CN117442637A - Pkp2及其表达抑制剂在治疗胰腺癌中的应用 - Google Patents
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Abstract
本发明公开了PKP2及其表达抑制剂在治疗胰腺癌中的应用,PKP2表达在癌组织中相对于正常组织表达明显增加,并且与肿瘤恶性程度和更差的预后直接有关。PKP2在胰腺癌早期病变中具有促进病变进展的能力。因此,本发明表明PKP2可以成为治疗胰腺癌的药物靶标,靶向抑制PKP2代表一个新的恶性肿瘤治疗策略和方案,可用于临床早期诊断胰腺癌和治疗胰腺癌。本发明公开了PKP2基因的表达抑制剂,所述表达抑制剂为PKP2的siRNA,对PKP2基因的表达具有良好的干扰效果,具有临床基因治疗的应用潜力。
Description
技术领域
本发明属于肿瘤分子生物学领域,具体涉及本发明属于生物医学领域,主要涉及PKP2及其表达抑制剂在治疗胰腺癌中的应用。
背景技术
目前广泛应用于临床的胰腺癌的传统治疗药物主要是核苷类似物吉西他滨。同时厄洛替尼或白蛋白紫杉醇联合吉西他滨的疗法也显示出一定的治疗益处。尽管采取积极的治疗方案,但胰腺癌的中位生存期没有得到明显的提升,仍然仅在6个月左右。
目前,有关调控胰腺癌细胞增殖和迁移的分子机制和细胞生物学特性尚不清楚。近年来,有关胰腺癌的发病机制,尤其是增殖机制方面的研究成为热点。其中HER2信号通路、RAF/MEK/ERK通路、KRAS、表皮生长因子受体(EGFR)等信号通路被认为是对胰腺癌细胞增殖能力影响最显著的几条信号通路。
虽然胰腺癌的生物学特征已被充分地研究,但新的分子靶点的确定进展却仍然是极为缓慢的,潜在的候选药物非常少,这可能是由于胰腺癌的遗传复杂性所致。另外,由于疾病存活时间短,很难有机会测试任何可能的免疫疗法或其它疗法的有效性。
Plasma miRNAs in diagnosis and prognosis of pancreatic cancer:A miRNAexpressio n analysis中作者将血浆中发现了miRNA作为胰腺癌诊断和预后的非侵入性生物标志物。但不能在胰腺癌前病变时提供检测手段。
Dermokine contributes to epithelial-mesenchymal transition throughincreased activation of signal transducer and activator of transcription 3inpancreatic cancer中DMKN敲低降低了PDAC的侵袭和迁移,通过降低微血管密度在异种移植动物模型中延缓肿瘤生长,并在小鼠模型中减弱人PDAC的远处转移。但对于胰腺癌细胞增殖的影响效果不明显。
Lipocalin-2Promotes Pancreatic Ductal Adenocarcinoma by RegulatingInflammation in the Tumor Microenvironment中作者将Lipocalin-2(Lcn2)与肥胖及胰腺炎、胰腺上皮内瘤变(PanIN)和胰腺癌联系起来,Lcn2的消耗减少了细胞外基质沉积、免疫细胞浸润、PanIN形成和肿瘤生长,它还增加了肥胖驱动和同源原位PDAC小鼠模型的存活率。与肥胖相联系增加了该分子在胰腺癌早期诊断的局限性。
Galectin-1expression in activated pancreatic satellite cells promotesfibrosis in chroni c pancreatitispancreatic cancer via the TGF-β1Smad pathway中,galectin-1的过表达促进胰腺星状细胞活性(增殖和迁移)并通过TGF-β1/Smad途径增加细胞外基质合成和降低MMP/TIMP比率来刺激纤维化。但缺少急性胰腺炎模型。
