CN112168968A - Fto抑制剂在制备防治乳腺癌产品中的应用 - Google Patents
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Abstract
本发明属于医药和保健品技术领域,具体涉及FTO抑制剂在制备防治乳腺癌产品中的应用,为寻找有效治疗乳腺癌的新型靶点药物,本发明提供FTO抑制剂在制备防治乳腺癌产品中的应用,本发明经研究发现通过抑制乳腺癌的FTO表达水平能显著抑制肿瘤的形成和生长进展,说明FTO是乳腺癌的潜在治疗靶点,FTO抑制剂是具有前景的乳腺癌治疗物质。
Description
技术领域
本发明属于医药和保健品技术领域,具体涉及FTO抑制剂在制备防治乳腺癌产品中的应用。
背景技术
m6A(N6-methyladenosine,6-甲基腺苷甲基化)修饰是指RNA腺嘌呤第6位氮原子上的甲基化修饰,是真核生物mRNA序列中最常见的一种转录后修饰,受到甲基转移酶(METTL3,METTL14,WTAP,RBM15,KIAA1429等)、去甲基化酶(FTO,ALKBH5等)和RNA结合蛋白(YTHDF1/2/3,ELAVL1,eIF3,IGF2BP等)这三种调控因子的调节,是一个动态可逆的过程。2012年,有学者提出用高通量测序与抗体免疫沉淀相结合的方法(MeRIP-seq和m6A-seq)对m6A修饰进行大规模检测,发现超过20%的人群中有超过5000种mRNA上有m6A修饰,而这些mRNA中很多是与疾病相关的基因转录产生的。抑制或敲除调控m6A的酶组分会导致重要表型发生改变。
FTO(Fat mass and obesity associated,脂肪与肥胖相关基因)最早是通过GWAS(全基因组关联分析)鉴定到的与肥胖相关的基因,但其具体机制在很长一段时间里是未知的,直到2011年才有研究发现FTO是m6A修饰的去甲基化酶,并且相继发现FTO既参与mRNA、snRNA的m6A修饰,也参与mRNA、snRNA的m6Am修饰,还作用于tRNA的m1A修饰,这些发现让FTO得到广泛关注,对其的研究不再局限于肥胖、糖尿病等代谢性疾病,广泛涉及多种生理病理过程。近年来,越来越多的研究发现FTO在多种癌症中表达异常,通过调控靶基因的mRNAm6A修饰影响癌症的发生发展,说明FTO是一个潜在的肿瘤治疗靶点。近年来,虽然越来越多的研究发现FTO作为m6A修饰的去甲基化酶在多种癌症的发生发展中发挥重要中用,但是FTO在乳腺癌发生发展中的作用尚不清楚,在乳腺癌治疗中的潜能尚无研究。
乳腺癌是女性最常见的恶性肿瘤之一,居女性恶性肿瘤的首位。全世界每年约有135万妇女被确诊患乳腺癌,约有50万妇女死于该肿瘤。其发病率在我国占恶性肿瘤的7%~10%。近年来,乳腺癌的发病率呈逐年上升趋势,发病年龄也明显年轻化,严重威胁着妇女的健康。乳腺癌是一个多因素参与并相互作用的复杂过程,既关乎癌细胞本身,又与癌细胞、癌周微环境以及宿主免疫状态的相互作用有关。目前有多种基因异常表达被确定与乳腺癌的发生发展有关,但与免疫相关的指标非常少。因此,迫切需要寻找有效治疗乳腺癌的新型靶点药物,抑制这种靶点一方面直接抑制肿瘤的增殖,另一方面可以通过影响肿瘤免疫微环境达到抑制肿瘤的生长。
发明内容
为了克服上述现有技术的不足,本发明提出了FTO抑制剂在制备防治乳腺癌产品中的应用,本发明的研究表明,抑制乳腺癌的FTO表达水平会导致肿瘤的形成和生长进展均被显著抑制,说明FTO是乳腺癌的潜在治疗靶点。
