CN116392592A - Xbp1-us在制备抗肿瘤药物中的应用 - Google Patents
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Abstract
本发明公开了一种XBP1‑US在制备抗肿瘤药物中的应用。本发明的XBP1‑US可增强LUAD细胞和肿瘤对顺铂的耐药性。
Description
技术领域
本发明涉及药物技术领域，尤其涉及XBP1-US在制备抗肿瘤药物中的应用。
背景技术
非小细胞肺癌(NSCLC)约占所有肺癌的80％，而肺腺癌(LUAD)是NSCLC最常见的亚型。除了手术切除外，化疗也是LUAD治疗的有效方法。然而，化疗通常由于在晚期疾病中发生的化疗耐药性而失败。我们推测，逆转LUAD患者耐药性的关键是了解耐药性形成的关键分子机制。在本研究中，我们探讨了LUAD细胞对顺铂(DDP)耐药的机制。
X-box结合蛋白1(XBP1)是一种转录因子，可在内质网(ER)应激过程中作为传感器，从而促进多种癌症的肿瘤发生和肿瘤进展。剪接的XBP1(XBP1s)可以在包括LUAD在内的多种恶性肿瘤中作为致癌基因。例如，IRE1α诱导的XBP1通过激活c-MYC信号来加速前列腺癌的进展；XBP1的剪接参与了LUAD的铁垂病敏感性；XBP1激活p JNK MAPK通路，促进LUAD的发展。然而，XBP1及其香料亚型(XBP1s)在调节LUAD细胞的DDP抗性中的作用仍有待研究。
选择性多聚腺苷酸化(APA)是一种广泛存在的在mRNA水平上的基因转录后调控机制。根据多聚腺苷化(pA)位点的位置，APA可分为两种类型：非翻译区APA(UTR-APA)和编码区APA(CR-APA)。UTR-APA可以通过产生不同长度的3'UTR转录本来调节mRNA的稳定性、翻译效率以及mRNA和蛋白的细胞定位。这在很大程度上是由于替代的3'UTR(近端和远端pA位点之间的序列)和其他rna或蛋白质分子之间的相互作用。与mRNA3'末端形成和选择性剪接相关的RNA结合蛋白可以调节选择性pA位点的使用，这表明多聚腺苷酸化和剪接之间存在相互关系。例如，异质核核糖核蛋白C(HNRNPC)可以通过选择性剪接来影响APA对具有poly(U)基序的mRNA的调控。裂解和多聚腺苷酸化特异性因子亚基(CPSF)家族成员形成APA核心复合物。CPSF6是APA因子之一，已被证明是3'UTR长度的重要调节因子。根据之前的报道，CPSF6基因敲低增加了C2C12成肌细胞中近端PAS的使用。此外，另一项研究表明，CPSF6的沉默导致了HEK293细胞中近端多聚(A)位点的改变。重要的是，CPSF6被证明可以调节apa介导的VHL 3'UTR的缩短，从而促进胃癌细胞的生长。然而，CPSF6是否能以apa依赖的方式调节XBP1 3'UTR的缩短尚不清楚。
发明内容
为了解决现有技术的问题，本发明实施例提供了一种XBP1-US在制备抗肿瘤药物中的应用。所述技术方案如下：
第一方面，提供一种XBP1-US在制备抗肿瘤药物中的应用。
进一步的，所述肿瘤包括肺癌。
进一步的，所述抗肿瘤药物包括顺铂。
第二方面，提供一种降低肺腺癌耐药性的作用靶点，所述靶点为pre-XBP1链中dPAS和pPAS。
进一步的，所述dPAS的核苷酸序列为AAUAAA。
进一步的，所述pPAS的核苷酸序列AUUAAA。
第三方面，提供一种XBP1s在制备促进DNA损伤修复药物中的应用。
进一步的，所述XBP1s的氨基酸序列如SEQ ID NO.1所示。
本发明实施例提供的技术方案带来的有益效果是：本发明的XBP1-US可增强LUAD细胞和肿瘤对顺铂的耐药性。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例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是本发明实施例中shRNA诱导的A549/DDP细胞中XBP1蛋白质印迹图；
图2是本发明实施例中沉默XBP1后A549/DDP细胞的IC50图；
图3是本发明实施例中沉默XBP1后shRNA诱导的A549/DDP细胞中XBP1蛋白质印迹图；