因此,本领域迫切需要研究新的胰腺癌诊断或治疗靶点,从而为胰腺癌的疾病研究以及临床治疗提供新的途径。
发明内容
为了克服现有技术存在的上述不足,本发明的目的在于针对胰腺癌早期诊断困难、缺少治疗靶点的问题,提供一种高效的方案用以抑制胰腺癌的增殖、侵袭和迁移。
为实现上述目的,本发明采取的技术方案是:
本发明的首要目的是提供PKP2基因表达抑制剂在制备治疗胰腺癌及其早期病变的药物中的应用。
优选的,所述PKP2基因表达抑制剂为基于PKP2基因设计的siRNA。
更优选的,所述基于PKP2基因设计的siRNA为siPKP2,所述siRKP2由双链核酸分子1和2组成,所述核酸分子1由SEQ ID NO.1所示的正义链RNA分子和2个dT组成,2个dT位于3’端;所述核酸分子2由SEQ ID NO.2所示的反义链RNA分子和2个dT组成,2个dT位于3’端。
本发明的另一目的在于提供一种用于治疗胰腺癌及其早期病变的药物组合物,所述药物组合物包括PKP2基因表达抑制剂。
优选的,所述PKP2基因表达抑制剂为基于PKP2基因设计的siRNA。
更优选的,所述基于PKP2基因设计的siRNA为siPKP2,所述siRKP2由双链核酸分子1和2组成,所述核酸分子1由SEQ ID NO.1所示的正义链RNA分子和2个dT组成,2个dT位于3’端;所述核酸分子2由SEQ ID NO.2所示的反义链RNA分子和2个dT组成,2个dT位于3’端。
本发明的再一目的在于提供一种用于胰腺癌早期诊断和治疗的分子标记物,所述一种用于胰腺癌早期诊断和治疗的分子标记物包括PKP2基因、PKP2 mRNA和PKP2蛋白的一种或两种以上。
本发明的第四目的是提供7.如下a1-a3中的至少一种在如下b1-b4至少一种中的用途:
a1,PKP2基因;a2,PKP2 mRNA;a3,PKP2蛋白;
b1,作为癌症及其癌前病变的诊断标志物,或者制备用于癌症诊断的产品;
b2,作为癌症的预后标志物,或者制备用于癌症预后评估的产品;
b3,制备用于癌症疗效监测的产品;
b4,制备治疗癌症的药物。
优选的,所述癌症为胰腺癌。
优选的,所述癌症诊断包括癌症早期诊断、癌症远处转移诊断和/或癌症淋巴结转移诊断。
优选的,所述用于癌症诊断的产品、用于癌症预后评估的产品和/或用于癌症疗效监测的产品包括芯片、试剂盒。
优选的,所述用于癌症诊断的产品、用于癌症预后评估的产品和/或用于癌症疗效监测的产品包括扩增PKP2的引物、探针或抗体。
本发明的目的至少通过如下技术方案之一实现。
与现有技术相比,本发明具有如下优点和有益效果:
(1)提供了一种在胰腺癌癌前病变时期的检测手段,一定程度弥补了胰腺癌早期检测手段缺乏的问题。
(2)通过抑制胰腺癌病变过程中PKP2的表达可以抑制恶性肿瘤细胞的增殖和迁移。
(3)提供一种PKP2基因的表达抑制剂与肿瘤治疗方法的组合,提高患者的治愈率,并为胰腺癌预后分析提供了一项指标。
附图说明
图1中的A是应用数据库数据分析胰腺癌标本(T)及配对的癌旁正常组织(N)中PKP2mRNA的表达水平图;图1中的B是用免疫组化的方法检测胰腺癌患者标本(T)配对的癌旁正常(N)组织中PKP2蛋白水平照片;图1中的C是PKP2高表达和低表达患者的总生存率图。
图2中的A是PKP2在小鼠胰腺癌细胞系中的表达情况图;图2中的B是在PKP2高表达的细胞系SW1990和CFPAC-1中敲低PKP2以及在PKP2低表达的细胞系AsPC-1和PL-45中过表达PKP2的情况图;图2中的C是在PKP2高表达的细胞系SW1990和CFPAC-1中敲低PKP2以及在PKP2低表达的细胞系AsPC-1和PL-45中过表达PKP2后,对细胞增殖能力的影响图;图2中的D是在PKP2低表达的细胞系AsPC-1和PL-45中过表达PK P2,转染细胞在转染后0小时和72小时拍照,并用虚线勾画伤口区域,对细胞迁移能力的影响图。
