CN110787296B - 一种用于预防或治疗胰腺癌的药物组合物及检测胰腺癌的试剂盒 - Google Patents
一种用于预防或治疗胰腺癌的药物组合物及检测胰腺癌的试剂盒 Download PDFInfo
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Abstract
本发明公开一种用于预防或治疗胰腺癌的药物组合物及检测胰腺癌的试剂盒,用于预防或治疗胰腺癌的药物组合物,所述药物组合物能够降低或抑制a)BCAT2的生物活性或b)编码BCAT2的基因的表达;含检测BCAT2的试剂的试剂盒;本发明首次公开了BCAT2促进胰腺癌细胞增殖,体内敲除BCAT2抑制胰腺导管上皮内瘤变(PanIN),并提供了胰腺癌预防和治疗的药物组合物,及胰腺癌评估试剂盒。
Description
技术领域
本发明涉及医药卫生领域,尤其涉及一种用于预防或治疗胰腺癌的药物组合物及检测胰腺癌的试剂盒。
背景技术
胰腺导管上皮内瘤变(pancreatic intraepithelial neoplasia,PanIN)是恶性胰腺导管腺癌的癌前病变,目前对其发生发展仍缺乏足够认识。
代谢重编程是由Otto Warburg首先提出的肿瘤代谢特征之一,主要指肿瘤细胞即使在氧含量充足时也优先进行糖酵解。随着对肿瘤代谢的不断研究,Warburg效应的概念也不断扩充。除了糖酵解,在其他代谢途径如脂肪酸代谢,氨基酸代谢和一碳单位循环等(Hanahan and Weinberg,2011)也不断地涵盖到广义的Warburg效应。
约有90%的胰腺癌存在KRAS突变(Halbrook and Lyssiotis,2017)。在KRAS突变的PDAC动物模型中,血浆中支链氨基酸(BCAA)浓度在PDAC早期已显著升高,这提示BCAA代谢可能与PDAC的发生发展相关联(Mayers et al.,2014)。有意思的是,研究表明在KRAS突变引起的癌变模型中,非小细胞肺癌的发展是BCAT依赖的,而胰腺癌的发展是BCAT非依赖的(Mayers et al.,2016)。而最新的研究表明,在苹果酸酶缺失的PDAC中,过表达BCAT2显著促进肿瘤细胞的增殖(Dey et al.,2017)。显而易见,这些相互矛盾的报道,表明仍需深入的研究以阐明BCAA与PDAC发生发展之间的复杂关系。
支链氨基酸是必需氨基酸,包括亮氨酸、异亮氨酸和缬氨酸。支链氨基酸转氨酶(BCAT)和支链氨基酸酮酸脱氢酶复合物(BCKDC)是BCAA分解代谢的两个关键酶(Shimomuraet al.,2001)。BCAT参与催化BCAA的第一步反应,主要有两种亚型,一种是主要位于细胞胞浆中的BCAT1或BCATc,另一个是主要位于线粒体中的BCAT2或BCATm。尽管它们在细胞内分布不同,但均催化相同的化学反应,即将支链氨基酸上的氨基转给阿尔法-酮戊二酸(α-KG),产生对应的支链酮酸(BCKA)和谷氨酸,该催化过程中以磷酸吡哆醛(PLP)为辅酶(Ichihara and Koyama,1966;Taylor and Jenkins,1966)。进一步BCKA在BCKDC等一系列相关酶的催化下最终生成乙酰辅酶A(ace-CoA)和琥珀酰辅酶A(suc-CoA),进入TCA循环。
然而,现有研究并没有阐明哪种亚型的BCAT影响胰腺癌,并且,更多研究指向BCAT1与癌症的关系密切。
专利号为US20130072397A1的美国专利,应用BCAT1蛋白对肿瘤进行诊断和预后判断方法,公开了一种肿瘤的诊断方法,特别是脑瘤的诊断方法,以及基于对患者样本中BCAT1的表达的测定对此类肿瘤患者的预后进行评估的方法。
综上所述,现有研究认为BCAT与癌症关系密切,但是并没有阐明哪种亚型的BCAT影响胰腺癌。
发明内容
针对上述技术问题,本发明提供了一种用于治疗胰腺癌的药物组合物,所述药物组合物能够降低或抑制a)BCAT2的生物活性或b)编码BCAT2的基因的表达。