图4是本发明实施例中DDP处理下，A549/DDP细胞的凋亡图；
图5是本发明实施例中A549细胞耐药性XBP1蛋白质印迹图；
图6是本发明实施例中A549细胞耐药性图；
图7是本发明实施例中A549/DDP细胞耐药性XBP1蛋白质印迹图；
图8是本发明实施例中A549/DDP细胞耐药性图；
图9是本发明实施例中A549细胞在不同小鼠中肿瘤生长速率图；
图10是本发明实施例中A549细胞在不同小鼠中肿瘤重量和小鼠重量图；
图11是本发明实施例中不同小鼠中XBP1-T表达水平图；
图12是本发明实施例中不同小鼠中A549细胞在Ki67和XBP1s免疫染图色；
图13是本发明实施例中不同小鼠中A549细胞在Ki67和XBP1s数据图；
图14是本发明实施例中DDP治疗下不同小鼠的肺和肝脏照片；
图15是本发明实施例中DDP治疗下不同小鼠的肺和肝脏淋巴数量图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明实施方式作进一步地详细描述。
(1)临床样本
从2019年至2021年，在南京第一医院收集了60名LUAD患者和30名非LUAD对照组的外周血样本。所有LUAD患者均接受DDP型化疗，并采集治疗前后的血样。样品保存在-值为80C下，用于后续分析。
该研究得到了南京第一医院伦理委员会的批准，并遵守了《赫尔辛基宣言》。所有患者及其法定监护人均签署了知情同意书。
(2)细胞培养与处理
休曼LUAD细胞(A549、H1975、H838、HCC827)购自美国型培养标本(ATCC；马纳萨斯，VA，USA)，PC-9细胞系购自BeNa培养标本(BNCC，北京，中国)。LUAD细胞系均在含有10％胎牛血清(FBS，Gibco，罗克福德，IL，美国)的RPMI-1640培养基(英特朗，卡尔斯巴德，美国)中培养。A549/DDP细胞购自KeyGENBioTECH(南京，中国)，在添加10％胎牛血清、1％ P/S和DDP(1000ng/ml)的RPMI-1640培养基中培养。细胞系在含有5％二氧化碳的加湿培养箱中保持在37℃。
DDP(拓扑科学，上海，中国)、ActD(默克，达姆施塔特，德国)、CHX(医学化学快递，新泽西州，美国)和MG132(医学化学快递)分别用于细胞处理。伊卡素(ICT)来自上海WinHerb医学科学公司(上海，中国)，纯度高达99.5％。在DMSO(Sigma-Aldrich，圣路易斯，密苏里州，美国)中溶解的ICT用于处理A549或A549/DDP细胞。
(3)细胞转染和感染
专门针对XBP1(sh-XBP1-1和sh-XBP1-2)、CPSF6(sh-CPSF6-1和sh-CPSF6-2)、METTL3(sh-METTL3-1和sh-METTL3-2)、WTAP(sh-WTAP-1和sh-WTAP-2)、BRCA1、BRCA1(sh-BRCA1-1和sh-BRCA1-2)、LINC00221(LINC00221-1和sh-LINC00221-2)和p53(sh-p53)由上海基因制药公司(中国)合成。以非特异性序列的ShRNA作为阴性对照(sh-NC)。
分别合成CPSF6、BRCA1、LINC00221、XBP1-UL、XBP1-US、METTL3和WTAP的序列，并将其亚克隆到pcDNA3.1载体(Invitrogen，卡尔斯巴德，USA)中，得到相应的表达载体。脂质体2000用于转染。
表达剪接XBP1的重组腺病毒(Ad-XBP1s)由R&S公司(上海，中国)构建。以一种表达增强型绿色荧光蛋白(Ad-GFP)的腺病毒作为阴性对照。用重组腺病毒感染细胞24h，实验前用含1％胎牛血清的RPMI-1640培养基静息12h。
(4)定量逆转录聚合酶链反应(RT-qPCR)
使用Trizol(生命技术公司，美国)从组织样本或细胞系中分离总RNA。逆转录使用PrimeScript RT试剂试剂盒(完美实时)(Takara，日本)完成。根据制造商的协议，使用TBGreenPremixExTaqII(TliRNaseHPalus)(Takara)进行实时qRT-PCR分析。扩增产物经琼脂糖凝胶电泳(AGE)分离。采用2-ΔΔct法计算相对RNA表达量，将对照组的平均RNA表达量定义为1.0。用GAPDH作为归一化的内部对照。