图3中的A是成瘤的裸鼠照片;图3中的B是肿瘤照片;图3中的C是肿瘤称重图;图3中的D是肿瘤生长曲线图。
图4是PKP2在KRAS-G12D驱动的PanIN中的表达情况照片。
图5是在使用雨蛙素和胰腺导管结扎的胰腺炎模型中,PKP2在腺泡集团顶端的表达量照片。
图6为在小鼠模型胰腺中特异性敲除PKP2后会降低ADM的病变恶性程度照片。
具体实施方式
下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
PL45细胞、HPDE细胞和HPAC细胞购自广州市深华生物技术有限公司;AsPC-1细胞、CFPAC-1细胞和SW1990细胞购自广州赛库生物技术有限公司;HPAF-2细胞、BxPC-3细胞、MIAPaCa-2细胞、PANC-1细胞和PK-59细胞购自广州致邦生物科技有限公司。所有细胞系在37℃、5% CO2中作为单层贴壁物,加入10%胎牛血清、1%青霉素/链霉素溶液进行培养。
抗PKP2(sc-393711)抗体购自圣克鲁斯生物技术(Santa Cruz Biotechnology);抗Amyl ase(PA5-117115)抗体购自Invitrogen公司;抗Krt19(TROMA-III)抗体购自Development al Studies Hybridoma Bank。
特异性靶向寡聚核酸siRNA和空白对照siCtrl由吉玛基因公司(GenePharma)合成,序列如表1所示。
表1
PKP2质粒(过表达PKP2质粒,pPKP2)以及作为对照的空白质粒(pcDNA3.1)购自金斯瑞科技公司,PKP2过表达质粒克隆载体主干为pcDNA3.1(+)-C-DYK,将CMV作为强启动子,选取EcoRI和XbaI进行切割,在启动子序列后添加了人类PKP2基因序列(序列如SEQ IDNO.5所示),长度为2522bp,可使用含氨苄青霉素的培养基作为筛选条件,待内含PKP2过表达质粒的大肠杆菌生长到适宜浓度后进行质粒提取,所用质粒提取试剂(NucleoBond XtraMidi Plus EF,740422.50)购自基因生物技术国际贸易(上海)有限公司广州分公司(MACHEREY-NAGEL)。
异位移植瘤实验所需基质胶(#356234)购自美国BD公司(Becton,Dickinson andCo mpany)。CCK8(#CK04)购自Dojindo公司。
用于异位异种移植瘤模型的雌性裸鼠和以C57BL/6小鼠构建的基因敲除鼠(PKP2fl/+小鼠与PDX-1-cre小鼠)购自上海南方模式生物科技股份有限公司。小鼠在8周大的时候被使用。所有动物都被饲养在华南理工大学动物设施中,该设施是由国家有关实验室动物护理评估和认证机构根据现行法规和标准批准的。
数据库数据来自GSE16515以及Kaplan-Meier Plotter。
实施例一:人类胰腺癌中PKP2情况探究
在GEO数据库中检索胰腺癌相关数据集后选取了GSE16515,该数据集是由36个人类胰腺癌肿瘤样本和16个正常样本组成;总共52个样本。通过R Studio软件进行两组样本中PKP2 mRNA表达量的比对。在Kaplan-Meier Plotter数据库中进行了PKP2表达量对于胰腺癌生存时间影响的分析。利用人类胰腺癌组织样品进行免疫组织化学染色确定胰腺癌组织中PKP2蛋白表达情况。
实验结果见图1:通过GSE16515数据分析,PKP2的mRNA表达量在胰腺癌组织中的表达量高于正常胰腺组织。同时Kaplan-Meier Plotter数据库生存时间分析说明PKP2高表达会导致胰腺癌患者生存时间缩短。对人类胰腺癌组织的免疫组织化学染色中可以观察到PKP2在胰腺癌组织中蛋白表达量显著高于正常胰腺组织。
