CN107502658A - 针对epcr基因或epcr蛋白的表达制备癌症诊断和治疗产品的方法 - Google Patents
针对epcr基因或epcr蛋白的表达制备癌症诊断和治疗产品的方法 Download PDFInfo
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Abstract
本发明公开了一种针对EPCR基因或EPCR蛋白的表达制备癌症诊断、治疗产品的方法及诊断试剂盒。具体地，所述癌症诊断产品为用实时荧光定量PCR诊断癌症的产品或免疫检测诊断的产品。所述实时荧光定量PCR诊断癌症的产品包括一对特异性针对EPCR的引物及探针。所述癌症治疗药物包括抑制EPCR基因表达和/或抑制EPCR蛋白活性的物质。本发明为癌症诊断和治疗提供了新的有效途径。
Description
技术领域
本发明涉及针对EPCR基因或EPCR蛋白的表达制备癌症诊断和治疗产品的方法。
背景技术
恶性肿瘤是严重危害人类健康的高发病率和高致死率的疾病。近年来许多实验及临床观察证实，凝血酶及其受体具有促进肿瘤生长和转移的作用。事实上，肿瘤细胞既有促凝活性又有纤溶活性，因为许多肿瘤细胞表面能够表达纤溶系统所需的全部蛋白，从而降解多种细胞外基质，有利于肿瘤周围胶原组织水解，促进肿瘤细胞向临近组织侵袭和转移。由此可见，恶性肿瘤发病的各个阶段均不同程度的涉及止凝血障碍和纤溶机制的异常。
内皮细胞蛋白C受体(Endothelial cell protein C receptor，EPCR)是蛋白C抗凝途径新发现的成员，也是继血栓调节蛋白之后在肿瘤细胞表面发现的另一种与抗凝相关的蛋白。EPCR的基因如序列表中SEQ ID NO.1号序列所示。EPCR的蛋白如序列表中sequenceID No.2号序列所示。已有的研究表明EPCR可通过与活化蛋白C(APC)结合激活蛋白酶活化受体(PAR-1)，促进细胞增殖及抑制凋亡，EPCR在此过程中起着关键的介导作用；新近发现，APC通过与细胞表面的EPCR及PAR-1结合可呈浓度依赖型的提高乳腺癌细胞株的迁移性和趋化性，提示肿瘤细胞和组织EPCR的过度表达有利于其增殖，抑制细胞凋亡，从而促进肿瘤的进展和转移。因此，EPCR除了参与抗凝和调节炎症反应外，还参与抑制细胞凋亡与肿瘤的耐药和转移等诸多病理过程。
人EPCR的cDNA含1302个碱基，开放阅读框含有714个氨基酸，编码238个氨基酸，在加工过程中去除17个氨基酸信号肽，即成为221个氨基酸组成的成熟蛋白。EPCR是相对分子质量为46KD的I型跨膜蛋白，其由胞外区、跨膜区和一个短的高度保守的胞浆尾组成。细胞膜上的EPCR属于结合型EPCR，另外血浆中还存在可溶性的EPCR(rEPCR)，同样具有与蛋白C及APC结合能力。新近研究证实，EPCR在肺癌、乳腺癌、卵巢癌、肾癌、结肠癌、恶性胶质瘤、黑色素瘤等多种肿瘤细胞及白血病细胞中均具有表达，尤其是在恶性实体瘤当中。EPCR基因高表达是多种肿瘤细胞的重要特征，提示EPCR可作为癌症诊断的肿瘤标记物。
发明内容
本发明的目的在于提出一种针对EPCR基因或EPCR蛋白的表达制备癌症诊断和治疗产品的方法。
为解决上述技术问题，本发明通过如下技术方案实现：
一种针对EPCR基因或EPCR蛋白的表达制备癌症诊断产品的方法。
进一步地：
所述癌症诊断产品为用实时荧光定量PCR诊断癌症的产品或免疫检测诊断的产品。
所述实时荧光定量PCR诊断癌症的产品包括一对特异性针对EPCR的引物及探针。
所述引物及探针为如下序列：
EPCR-F：TCACCTTCACCCTGCAGCA，对应序列表中的SEQ ID NO.3号序列，
EPCR-R：TTGTTTGGCTCCCTTTCGTG，对应序列表中的SEQ ID NO.4号序列，
探针序列：GCTCAATGCCTACAACCGCACTCGG，对应序列表中的SEQ ID NO.5号序列。
所述用于免疫检测癌症诊断的产品包括与EPCR蛋白特异性结合的抗体。
优选地，所诉抗体的基因序列包括如序列表中的SEQ ID NO.6所示的重链可变区序列以及如序列表中的SEQ ID NO.7所示的轻链可变区序列。
一种用于癌症诊断的试剂盒，所述试剂盒包括特异性针对EPCR基因的引物及探针和/或特异性结合EPCR蛋白的抗体。
一种针对EPCR基因或EPCR蛋白的表达制备癌症治疗药物的方法。
进一步地：