(5)荧光素酶报告基因分析
将293T、A549和A549/DDP细胞接种于24孔板中，孵育24h，直到细胞浓度达到60-70％。构建Psi-CHECK2/XBP1-US和Psi-CHECK2/XBP1-UL质粒，用脂质体2000转染。48h后，用双荧光素酶报告检测系统(Promega，美国)检测相对荧光素酶活性，用GloMax 96微孔板光度计(Promega，美国)记录，并归一化至肾素酶活性。
(6)蛋白质印迹
将细胞裂解物收集到含有10个μL PMSF的1mL RIPA(Solarbio，北京，μL)中。采用BCA蛋白检测试剂盒(生工生物技术公司，上海，中国)测定细胞裂解液的蛋白浓度。用十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)分离40μg蛋白质，并在恒定240mA电转移到聚偏氟乙烯(PVDF)膜上4小时。用5％脱脂牛奶封闭膜，用TBST缓冲液洗涤，然后用一抗孵育，包括抗xbp1、抗IREα、抗p-perk、抗atf6、抗chop、抗mettl3、抗mettl14、抗WTAP、抗brca1、抗cpsf6、抗p53和抗xbp1在4C下过夜。然后，用TBST洗涤膜3次，与HRP连接二抗(Abcam)室温孵育1小时，以β-actin(Abcam)作为内参。信号通过固定西部化学发光HRP基底物(密孔公司，比勒里卡，MA，美国)和美国成像600(GE医疗保健生命科学，匹兹堡，宾夕法尼亚州，美国)可视化。
(7)CCK-8的化疗耐药性检测
用CCK-8溶液(日本熊本博士有限公司)评价DDP的细胞活力和半最大抑制浓度(半抑制浓度)值。简单地说，24孔板中的A549或A549/DDP细胞分别用不同剂量的DDP(100、100.5、101、101.5、102和102.5μg/ml)处理。48h后，更新培养基，用10μL CCK-8溶液(江苏碧，中国)处理细胞2h。用酶标仪(Thermo Fisher)在450nm处测定吸光度，确定半抑制浓度值。
(8)克隆形成实验
转染24h后，将6孔板上的500个细胞接种于每孔中，培养2周。集落形成后，细胞用4％多聚甲醛(PFA)(Biosharp，合肥，中国)固定20min，菌落用1％结晶紫(KeyGen BioTECH，江苏，中国)染色15min。最后，人工计算三个独立实验中菌落形成单位的数量。
(9)流式细胞术分析
采用膜联蛋白V-FITC检测试剂盒(DojinDo，日本)检测细胞凋亡情况。简单地说，将1个×106A549/DDP细胞接种于6孔板的每个孔中，培养至90％的融合度。胰蛋白酶化和悬浮后，细胞用5μL Annexin V-FITC染色，然后用5μL PI溶液黑暗孵育15min，加入400μL膜联蛋白V结合溶液。样本使用BD Accuri C6 Plus(BD)流式细胞仪进行分析。采用BD AccuriC6 Plus软件鉴定坏死细胞、早期细胞和晚期凋亡细胞。
(10)体内异种移植实验
动物研究以南京中医药大学动物护理与使用委员会批准的方案为指导。动物研究经南京中医药大学伦理委员会批准。BALB/c小鼠，年龄5-6周龄，体重22-28克，雌雄混合，来自Slac实验室(上海，中国)。将小鼠随机分为三组进行转染：Vector、XBP1-UL或XBP1-US。将稳定转染的A549细胞(5×106,100μlPBS)皮下注射到每只小鼠体内，建立体内肿瘤发生模型。每三天观察和测量一次肿瘤。肿瘤体积的评估公式为：(长度×宽度2)×0.5，使用卡尺测量每个肿瘤的长度和宽度。当肿瘤组织体积达到100mm3时，每周用尾静脉注射DDP(3mg/kg)治疗小鼠3次。6周后处死所有小鼠。分离各组肿瘤组织，立即在-80℃下保存，用于后续的免疫组化(IHC)检测。为了模拟体内转移，将1个转染了载体、XBP1-UL或XBP1-US的×107A549细胞通过尾静脉注射到小鼠体内。两周后，小鼠每周三次尾静脉注射DDP(3mg/kg)。6周后，处死小鼠，切除肺和肝组织。计算各组肺、肝组织中的转移性结节。