实施例二:人胰腺癌细胞系转导实验
转染前一天,将SW1990细胞、CFPAC-1细胞、AsPC-1细胞和PL-45细胞接种在6孔板上,加入1mL含10%胎牛血清(FBS)的细胞培养基。选择用于初期接种的细胞数量,转导siRNA的细胞应能在24小时内使细胞汇合达到50-60%,转导质粒的细胞应能在24小时内使细胞汇合达到70-80%。在125μl的减血清培养基(Opti-MEM)加入100pmol siR NA(siPKP2/siCtrl)(或2μg DNA(pcDNA3.1/pPKP2)和5μl P3000),柔和混匀,同时用125μlOpti-MEM稀释5μl lipofectamin3000,轻轻混匀,室温放置5分钟;将稀释好的siRNA\DNA和lipofectamin3000混合;轻柔混匀,室温放置15分钟,以便形成siRNA(siPKP2/siCtrl)/lipofectamin(或DNA(pcDNA3.1/pPKP2)/lipofectamin)复合物。将500μl siPKP2/lipofectam in(或DNA(pcDNA3.1/pPKP2)/lipofectamin)复合物加到相应的含有细胞和培养基的培养板的孔中,来回轻柔摇晃细胞培养板板。在37℃培养箱中继续培养6小时后弃掉培养板中的培养基并在每孔加入2mL含10% FBS的细胞培养基,继续放入37℃培养箱中培养,42小时后收取细胞蛋白。
实验结果见图2中的B,在分别使用siCtrl和siPKP2进行转染处理的细胞系(SW1990和CFPAC-1)中,转染了siPKP2的实验组中PKP2的表达量显著低于转染了siCtrl的对照组;同时在分别转染pcDNA3.1和pPKP2的细胞(AsPC-1和PL-45)中,转染了pPKP2的实验组出现了PKP2条带。以上结果说明对于所选取的人胰腺癌细胞系进行的PKP2敲低及过表达的操作成功,可以进行后续功能实验。
实施例三:小鼠胰腺导管腺癌(胰腺癌)异位移植瘤实验
在本实验中所进行的异位异种移植瘤模型为皮下移植模型,选取的细胞系为AsPC-1和CFPAC-1,分别进行PKP2过表达和敲低后探究PKP2对细胞成瘤能力的影响。在每组实验中选取十只五周龄左右的免疫缺陷裸鼠,将其分为实验组与对照组,每组各五只;在对As PC-1分别转染pPKP2和pcDNA3.1(或对CFPAC-1分别转染siPKP2和siCtrl)后,以每只鼠2*106(或1*106)的细胞量制成细胞悬液,细胞悬液的总体积为100ul(50ulPBS+50ul基质胶),向每只鼠注射内含2*106(或1*106)的细胞量的100ul的细胞悬液,九天后以每三天记录测量每只鼠的皮下荷瘤的长宽,并计算体积(体积=0.52*长*宽2)。
在异位异种移植瘤模型中,未经处理的对照细胞与经过PKP2敲低或过表达的小鼠胰腺导管腺癌(胰腺癌)细胞(1×106或2×106)重悬于0.1mL基质胶中,注射到裸鼠侧翼皮下,对照组和实验组分别为五只裸鼠。注射9天后每隔三天用卡尺测量肿瘤的长度和宽度。以未经处理的细胞作为对照,荷瘤小鼠在组内最大肿瘤体积临近动物伦理要求范围内的时间点实施安乐死,切除肿瘤并称重。肿瘤体积(mm3)计算公式为:短径2*长径*0.52。
实验结果见图3:从移植瘤形态、瘤体积和瘤重的测量结果显示抑制PKP2的表达可以抑制小鼠肿瘤的生长,且PKP2表达量的升高可以促进小鼠肿瘤的生长。
实施例四:人胰腺癌细胞系增殖实验