所述癌症治疗药物包括抑制EPCR基因表达和/或抑制EPCR蛋白活性的物质。
所述癌症治疗药物包括通过RNA干涉抑制EPCR基因表达的核糖核酸，和/或抑制EPCR蛋白活性的蛋白质。
所述癌症包括：肺癌、卵巢癌、乳腺癌、肾瘤、前列腺癌、膀胱癌、黑色素瘤、多发性骨髓瘤。
一种针对EPCR基因或EPCR蛋白的表达筛选癌症治疗药物的方法，以EPCR基因作为靶点，筛选抗肿瘤药物。
本发明提供了针对EPCR基因及表达产物制备癌症诊断试剂的方法或试剂盒。根据本发明，EPCR基因及其表达产物还可作为癌症治疗药物的靶基因，可针对EPCR基因或EPCR蛋白的表达制备癌症治疗药物。从而，本发明提供了有效诊断和治疗癌症的新途径。
具体实施方式
下面结合具体实施方式对本发明作进一步详细说明。应该强调的是，下述说明仅仅是示例性的，而不是为了限制本发明的范围及其应用。未注明具体条件的实验方法，通常按常规条件中所述的方法进行。
实施例1实时定量PCR检测EPCR基因的差异表达
(1)引物及探针设计
采用Primer Premier 5.0软件对EPCR基因的引物及探针进行优化设计如下：
EPCR-F：TCACCTTCACCCTGCAGCA(对应序列表中的SEQ ID NO.3号序列)，
EPCR-R：TTGTTTGGCTCCCTTTCGTG(对应序列表中的SEQ ID NO.4号序列)，
探针序列：GCTCAATGCCTACAACCGCACTCGG(对应序列表中的SEQ ID NO.5号序列)。
(2)组织及细胞总RNA提取
1)采用TRIzol Reagent(Invitrogen)试剂抽提RNA，具体操作如下：将相关组织从液氮中取出，在研钵中研磨成粉末，转移至装有适量体积(1mL)TRIzol试剂的离心管中，充分匀浆；室温放置5分钟，按比例向离心管中加入氯仿(200μL/1ml TRIzol)，迅速剧烈振荡15秒，室温静置10分钟，4℃，12000rpm条件下离心15分钟；小心吸取上清至新的无RNA酶的EP管中，加入等体积的异丙醇，轻轻颠倒混匀，室温静置10分钟；4℃，12000rpm条件下离心10分钟后，小心吸去上清，加入2/5体积70％乙醇，轻轻混匀洗涤RNA；4℃，12000rpm条件下离心15分钟；弃上清，尽可能除尽残留乙醇，沉淀室温干燥5–10min；加入适量DEPC水充分溶解沉淀，采用无RNA酶的DNA酶I去除基因组DNA的污染；酶标仪测定RNA浓度及纯度OD 260/280(1.8–2.0)；凝胶电泳观察有无降解，－80℃保存。
2)细胞株RNA抽提，取对数生长期的细胞，吸取培养液，根据培养皿的面积加入相应量的TRIzol试剂(1mL TRIzol/10cm2)裂解细胞，吹打几次，将裂解下来的细胞收集至无RNA酶的EP管中，其余按照上述步骤完成氯仿—异丙醇法分离纯化RNA。
(3)cDNA制备
取2μg总RNA，依次加入Oligo(dT)1μL和DEPC水至20μL体系，70℃变性5min，迅速置冰上；然后加入5×逆转录缓冲液8μL、dNTP(10nmol/L)1μL、RNasin 0.5μL、M-MLV 1μL及DEPC水9.5μL，37℃1h，95℃5min后置冰上，-20℃保存备用。
(4)实时定量PCR
反应采用ABI 7500实时荧光定量PCR仪，PCR反应条件设置为：50℃2分钟，1个循环；95℃15分钟，1个循环；94℃15秒→55℃,45秒(收集荧光)，40个循环。保存文件，运行；设探针检测模式设置为：Reporter Dye：FAM，Quencher Dye：NONE，Passive Reference：NONE。
(5)结果分析
荧光本底信号和阈值采用仪器设置的默认值，每次PCR反应结束后会自动生成，分析条件设置：根据分析后图像调节Baseline的start值、stop值以及Threshold的Value值(用户可根据实际情况自行调整，Start值可以在3～15、End值可设在5～20，调整阴性对照的扩增曲线平直或低于阈值线)，点击Analysis自动获得分析结果，在Report界面察看结果。
(6)结果判定
如果检测样品的扩增曲线无对数增长期或Ct值＞38，可判样品为EPCR表达阴性；
如果检测样品Ct值≤38，且曲线有明显的对数增长期，可判样品为EPCR表达阳性。
实施例2EPCR在癌症细胞中的表达水平
(1)EPCR单克隆抗体制备方法