优选地,所述药物组合物包括BCAT2抑制剂;所述的BCAT2抑制剂包括二萜、三萜、苯并咪唑、磺酰肼,及其衍生物、前药。
优选地,所述药物组合物包括针对BCAT2或BCAT2片段的抗体。
优选地,所述药物组合物包括针对BCAT2基因的shRNA;进一步优选地,shRNA的碱基序列如SEQ ID NO:1-6所示。
优选地,所述药物组合物还包括其他药用辅料。
本发明还公开了BCAT2抑制剂在制备用于预防和治疗胰腺癌的药物中的应用,BCAT2抑制剂能够降低或抑制a)BCAT2的生物活性或b)编码BCAT2的基因的表达。
优选地,所述的BCAT2抑制剂包括二萜、三萜、苯并咪唑、磺酰肼,及其衍生物、前药。
优选地,所述的BCAT2抑制剂包括针对BCAT2或BCAT2片段的抗体。
优选地,所述的BCAT2抑制剂包括针对BCAT2基因的shRNA。
本发明还公开了,含检测BCAT2的试剂盒。
优选地,所述的BCAT2检测试剂盒包括所述的生物学样品是胰腺癌新鲜组织时,针对BCAT2转录RNA量的qPCR引物;进一步优选地,qPCR引物的碱基序列为SEQ ID NO:7和SEQID NO:8。
优选地,所述的BCAT2检测试剂盒包括所述的生物学样品是胰腺癌组织石蜡切片时,针对BCAT2蛋白表达量的免疫组织化学方法。
优选地,所述的BCAT2检测试剂盒包括所述生物学样品是活体的生物个体时,针对BCAT2代谢酶活性,结合18F或11N标记氨基酸衍生物为亮氨酸、异亮氨酸和缬氨酸类似物的正电子发射断层(PET)显像。
本发明还公开了,检测BCAT2的试剂在制备用于检测胰腺癌产品中的应用。
优选地,本发明所述胰腺癌为胰腺导管腺癌。
与现有技术相比,本发明的技术方案具有以下优点:本发明首次公开了BCAT2促进胰腺癌细胞增殖,体内敲除BCAT2抑制胰腺导管上皮内瘤变,并提供了胰腺癌预防和治疗的药物组合物,及胰腺癌评估试剂盒。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其他的附图。
图1是本发明实施例2的7个样本Western bolt(WB)结果;
图2是本发明实施例2的7个样本细胞消耗培养基中BCAA含量;
图3是本发明实施例2的BCAT2对细胞产酸速率的影响;
图4是本发明实施例2的BCAT2对耗氧率的影响;
图5是本发明实施例2的BCAT2对细胞内NADH/NAD+的比值,及乙酰辅酶A(ace-CoA)和琥珀酰辅酶A的水平的影响;
图6是本发明实施例2的胰腺导管细胞和胰腺导管癌细胞中BCAT1蛋白水平;
图7是本发明实施例2的BXPC3细胞BCAT2的敲减效率;
图8是本发明实施例2的SW1990细胞BCAT2的敲减效率;
图9是本发明实施例3的三株细胞系中过表达KRAS活化突变和三株细胞系中敲减KRAS的结果;
图10是本发明实施例3的SW1990、PANC1和AsPC1细胞中敲减KRAS对BCAT2和TRIM21相互作用的影响;
图11是本发明实施例3的处理后BCAT2含量变化;
图12是本发明实施例3的KRAS对BCAA的代谢的影响;
图13是本发明实施例3的将BCAT2-Flag与HA-UB的质粒共转染HEK293T细胞中的结果;
图14是本发明实施例3的在MG132处理的、敲减TRIM1的HEK293T细胞中共转染BCAT2-Flag与HA-UB质粒的结果;
图15是本发明实施例3的敲减TRIM1的细胞内BCAT2的蛋白水平;
图16是本发明实施例3的BxPC3细胞过表达KRAS活化突变对BCAT2和TRIM21相互作用的影响;
图17是本发明实施例1的过表达BCAT2和敲减BCAT2对细胞消耗培养基中BCAAs的含量的影响;
图18是本发明实施例1的细胞生长曲线;
图19是本发明实施例1的细胞克隆形成能力检测;
图20是本发明实施例1的对照组和KC组小鼠胰腺组织Bcat2的免疫组织化学染色镜下图;
图21是本发明实施例1的KC小鼠胰腺组织连续切片中Ck19、Bcat2和Ki67的免疫组织化学染色镜下图;
图22是本发明实施例1的WB鉴定在H6C7和HPNE细胞中过表达BCAT2-Flag质粒后BCAT2的蛋白表达水平;
