抑制和促进细胞生长(图2A)。克隆形成试验也显示出类似的效果(图2B)。Transwell分析表明敲低PRPF6导致细胞侵袭和迁移减少,而过表达PRPF6导致侵袭和迁移增加(图2C)。药物敏感性实验表明敲低PRPF6抑制紫杉醇耐药性,而高表达PRPF6促进紫杉醇耐药性(图2D)。流式细胞术显示敲低PRPF6诱导细胞凋亡,过表达PRPF6则相反(图2E)。构建敲低PRPF6荷瘤鼠模型结果提示(图2F),与NC相比,结果显示敲低PRPF6抑制肿瘤生长和重量(图2G&H)。WB结果提示敲低PRPF6抑制GATA3、N-cadherin、Vimentin和β-tubulin III的表达,上调E-cadherin(图2I)。
综上,本发明证明了PRPF6应用于卵巢癌紫杉醇化疗耐药检测。抑制PRPF6可抑制紫杉醇耐药性,而高表达PRPF6促进紫杉醇耐药性,敲低PRPF6导致细胞侵袭和迁移减少,诱导细胞凋亡,抑制肿瘤生长和重量。提示PRPF6可作为卵巢癌紫杉醇化疗耐药治疗的潜在靶点。
Claims (10)
1.PRPF6基因及其编码的蛋白的表达水平的检测试剂在制备辅助诊断化疗药物耐药/敏感型卵巢癌的产品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述化疗药物为紫杉醇。
3.根据权利要求1所述的应用,其特征在于,所述产品通过逆转录PCR、实时定量PCR、免疫组织化学染色或酶联免疫吸附检测样本中PRPF6基因及其编码的蛋白的表达水平。
4.根据权利要求1所述的应用,其特征在于,所述产品中含有扩增PRPF6的特异性引物、与PRPF6核苷酸序列杂交的探针或与其蛋白特异性结合的抗体。
5.根据权利要求4所述的应用,其特征在于,扩增PRPF6的特异性引物序列表SEQ IDNO.1-2;所述抗体为单克隆抗体或多克隆抗体。
6.PRPF6基因的表达水平的抑制剂在制备治疗化疗药物耐药型的卵巢癌的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述药物通过抑制PRPF6基因的表达水平抑制化疗药物耐药型卵的巢癌细胞的侵袭、迁移、生长。
8.根据权利要求6所述的应用,其特征在于,所述PRPF6的表达抑制剂包括特异性siRNA,所述siRNA的序列SEQ ID NO.3所示。
9.根据权利要求6所述的应用,其特征在于,所述化疗药物为紫杉醇。
10.根据权利要求6所述的应用,其特征在于,所述药物与紫杉醇联合用药。
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