转染前一天,将SW1990细胞(5×103/孔)、CFPAC-1(3×103/孔)细胞、AsPC-1细胞(5×103/孔)和PL-45(4×103/孔)细胞接种在96孔板上,200μl含10% FBS的细胞培养基。选择用于初期接种的细胞数量,应能在24小时内使细胞汇合达到70-90%。每孔按照以下方案进行转染:在5μl的Opti-MEM加入100pmol siRNA(siPKP2/siCtrl)(或80ng DNA(pc DNA3.1/pPKP2)和0.2μlP3000),柔和混匀,同时用5μl Opti-MEM稀释0.2μl lipofectamin3000,轻轻混匀,室温放置5分钟;将稀释好的DNA(pcDNA3.1/pPKP2)和lipofectamin3000混合;轻柔混匀,室温放置15分钟,以便形成siRNA(siPKP2/siCtrl)/lipofectamin(或DNA(pcDNA3.1/pPKP2)/lipofectamin)复合物。将10μl siRNA(siPKP2/siCtrl)/lipofectamin(或DN A(pcDNA3.1/pPKP2)/lipofectamin)复合物加到相应的含有细胞和培养基的培养板的孔中,来回轻柔摇晃细胞培养板。在SW1990和CFPAC-1(细胞中转入siPKP2,siCtrl作为对照;在AsPC-1和PL-45细胞中转入pPKP2,pcDNA3.1作为对照。进行PKP2敲低的细胞系分别在转染后第0、1、3、5、7天使用CCK8测定细胞含量,进行PKP2过表达的细胞系分别在转染后第0、1、2、3、5天(或第0、1、3、5、7天)使用CCK8测定细胞含量。测定方法如下:取一定量的CCK8试剂并加入其十倍体积的培养基混合均匀,吸掉96孔板中需要测量的孔中剩余培养基,注意不要吸掉细胞,每孔加入100μlCCK8与培养基的混合液。将体系放入37℃培养箱中继续孵育2小时,采用450nm单波长检测吸光度。
实验结果见图2中的C:高表达PKP2的人胰腺导管癌细胞SW1990和CFPAC-1,在通过siRNA敲低PKP2表达后,其增殖能力被抑制;在低表达PKP2的人胰腺导管癌细胞As PC-1和PL-45中过表达PKP2后,其增殖能力增强,说明PKP2具有促进肿瘤细胞增殖的能力。
实施例五:人胰腺癌细胞系迁移实验
转染前一天,8×105AsPC-1和PL-45细胞接种在6孔板上,2mL含10% FBS的细胞培养基。选择用于初期接种的细胞数量,应能在24小时内使细胞汇合达到70-90%。在125μl的Opti-MEM加入2μg DNA和5μlP3000,柔和混匀,同时用125μl Opti-MEM稀释5μllipofectamin3000,轻轻混匀,室温放置5分钟;将稀释好的pPKP2和pcDNA3.1和lipofectamin3000混合;轻柔混匀,室温放置15分钟,以便形成DNA/lipofectamin复合物。将500μl DNA/lipofectamin复合物加到相应的含有细胞和培养基的培养板的孔中,来回轻柔摇晃细胞培养板。在AsPC-1和PL-45细胞中转入pPKP2,以pcDNA3.1作为对照,转染后第二天进行细胞划痕,PBS洗细胞3次,加入无血清的细胞培养基(加1%青霉素链霉素)1毫升;细胞培养条件37℃,5%二氧化碳,细胞培养72小时后拍照。测量0和72小时的划痕宽度。
实验结果见图2中的D:在低表达PKP2的人胰腺导管癌细胞AsPC-1和PL-45中过表达PKP2后,其迁移能力增强,说明PKP2具有促进肿瘤细胞侵袭和迁移的能力。
实施例六:验证PKP2在正常胰腺组织、胰腺炎组织以及不同程度胰腺癌前病变组织中的表达
在验证PKP2在正常胰腺组织表达情况的实验中,选取成年野生型小鼠进行取样。在验证PKP2在胰腺炎组织表达情况的实验中,取野生型小鼠进行雨蛙素注射实验,按照小鼠体重确定注射剂量,80ug/kg(雨蛙素浓度10ug/ml),每天8次,间隔1h,注射两天,最后一次注射完成后48h取样。在验证PKP2在不同程度胰腺癌前病变组织表达情况的实验中,选取胰腺导管腺癌经典模型LSL-KrasG12D;Pdx1-Cre小鼠(KC鼠),在其三十周时取样。
包埋后通过免疫荧光染色判断PKP2在胰腺炎组织中的表达情况。