图23是本发明实施例1的BCAT抑制剂2处理对细胞消耗培养基中BCAAs的含量的影响;
图24是本发明实施例1的H6C7和HPNE细胞分别过表达BCAT2的细胞克隆形成结果镜下图;
图25是本发明实施例1的H6C7和HPNE细胞分别过表达BCAT2对细胞迁移影响的检测;
图26是本发明实施例1的在SW1990和BxPC3细胞敲减BCAT2的细胞克隆形成结果镜下图;
图27是本发明实施例1的在SW1990和BxPC3细胞敲减BCAT2的细胞迁移结果检测。
图28是本发明实施例1的在对照组和KCB组小鼠胰腺组织Bcat2的免疫组织化学染色镜下图;
图29是本发明实施例1的在对照组和KCB组小鼠胰腺组织根据不同分期的统计图;
图30是发明实施例1的在癌旁和胰腺癌组织BCAT2的免疫组织化学染色镜下图。
具体实施方式
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明,以充分地了解本发明的目的、特征和效果。
实施例1BCAT2促进胰腺导管癌细胞的增殖
1、采用BCAT2抑制剂磺酰肼类BCAT2抑制剂,剂量为7.5微摩(μM)、30μM、60μM。
2、制备小鼠模型制备了条件性敲除Bcat2的转基因小鼠模型,并通过不同转基因小鼠杂交分别获得了Pdx1-cre;LSL-KRAS G12D(简称KC),Pdx1-Cre;Bcatflox/flox和LSL-KrasG12D;Bcat2flox/folx;Pdx1-Cre(简称KCB)的小鼠模型。KC小鼠模型能够很好的模拟胰腺癌前病变PanIN期的发生发展的进程及其病理表现(Hingorani et al.,2003),而KCB小鼠模型能观察BCAT2对PanIN发生发展的影响。
3、检测BCAT2对胰腺导管上皮细胞和PDAC细胞吸收BCAA的影响。结果如图17和22所示,稳定性过表达BCAT2明显增加H6C7和HPNE细胞吸收BCAA的能力;而稳定性敲减BCAT2造成SW1990和BxPC3细胞吸收BCAA的能力明显减弱。其中,图17为BCAT2促进细胞对BCAAs的吸收。过表达BCAT2的H6C7和HPNE细胞中,检测细胞消耗培养基中BCAAs的含量(图17,左图);敲减BCAT2的SW1990和BxPC3细胞中,检测细胞消耗培养基中BCAAs的含量(图17,右图)。*:p<0.05。图22为过表达BCAT2的稳定细胞株鉴定。WB鉴定BCAT2在H6C7(图22,左图)和HPNE(图22,右图)细胞中的稳定性表达。此外,随着BCAT2抑制剂处理时间延长和处理浓度的增加,细胞消耗BCAA的能力也逐渐减弱(如图23所示)。图23为BCAT2抑制剂下调细胞对BCAAs的吸收。不同浓度的BCAT2抑制剂处理BxPC3细胞24小时(h)(图23,左图),48h(图23,右图),检测细胞消耗培养基中BCAAs的含量。*:p<0.05;**:p<0.01;***:p<0.001。
4、计数不同时间点的细胞数绘制生长曲线检测BCAT2对胰腺导管上皮细胞和PDAC细胞增殖的影响。结果如图18所示,在永生化的正常胰腺细胞中过表达BCAT2显著促进H6C7和HPNE的细胞增殖。同时过表达BCAT2显著促进上述细胞的克隆形成能力和细胞迁移能力(图19,左图;图24-25)。反之,在癌变细胞中敲减BCAT2显著抑制SW1990和BxPC3细胞的增殖(图18,下图),并且减弱细胞的克隆形成能力和细胞迁移能力(图19,右图;图26-27)。*:p<0.05;**:p<0.01;***:p<0.001。如图19所示,BCAT2促进胰腺导管上皮细胞克隆形成。在H6C7和HPNE细胞分别过表达BCAT2促进细胞克隆形成(图19,左图),在SW1990和BxPC3细胞中分别稳定敲减BCAT2抑制PDAC细胞克隆形成(图19,右图)。*:p<0.05;**:p<0.01。图24为过表达BCAT2促进胰腺导管上皮细胞克隆形成。H6C7和HPNE细胞分别稳定过表达BCAT2,两周后显微镜下拍照记录克隆形成。