(11)IHC染色
从体内实验中获得的组织样本被固定在福尔马林溶液中，在乙醇中脱水，并用石蜡包埋。分别使用抗Ki67(细胞信号技术，波士顿，MA，美国)和抗xbp1(Abcam，剑桥，MA，美国)在石蜡玻片上进行Ki67和xbp1的IHC分析。DAB试剂盒(Biosharp，上海，中国)用于染色观察。选取5个不连续视野，在40×或400×光学显微镜下观察。相对于Ki67或xbp1阳性，评估染色面积的百分比。
(12)RNA免疫沉淀(RIP)和m6A RNA免疫沉淀(MeRIP)检测
对于RIP检测，EZMagna RIP试剂盒(Sigma-Aldrich，圣路易斯，密苏里州，美国)根据方案应用。简单地说，在冰冷的PBS中收集细胞，用RIP裂解缓冲液裂解，裂解液与磁珠和单个抗体(抗cpsf6、抗mettl3或抗WTAP)或阴性对照IgG在4C下孵育6小时。然后，用RIP洗涤缓冲液洗涤珠子，用蛋白酶K在55C下孵育30分钟以去除蛋白质。最后，洗脱纯化后的RNA并进行RT-qPCR分析。在MeRIP实验中，提取A549或A549/DDP细胞的RNA，并用DNaseI(SigmaAldrich)从A549或A549/DDP细胞中提取RNA并纯化RNA。然后，将RNA提取物与磁性dynabead结合的抗m6a抗体(Abcam)孵育过夜。用RT-qPCR对珠粒捕获的RNA进行分析。
(13)染色质免疫沉淀(ChIP)分析
使用MagnaChIP试剂盒(Millipore)用于ChIP检测，并根据制造商的协议使用。简单地说，将细胞接种在6孔板中，并分别用1％的甲醛和125nM的甘氨酸处理。然后，用裂解缓冲液裂解细胞，用细胞裂解液中的超声染色质产生DNA片段。然后，分别用brca1特异性抗体(抗brca1)或IgG抗体免疫沉淀。最后，用qPCR方法对衍生的DNA进行检测。
(14)DNA-RNA混合免疫沉淀(DRIP)
悬浮细胞在核提取缓冲液中分离，缓冲液包含10mM HEPES、pH 7.9、1.5mM氯化镁、0.34M蔗糖、10％甘油、1mM DTT、10mM氯化钾和1％蛋白酶抑制剂。然后将悬液与Triton X-100(1％)在冰上孵育5min。核收集颗粒在1300g离心5min 4℃，然后溶解在25毫升Tris-HCl，pH 8.0，250毫升氯化钠，1％ Triton X-100有或没有1μg/毫升RNAseH130 min，然后超声处理，直到DNA碎片成200个基点。上清液以12000g离心20分钟，用anti-S9.6-specific抗体(抗s9.6)处理4h。最后，免疫沉淀用裂解缓冲液洗涤3次，然后在SDS上载缓冲液中直接煮沸。
(15)亚细胞分馏法
根据制造商的协议，一个巴黎试剂盒(生命技术)被用于分离细胞质和核组分。采用免疫印迹法检测细胞质蛋白和细胞核蛋白。
(16)荧光原位杂交(FISH)检测
linc00221特异性探针由Ribobio(中国广州)设计合成。细胞核用4,6-二氨基-2苯林多尔(DAPI)染色。所有的FISH程序都符合制造商的FISH试剂盒(基因法，中国)的说明。图像采集使用蔡司LSM880 NLO显微镜(德国)。
(17)免疫荧光(IF)测定
将1个×10个5细胞接种在24孔板中的盖玻片上。转染36h后，在室温下用4％多聚甲醛固定细胞15min，PBS洗涤2次。接下来，细胞用猝灭溶液(PBS+0.1％甘氨酸)洗涤两次，用0.1％ Triton X-100渗透10min，并在室温下用10％胎牛血清的PBS+封闭1小时。盖玻片与抗XBP1或p53的一抗(细胞信号技术)孵育，然后与二抗Alexa Fluor 594偶联的山羊抗兔IgG(1：50，ZF-0516，ZSGB-Bio，北京，China)孵育。细胞核用DAPI染色，用抗荧光猝灭剂(Beyotime，上海，中国)安装盖玻片。图像在蔡司LSM880 NLO显微镜下获得。
(18)RNA下拉试验