实验结果分别见图4和图5:PKP2在正常胰腺组织中表达仅限于导管细胞顶端,在腺泡细胞中表达量很低甚至不表达。但在ADM过程中,PKP2在腺泡的表达量明显上升,主要集中在腺泡集团中心位置,且出现时间覆盖了整个ADM过程,并在PanIN中有表达量上升的趋势。
实施例七:验证PKP2敲除后在小鼠模型中对胰腺炎形成和发展的影响
构建PKP2-/-;PDX-1-cre小鼠,将PKP2fl/+小鼠与PDX-1-cre小鼠杂交产生PKP2+/-;PDX-1-cre小鼠,再利用PKP2+/-;PDX-1-cre小鼠与PKP2fl/+小鼠杂交产生PKP2-/-;PDX-1-cre小鼠作为实验组,同时生产出的PKP2+/-;PDX-1-cre小鼠、PKP2+/+;PDX-1-cre小鼠以及PKP2fl/fl小鼠作为实验的对照组。PKP2fl/fl小鼠实际上是没有敲除的鼠,只存在敲除位点,但因为没有PDX1-CRE不能将PKP2敲除,设计这种鼠的目的是排除PDX1-CRE的影响。
每种基因型小鼠各取三只同性别的进行雨蛙素注射实验,按照小鼠体重确定注射剂量,80ug/kg(雨蛙素浓度10ug/ml),每天8次,间隔1h,注射两天,最后一次注射完成后48h取样。包埋后通过HE染色判断胰腺病变程度。
实验结果见图6:通过HE染色,发现从总体上看PKP2敲除后病变严重的区域会相对减少,但病变区域的严重程度没有明显的差异。证明了PKP2敲除会抑制正常腺泡细胞在环境刺激下化生为导管的过程。
以上实施例仅为本发明较优的实施方式,仅用于解释本发明,而非限制本发明,本领域技术人员在未脱离本发明精神实质下所作的改变、替换、修饰等均应属于本发明的保护范围。
Claims (10)
1.PKP2基因表达抑制剂在制备治疗胰腺癌及其早期病变的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述PKP2基因表达抑制剂为基于PKP2基因设计的siRNA。
3.根据权利要求2所述的应用,其特征在于,所述基于PKP2基因设计的siRNA为siPKP2,所述siRKP2由双链核酸分子1和2组成,所述核酸分子1由SEQ ID NO.1所示的正义链RNA分子和2个dT组成,2个dT位于3’端;所述核酸分子2由SEQ ID NO.2所示的反义链RNA分子和2个dT组成,2个dT位于3’端。
4.一种用于治疗胰腺癌及其早期病变的药物组合物,其特征在于,包括PKP2基因表达抑制剂。
5.根据权利要求4所述的药物组合物,其特征在于,所述PKP2基因表达抑制剂为基于PKP2基因设计的siRNA。
6.一种用于胰腺癌早期诊断和治疗的分子标记物,其特征在于,所述一种用于胰腺癌早期诊断和治疗的分子标记物包括PKP2基因、PKP2 mRNA和PKP2蛋白的一种或两种以上。
7.如下a1-a3中的至少一种在如下b1-b4至少一种中的用途:
a1,PKP2基因;a2,PKP2 mRNA;a3,PKP2蛋白;
b1,作为癌症及其癌前病变的诊断标志物,或者制备用于癌症诊断的产品;
b2,作为癌症的预后标志物,或者制备用于癌症预后评估的产品;
b3,制备用于癌症疗效监测的产品;
b4,制备治疗癌症的药物。
8.根据权利要求7所述的用途,其特征在于,所述癌症为胰腺癌;所述癌症诊断包括癌症早期诊断、癌症远处转移诊断和/或癌症淋巴结转移诊断。
9.根据权利要求7所述的用途,其特征在于,所述用于癌症诊断的产品、用于癌症预后评估的产品和/或用于癌症疗效监测的产品包括芯片、试剂盒。
10.根据权利要求7所述的用途,其特征在于,所述用于癌症诊断的产品、用于癌症预后评估的产品和/或用于癌症疗效监测的产品包括扩增PKP2的引物、探针或抗体。
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