图25为BCAT2促进细胞迁移。H6C7和HPNE细胞分别稳定过表达BCAT2,Transwell穿膜实验实验检测细胞迁移(图25,左图)并定量(图25,右图)。比例尺为200μm。*:p<0.05;**:p<0.01。图26为敲减BCAT2抑制PDAC细胞克隆形成。SW1990和BxPC3细胞中分别稳定敲减BCAT2,两周后显微镜下拍照记录克隆形成(图26,左)并定量(图26,右)。比例尺为200μm。**:p<0.01。图27为敲减BCAT2抑制PDAC细胞迁移。SW1990和BxPC3细胞中分别稳定敲减BCAT2,transwell穿膜实验检测细胞迁移(图27,左)并定量(图27,右)。比例尺为200μm。*:p<0.05;**:p<0.01。
以上数据表明,BCAT2促进胰腺导管上皮细胞和PDAC细胞对BCAA的吸收,并调控胰腺导管上皮细胞和PDAC细胞的增殖和迁移。
5、为深入研究BCAT2在体内生理和病理条件下的功能,收集了正常小鼠和KC以及KCB小鼠胰腺组织标本,通过免疫组织化学染色(Immunohistochemistry,IHC)的方法,发现Bcat2在正常对照小鼠(包括WT,Pdx1-Cre和LSL-KRAS G12D)和KC小鼠的胰腺腺泡细胞中均有一定表达,但在正常对照组中的胰腺导管上皮细胞中无表达(图20)。然而,在KC组PanIN期的导管上皮细胞中Bcat2呈现高表达,甚至高于胰腺细胞的表达(图20)。此外,KCB组未能检测到导管上皮细胞中Bcat2的表达(图28、图29)。进一步选取同一组织块的连续切片,用Ck19(导管标志分子),Ki67(细胞增殖标志分子)和Bcat2抗体,对KC组小鼠胰腺组织分别进行IHC染色。我们发现Ck19,Ki67和Bcat2的表达在发生PanIN病变的胰腺导管组织内共定位(图21)。对KCB组小鼠胰腺组织分别进行IHC染色,我们发现敲除Bcat2能显著抑制PanIN的发生发展(图28、图29)。IHC鉴定Bcat2在小鼠胰腺中的表达水平(16周龄,6只)。三角指示为正常导管组织,五星指示为腺泡组织,箭头指示为PanIN期导管。比例尺为50μm。IHC鉴定CK19,Bcat2和Ki67在小鼠胰腺中的表达水平(16周龄,5只)。箭头分别指示Ck19、Bcat2和Ki67染色。比例尺为12.5μm。此外,我们对胰腺癌及其癌旁组织分别进行IHC染色,我们发现BCAT2在胰腺癌组织中明显高表达(图30)
以上数据显示Bcat2在胰腺癌发生的早期PanIN期的导管上皮细胞中高表达,提示Bcat2在PanIN发生发展过程中发挥重要作用。此外,临床样品数据进一步证明BCAT2在胰腺癌的发展中也起着重要作用。
本实施例的BCAT2抑制剂预防和治疗胰腺癌的机制如下。
实施例2胰腺癌中BCAT2显著上调,从而促进BACC代谢
为研究支链氨基酸代谢与胰腺癌的关系,我们重点关注了参与支链氨基酸分解代谢的第一个关键酶——支链氨基酸转氨酶(BCAT)。它包括两种亚型,位于胞浆中的BCAT1和位于线粒体的BCAT2。通过以下大量实验分析支链氨基酸代谢与胰腺癌的关系。
1、在永生化的正常胰腺导管上皮细胞和胰腺导管癌细胞中分别检测了BCAT1和BCAT2的蛋白水平。选取2株永生化的正常胰腺导管上皮细胞hTERT-HPNE及HPDE6C7(以下简称HPNE和H6C7),和5株胰腺导管癌细胞作为研究对象。利用Western Blot分别检测胰腺细胞中BCAT2的蛋白水平。HPNE和H6C7为永生化的正常胰腺导管上皮细胞,PANC1、BxPC3、ASPC1、Capan1和SW1990为PDAC细胞株,以β-actin为内参进行定量。Western bolt的数据结果如图1和6所示:胰腺癌细胞中BCAT2的蛋白水平较永生化的正常细胞有显著上调(如图1所示);而BCAT1蛋白仅在PANC1细胞中上调,在其他胰腺导管癌细胞中未发生显著变化(如图6所示)。