(BersinBio，广州，中国)证明了CPSF6与LINC00221之间的相互作用。简单地说，针对LINC00221的生物素标记探针LINC00221(Bio-LINC00221)。然后，将细胞裂解物与linc00221特异性探针孵育，形成rna-蛋白复合物。用链霉亲和素偶联磁珠拉下复合物，用抗CPSF6抗体的westont检测复合物中的CPSF6蛋白。
(19)共免疫共沉淀(Co-IP)和质谱分析
用FLAG或FLAG-XBP1s质粒转染DDP处理下的A549细胞，培养24h。co-IP分析和质谱程序如前所述的进行。
(20)统计分析
本研究中进行的每个实验至少重复3次。所有数据均使用SPSS 21.0(IBM，芝加哥，IL，USA)进行分析，并使用GraphPad Prism 9.0以平均±标准差(SD)表示。p值小于0.05。两组样本的比较采用未配对的学生t检验，而两组以上样本的比较采用Tukey检验校正的单因素方差分析(ANOVA)。
(21)不同3'UTR的XBP1及其转录本在LUAD细胞DDP抗性中的作用
通过蛋白质印迹验证了由XBP1特异性shRNA诱导的A549/DDP细胞中XBP1的有效下调(图1)。
如CCK-8测定法所检测，沉默XBP1后，A549/DDP细胞的IC50值迅速下降(图2)。
当XBP1沉默时，DDP处理更有效地抑制了A549/DDP细胞的集落形成(图3)。
如图4所示，在用10μg/ml DDP处理下，A549/DDP细胞的凋亡响应于XBP1干扰而增加。这些结果表明，XBP1是耐药性的增强子。
(22)不同长度3'UTR的XBP1转录本对LUAD细胞和转染含有等量质粒报告基因携带XBP1-UL或XBP1-US的A549细胞耐药性的影响
两次转染均增加XBP1的蛋白水平，但XBP1-US转染后其水平升高更显著，DDP治疗剂量扩大了XBP1-UL组和XBP1-US组之间的差异(图5和7)。
根据CCK-8检测结果，尽管转染XBP1-UL和XBP1-US增强了A549或A549/DDP细胞中的耐药性，但XBP1-US组的增强更有效(图6和8)。总体而言，XBP1-US更容易翻译成XBP1蛋白，从而增强耐药性。
进行体内实验以验证体外数据。因此，将相同数量的A549细胞分别皮下注射到三组小鼠中，用空载体XBP1-UL或XBP1-US转染。在相同DDP剂量下，XBP1-UL组和XBP1-US组肿瘤大小大于对照组；此外，在XBP1-US组中观察到最大尺寸的肿瘤。XBP1-UL和XBP1-US组的肿瘤，特别是XBP1-US组的肿瘤，比载体组的肿瘤生长得更快(图9)。三组中肿瘤的重量呈现与肿瘤生长速率相同的趋势，小鼠重量没有任何明显的变化(图10)。RT-qPCR检测表明，XBP1-UL组和XBP1-US组肿瘤组织中XBP1-T的表达水平高于载体组；此外，XBP1-US基团表现出最高的XBP1-T表达水平(图11)。Ki67或XBP1s免疫染色在XBP1-US组肿瘤中最高，在对照组中最低(图12和13)。此外，在相同的DDP治疗下，XBP1-US组小鼠肺和肝脏中转移淋巴结的数量最多，而对照组检测到的转移淋巴结最少(图14和15)。因此，XBP1-US加速LUAD肿瘤的生长和转移，并增强耐药性。
以上仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.XBP1-US在制备抗肿瘤药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述肿瘤包括肺癌。
3.根据权利要求1所述的应用，其特征在于，所述抗肿瘤药物包括顺铂。
4.一种降低肺腺癌耐药性的作用靶点，其特征在于，所述靶点为pre-XBP1链中dPAS和pPAS。
5.根据权利要求4所述的靶点，其特征在于，所述dPAS的核苷酸序列为AAUAAA。
6.根据权利要求4所述的靶点，其特征在于，所述pPAS的核苷酸序列AUUAAA。
7.XBP1s在制备促进DNA损伤修复药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述XBP1s的氨基酸序列如SEQ ID NO.1所示。
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