为了实现上述目的,本发明所采用的技术方案是:
本发明提供FTO抑制剂在制备防治乳腺癌产品中的应用。
本发明研究发现,FTO表达水平在乳腺癌中显著上调,通过抑制乳腺癌的FTO表达水平能显著抑制肿瘤的形成和生长进展,说明FTO抑制剂在乳腺癌防治中是具有前景的抗癌物质。
优选地,所述FTO抑制剂包括但不限于大黄酸。
大黄酸(Rhein,1,8-二羟基-3-羧基蒽醌):在芦荟、大黄、何首乌等许多药用植物中都有发现,也是大黄苷和番泻叶苷的蒽醌代谢物,分子式为C15H8O6,分子量为284.22,其结构式如下:
本发明研究发现,通过在小鼠腹腔内注射大黄酸,可以使肿瘤小鼠的肿瘤体积变小、重量变轻,说明大黄酸可以通过抑制肿瘤细胞的FTO表达,从而抑制肿瘤的生长。
优选地,所述防治乳腺癌的产品包括但不限于防治乳腺癌的药品和防治乳腺癌的保健功能食品。
优选地,所述防治乳腺癌为抑制乳腺癌FTO的表达。本发明的研究表明抑制乳腺癌的FTO表达水平会导致肿瘤的形成和生长进展均被显著抑制,说明FTO是乳腺癌的潜在治疗靶点。
本发明还提供一种防治乳腺癌的药物,包括FTO抑制剂。
优选地,所述FTO抑制剂为大黄酸。
优选地,为提高药物的适用范围,还包括药学上可接受的载体和/或辅料。如酸味剂、调色剂、香味剂、甜味剂,或其组合。
优选地,所述防治乳腺癌药物的剂型包括但不限于口服液、冲剂、胶囊剂、片剂、颗粒剂、丸剂、膏剂和注射剂。
本发明还提供一种防治乳腺癌的保健功能食品,包括FTO抑制剂。
优选地,所述FTO抑制剂为大黄酸。
优选地,为提高保健功能食品的适用范围,还包括食品上可接受的载体和/或辅料。如稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、甜味剂、香味剂,或其组合。
优选地,所述防治乳腺癌保健功能食品的剂型包括但不限于口服液、胶囊剂、片剂和粉剂。
与现有技术相比,本发明的有益效果是:
本发明提供FTO抑制剂在制备防治乳腺癌产品中的应用,本发明经研究发现通过抑制乳腺癌的FTO表达水平能显著抑制肿瘤的形成和生长进展,说明FTO是乳腺癌的潜在治疗靶点,FTO抑制剂是具有前景的乳腺癌治疗物质。
附图说明
图1为慢病毒感染稳定敲低乳腺癌细胞4T1的FTO表达水平的蛋白印迹实验;
图2为不同浓度大黄酸对乳腺癌细胞4T1中FTO的抑制作用免疫印迹实验;
图3为慢病毒敲低FTO或大黄酸抑制FTO对乳腺癌细胞4T1的肿瘤生长的影响图;
图4为敲低或抑制FTO对乳腺癌细胞4T1形成肿瘤的体积的影响情况;
图5为敲低或抑制FTO对乳腺癌细胞4T1形成肿瘤的肿瘤重量的影响情况;
图6为敲低FTO对乳腺癌细胞MDA-MB-231肿瘤形成的抑制情况;
图7为原位成瘤实验中荧光素酶活性的相对定量;
图8为敲低FTO对乳腺癌细胞4T1的肺转移肿瘤形成情况的抑制作用;
图9为敲低FTO对乳腺癌细胞4T1的肺转移肿瘤灶数量的影响情况;
图10为敲低FTO影响乳腺癌细胞4T1的肺转移肿瘤灶数量的切片图。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
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试验材料,如无特殊说明,均为可通过常规的商业途径购买得到的。
实施例1蛋白印迹实验