2、进一步,为验证胰腺导管细胞中BCAT2上调是否促进BCAA的代谢。将细胞培养24h后,检测各细胞消耗培养基中BCAAs的量,发现胰腺导管癌细胞消耗BCAA的量是正常胰腺导管细胞HPNE的1.5-2.5倍,与BCAT2的表达呈正相关,PDAC细胞消耗BCAAs能力增强(如图2所示)。
3、为研究BCAT2对BCAA代谢流的调控,首先用Seahorse技术分别检测了BCAT2对细胞糖酵解和有氧呼吸的影响,其中细胞产酸速率(ECAR)代表细胞糖酵解能力,耗氧率(OCR)代表细胞有氧呼吸能力。敲减BCAT2引起细胞ECAR升高和OCR降低。如图3上图所示,对照或敲减BCAT2的BxPC3细胞中,在指定的时间点依次加入葡萄糖(glucose),寡霉素(oligomycin)和2-脱氧-D葡萄糖(2-DG)。绘制ECAR曲线;如图3下图所示,对照或敲减BCAT2的BxPC3细胞中,在指定的时间点依次加入寡霉素(oligomycin),三氟氰苯腙(trifluoromethoxy carbonylcyanide phenylhydrazone,FCCP)和鱼藤酮(rotenone)。绘制OCR曲线。*:p<0.05;**:p<0.01;***:p<0.001。BCAT2抑制剂下调细胞OCR水平。如图四所示BCAT2抑制剂处理BxPC3细胞,在指定的时间点依次加入寡霉素(oligomycin),三氟氰苯腙(trifluoromethoxy carbonylcyanide phenylhydrazone,FCCP)和鱼藤酮(rotenone)。绘制OCR曲线。*:p<0.05;**:p<0.01。结果显示:在BxPC3细胞中,敲减BCAT2能够明显增强细胞的ECAR水平,同时减弱OCR水平(如图3和图7所示)。与之一致的是BCAT2抑制剂处理BxPC3细胞后,细胞中OCR水平也显著下调(如图4所示)
4、检测了细胞内NADH/NAD+的比值,及BCAA下游代谢产物乙酰辅酶A(ace-CoA)和琥珀酰辅酶A(suc-CoA)的水平。结果表明,在SW1990细胞中敲减BCAT2后,NADH/NAD+的比值明显上调,而细胞内ace-CoA和suc-CoA浓度没有明显变化(图5和图8)。如图5所示,敲减BCAT2上调细胞内NADH/NAD的比值但不影响ace-CoA和suc-CoA。对照或敲减BCAT2的SW1990细胞中,试剂盒检测NADH/NAD+的比值,LC-MS检测乙酰辅酶A(ace-CoA)和琥珀酰辅酶A(suc-CoA)。**:p<0.01;n.s.代表无显著差异。
实施例3KRAS活化突变稳定BCAT2蛋白
约有90%的胰腺导管癌存在KRAS活化突变(Kanda et al.,2012)。因此,我们进一步研究了KRAS活化突变是否调控BCAT2的蛋白水平。
1、选取三株KRAS野生型的细胞系,即H6C7、HPNE胰腺导管上皮细胞和BxPC3细胞,并在这三株细胞系中过表达KRAS活化突变体(KRAS G12V),发现KRAS突变上调BCAT2蛋白水平,而对BCAT2的mRNA水平无影响。H6C7,HPNE和BxPC3细胞中分别过表达KRAS活化突变体KRAS G12V,SW1990,PANC1和AsPC1细胞分别敲减KRAS,BCAT2和KRAS的蛋白水平通过WB检测。β-actin作为内进行定量。Q-PCR检测各细胞系中BCAT2的mRNA表达水平。n.s.代表无显著差异。KRAS G12V分别上调BCAT2的蛋白水平为1.9,1.7和1.2倍,而BCAT2的mRNA水平并无明显变化(图9,左图)。相应的,敲减SW1990、PANC1和ASPC1细胞中KRAS,BCAT2的蛋白水平明显下调,而BCAT2的mRNA水平并无明显变化(如图9,右图)。以上结果提示KRAS可能通过翻译后修饰调控BCAT2的蛋白水平。
2、将BCAT2-Flag与HA-UB的质粒共转染HEK293T细胞中,发现BCAT2受到显著的泛素化修饰(如图13)。