1)利用噬菌体展示技术进行初步筛选：表达并纯化EPCR蛋白，以此作为抗原；另用噬菌体展示的人类未免疫(naive)的抗体库进行筛选，得到可与EPCR蛋白相结合的候选抗体(约20-30个)。
2)利用ELISA技术对初筛得到的候选抗体进行亲和力测定：对初筛得到的抗体进行抗原特异性的ELISA测试，进一步得到亲和力好特异性强的抗体(3-5个)。
3)表达和纯化候选抗体：对候选抗体的基因序列进行测序，候选抗体由重链可变区(序列如SEQ ID NO.6所示)和轻链可变区(序列如SEQ ID NO.7所示)构成，分别将重链可变区和轻链可变区的基因序列克隆到真核细胞表达载体中，并转化到同一细胞中进行表达，表达完成后两者自动组装成一个完整的抗体，然后进行抗体的纯化。
(2)流式细胞术检测EPCR在癌症细胞中的表达
组织样本制备成单细胞悬液，调单细胞悬液浓度为±106细胞/μL。单细胞悬液分为2份，每份100μL。一份为处理组，加入一抗(上述抗EPCR单克隆抗体)，对照组与处理组同时置4℃孵育1小时；离心，以PBS洗3次，加入200μL PBS重悬。各加入FITC标记的羊抗鼠IgG(二抗)，室温避光反应25分钟。离心去除上清液，上机流式细胞仪检测、分析。
实施例3EPCR蛋白在癌症组织表达水平的检测
(1)组织样本制备成石蜡切片，并按常规步骤进行梯度脱蜡
(2)3％H 2O 2室温孵育5-10分钟，以消除内源性过氧化物酶的活性。
(3)蒸馏水冲洗3次，PBS浸泡5分钟。
(4)加5％-10％正常山羊血清封闭液，37℃孵育60分钟。
(5)吸掉多余的液体，不洗，加1:1,000稀释的抗EPCR单克隆抗体，37℃孵育过夜。
(6)PBS洗3次，每次5分钟。
(7)加入辣根过氧化物酶标记的二抗，37℃孵育30分钟。
(8)PBS洗3次，每次5分钟。
(9)显色剂显色3-15分钟
(10)自来水充分冲洗，复染，脱水，透明，封片。
实施例4抗肿瘤药物的筛选
以EPCR基因作为靶点，设计和筛选抗肿瘤药物。具体方法如下。
用候选药物处理高表达EPCR基因的实体肿瘤组织或细胞，然后检测上述肿瘤或细胞中EPCR基因或EPCR蛋白的表达水平。若候选物质可降低EPCR基因的表达，或降低过表达EPCR蛋白的活性，则表明该候选药物是能控制肿瘤发展的潜在物质。
以上内容是结合具体的/优选的实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，其还可以对这些已描述的实施例做出若干替代或变型，而这些替代或变型方式都应当视为属于本发明的保护范围。
序列表
<110> 深圳市亿立方生物技术有限公司
<120> 针对EPCR基因或EPCR蛋白的表达制备癌症诊断和治疗产品的方法
<130> 17A100304JYC
<160> 7
<210> 1
<211> 717
<212> DNA
<213> 智人（Homo sapiens）
<400> 1
atgttgacaa cattgctgcc gatactgctg ctgtctggct gggccttttg tagccaagac 60
gcctcagatg gcctccaaag acttcatatg ctccagatct cctacttccg cgacccctat 120
cacgtgtggt accagggcaa cgcgtcgctg gggggacacc taacgcacgt gctggaaggc 180
ccagacacca acaccacgat cattcagctg cagcccttgc aggagcccga gagctgggcg 240
cgcacgcaga gtggcctgca gtcctacctg ctccagttcc acggcctcgt gcgcctggtg 300
caccaggagc ggaccttggc ctttcctctg accatccgct gcttcctggg ctgtgagctg 360
cctcccgagg gctctagagc ccatgtcttc ttcgaagtgg ctgtgaatgg gagctccttt 420
gtgagtttcc ggccggagag agccttgtgg caggcagaca cccaggtcac ctccggagtg 480
gtcaccttca ccctgcagca gctcaatgcc tacaaccgca ctcggtatga actgcgggaa 540
ttcctggagg acacctgtgt gcagtatgtg cagaaacata tttccgcgga aaacacgaaa 600