3、泛素化的可逆调控主要由4种酶组成,E1,E2,E3泛素连接酶和去泛素化酶(DUB)(Leestemaker and Ovaa,2017)。其中,E3泛素连接酶是泛素化介导降解途径的底物特异性酶(Hershko and Ciechanover,1998)。通过串联亲和纯化和质谱技术(TAP-MS)筛选与BCAT2相互作用蛋白分子,鉴定结果显示三基序蛋白21(TRIM21)获得高得分。提示TRIM21可能是调节BCAT2蛋白降解的E3连接酶。将TRIM21敲减后,显著下调BCAT2的泛素化水平(如图14)。此外,在H6C7、SW1990、AsPC1和PANC1细胞中分别将内源性TRIM21敲减后,细胞内BCAT2的蛋白水平均出现不同程度的显著上升(如图15)。这些结果表明,TRIM21是BCAT2的E3泛素连接酶。
4、为进一步阐明KRAS G12V对BCAT2蛋白水平调控的分子机制。如图10所示,在SW1990、PANC1和AsPC1细胞中,敲减KRAS增强BCAT2与TRIM21的相互作用。在SW1990、PANC1和AsPC1细胞中分别敲减KRAS,内源IP和WB检测BCAT2和TRIM21的相互作用。BCAT2作为IP内参进行定量。相应的,如图16所示,在BxPC3细胞中过表达KRAS G12V,发现KRAS G12V能明显阻断TRIM21和BCAT2的结合。过表达KRAS G12V的BxPC3细胞结合MG132处理6h,内源IP和WB检测BCAT2和TRIM21的相互作用。TRIM21作为IP内参进行定量。如图11所示,过表达KRASG12V显著延长BCAT2的半衰期。H6C7细胞过表达KRAS G12V,CHX处理不同时间,WB检测BCAT2的蛋白量(如图11,左图)和定量(如图11,右图)。*:p<0.05)。
这些数据表明,KRAS突变能够阻断BCAT2和E3泛素连接酶TRIM21的结合,降低BCAT2的泛素化水平,稳定BCAT2的蛋白水平。
5、通过LC-MS进一步检测了KRAS对BCAA的代谢的影响,发现过表达KRASG12V可以上调H6C7细胞内BCAA和α-酮异己酸(KIC)水平,促进BCAAs分解代谢(图12、左图);反之,敲减KRAS引起PANC1细胞内BCAA及KIC的水平下降,抑制BCAAs分解代谢(图12、右图)。在H6C7细胞中过表达KRASG12V,用LC-MS检测BCAAs相关代谢物的含量;在PANC1细胞中敲减KRAS,LC-MS检测BCAAs相关代谢物的含量。*:p<0.05;**:p<0.01;***:p<0.001。
以上研究结果表明KRAS突变促进BCAA的分解代谢,而BCAT2是BCAA分解代谢中的关键酶。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术人员无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
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<120> 一种用于预防或治疗胰腺癌的药物组合物及检测胰腺癌的试剂盒
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Claims (3)
1.一种用于预防或治疗胰腺导管上皮内瘤变的药物组合物,其特征在于,所述
药物组合物能够降低或抑制 a)BCAT2 的生物活性或 b)编码 BCAT2 的基因的表达,其中药物组合物包括针对BCAT2基因的shRNA,其中所述shRNA的碱基序列如SEQ ID NO:1-6所示,所述药物组合物还包括药用辅料。
2. BCAT2 抑制剂在制备用于预防或治疗胰腺导管上皮内瘤变的药物中的应用,
BCAT2 抑制剂能够降低或抑制 a)BCAT2 的生物活性或 b)编码 BCAT2 的基因的表达,其中,BCAT2抑制剂为针对BCAT2基因的shRNA,所述shRNA的碱基序列如 SEQ ID NO:1-6所示。
3.检测BCAT2的试剂在制备用于检测胰腺导管上皮内瘤变产品中的应用。
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