gggagccaaa caagccgctc ctacacttcg ctggtcctgg gcgtcctggt gggcagtttc 660
atcattgctg gtgtggctgt aggcatcttc ctgtgcacag gtggacggcg atgttaa 717
<210> 2
<211> 238
<212> PRT
<213> 智人（Homo sapiens）
<400> 2
Met Leu Thr Thr Leu Leu Pro Ile Leu Leu Leu Ser Gly Trp Ala Phe
1 5 10 15
Cys Ser Gln Asp Ala Ser Asp Gly Leu Gln Arg Leu His Met Leu Gln
20 25 30
Ile Ser Tyr Phe Arg Asp Pro Tyr His Val Trp Tyr Gln Gly Asn Ala
35 40 45
Ser Leu Gly Gly His Leu Thr His Val Leu Glu Gly Pro Asp Thr Asn
50 55 60
Thr Thr Ile Ile Gln Leu Gln Pro Leu Gln Glu Pro Glu Ser Trp Ala
65 70 75 80
Arg Thr Gln Ser Gly Leu Gln Ser Tyr Leu Leu Gln Phe His Gly Leu
85 90 95
Val Arg Leu Val His Gln Glu Arg Thr Leu Ala Phe Pro Leu Thr Ile
100 105 110
Arg Cys Phe Leu Gly Cys Glu Leu Pro Pro Glu Gly Ser Arg Ala His
115 120 125
Val Phe Phe Glu Val Ala Val Asn Gly Ser Ser Phe Val Ser Phe Arg
130 135 140
Pro Glu Arg Ala Leu Trp Gln Ala Asp Thr Gln Val Thr Ser Gly Val
145 150 155 160
Val Thr Phe Thr Leu Gln Gln Leu Asn Ala Tyr Asn Arg Thr Arg Tyr
165 170 175
Glu Leu Arg Glu Phe Leu Glu Asp Thr Cys Val Gln Tyr Val Gln Lys
180 185 190
His Ile Ser Ala Glu Asn Thr Lys Gly Ser Gln Thr Ser Arg Ser Tyr
195 200 205
Thr Ser Leu Val Leu Gly Val Leu Val Gly Ser Phe Ile Ile Ala Gly
210 215 220
Val Ala Val Gly Ile Phe Leu Cys Thr Gly Gly Arg Arg Cys
225 230 235
<210> 3
<211> 19
<212> DNA
<213> 寡核苷酸
<400> 3
tcaccttcac cctgcagca 19
<210> 4
<211> 20
<212> DNA
<213> 寡核苷酸
<400> 4
ttgtttggct ccctttcgtg 20
<210> 5
<211> 25
<212> DNA
<213> 寡核苷酸
<400> 5
gctcaatgcc tacaaccgca ctcgg 25
<210> 6
<211> 140
<212> PRT
<213> 智人（Homo sapiens）
<400> 6
Leu Ala Leu Leu Pro Leu Leu Phe Thr Pro Val Ala Lys Ala Gln Val
1 5 10 15
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val
20 25 30
Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr Ala Ile
35 40 45
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Gly
50 55 60
Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln Gly
65 70 75 80
Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr Met Glu
85 90 95
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg
100 105 110
Gly Tyr Ser Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
130 135 140
<210> 7
<211> 140
<212> PRT
<213> 智人（Homo sapiens）
<400> 7
Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala Ala Gln Pro Ala Met
1 5 10 15
Ala Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
20 25 30
Gly Asp Arg Val Thr Met Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn
35 40 45
Asp Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu
50 55 60
Ile Tyr Ala Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
65 70 75 80
Gly Ser Gly Phe Gly Ala Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
85 90 95
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Ala Tyr Ser Tyr Pro
100 105 110
Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
115 120 125
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Claims (10)
1.一种针对EPCR基因或EPCR蛋白的表达制备癌症诊断产品的方法。
2.如权利要求1所述的方法，其特征在于，所述癌症诊断产品为用实时荧光定量PCR诊断癌症的产品或免疫检测诊断的产品。
3.根据权利要求2所述的用途，其特征在于，所述实时荧光定量PCR诊断癌症的产品包括一对特异性针对EPCR的引物及探针。
4.根据权利要求3所述的用途，其特征在于，所述引物及探针为如下序列：
EPCR-F：TCACCTTCACCCTGCAGCA，对应序列表中的SEQ ID NO.3号序列，
EPCR-R：TTGTTTGGCTCCCTTTCGTG，对应序列表中的SEQ ID NO.4号序列)，
探针序列：GCTCAATGCCTACAACCGCACTCGG，对应序列表中的SEQ ID NO.5号序列。
5.根据权利要求2所述的用途，其特征在于，所述用于免疫检测癌症诊断的产品包括与EPCR蛋白特异性结合的抗体。
6.一种用于癌症诊断的试剂盒，其特征在于，所述试剂盒包括特异性针对EPCR基因的引物及探针和/或特异性结合EPCR蛋白的抗体，优选地，所诉抗体的基因序列包括如序列表中的SEQ ID NO.6所示的重链可变区序列以及如序列表中的SEQ ID NO.7所示的轻链可变区序列。
7.一种针对EPCR基因或EPCR蛋白的表达制备癌症治疗药物的方法。
8.根据权利要求7所述的方法，其特征在于，所述癌症治疗药物包括抑制EPCR基因表达和/或抑制EPCR蛋白活性的物质。
9.根据权利要求7或8所述的方法，其特征在于，所述癌症治疗药物包括通过RNA干涉抑制EPCR基因表达的核糖核酸，和/或抑制EPCR蛋白活性的蛋白质。
10.根据权利要求7至9任一项所述的方法，其特征在于，所述癌症包括：肺癌、卵巢癌、乳腺癌、肾瘤、前列腺癌、膀胱癌、黑色素瘤、多发性骨髓瘤。
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