首先,我们用敲除FTO慢病毒感染乳腺癌细胞4T1,并且通过嘌呤霉素筛选得到稳定敲低FTO的细胞株,用与之对照的慢病毒感染4T1细胞并筛选得到对照的细胞株,然后用蛋白印迹实验验证FTO的敲低情况。分别将细胞接种到细胞培养皿中,放置于细胞培养箱中培养,用含蛋白酶抑制剂的RIPA裂解液裂解细胞后提取总蛋白,再用BCA蛋白定量试剂盒检测蛋白的浓度并进行等量分装和蛋白变性处理,使用SDS-PAGE凝胶进行蛋白电泳,用PVDF膜进行电转,封闭后在4度中孵育相应抗体过夜,分别为目的蛋白FTO抗体(ab124892,1:1000,Abcam)和内参蛋白β-actin(β肌动蛋白)抗体(AF1700,1:1000,R&D system),再常温孵育与一抗对应种属的二抗1小时,浸泡发光液,用凝胶成像系统检测蛋白条带的信号强度。
如图1的结果显示,与对照组相比,FTO敲低组的FTO蛋白表达水平显著下调,说明我们成功构建了敲低FTO的4T1细胞株。
同时,我们使用含不同浓度大黄酸(0、20、40、80μmol/L)的细胞培养基培养乳腺癌细胞4T1,再通过蛋白印迹实验检测FTO的表达情况,具体方法同上。
如图2的结果显示,与无大黄酸处理的对照组相比,FTO的表达水平在大黄酸处理组的4T1细胞中明显下调,并且大黄酸浓度越高,FTO表达水平越低,说明大黄酸对乳腺癌细胞的FTO具有显著抑制作用,是有效的FTO抑制剂。
实施例2皮下成瘤实验
在皮下成瘤实验中,将4周龄的雌性Balb/c小鼠随机分为对照组、大黄酸组和FTO敲低组,其中,FTO敲低组在小鼠皮下注射1×106个使用慢病毒感染稳定敲低FTO的乳腺细胞4T1,其他两组在皮下注射等量的对照4T1细胞。接下来的饲养过程中,大黄酸组在小鼠腹腔内注射大黄酸(10mg/kg),其余两组则注射等体积DMSO(二甲基亚砜),每周3次。每3天用游标卡尺测量肿瘤大小,肿瘤体积用公式V=ab2/2计算,其中a和b分别是肿瘤的长径和短径。在肿瘤体积达到1000mm3时结束实验,安乐死处死小鼠后解剖取出肿瘤组织,用天平称量肿瘤的重量。
如图3-5的结果显示,与对照组相比,大黄酸组和FTO敲低组的肿瘤体积明显较小、重量明显较轻,说明抑制FTO导致肿瘤的生长情况被显著抑制。
实施例3原位成瘤实验
在原位成瘤实验中,将4周龄的雌性Balb/c小鼠随机分为对照组和FTO敲低组,将1×106个乳腺癌细胞MDA-MB-231悬浮于50μL Hanks溶液中。麻醉后切开小鼠乳腺前面的皮肤,FTO敲低组在小鼠乳腺脂肪组织中注射1×106个使用慢病毒感染稳定敲低FTO并且有荧光素酶标记的MDA-MB-231细胞,对照组则注射等量的仅有荧光素酶标记的MDA-MB-231细胞,外科缝合皮肤后继续饲养30天。在小鼠腹腔内注射荧光素,15分钟后用动物成像系统进行监测,拍照并对荧光素酶的活性进行相对定量。
如图6和图7的结果显示,敲低FTO导致肿瘤的形成情况被显著抑制。
实施例4肺转移实验
在肺转移实验中,将4周龄的雌性Balb/c小鼠随机分为对照组和FTO敲低组,FTO敲低组在小鼠尾静脉注射1×106个使用慢病毒感染稳定敲低FTO的乳腺细胞4T1,对照组则尾静脉注射等量的对照4T1细胞。继续饲养3周后安乐死处死小鼠,解剖取出肺组织,用4%多聚甲醛固定,蜡块包埋并切片后进行观察,并统计肿瘤转移灶的数量。
如图8-10的结果显示,敲低FTO导致肿瘤的肺转移情况被显著抑制。
综合实施例1-3的研究结果显示,抑制乳腺癌的FTO表达水平会导致肿瘤的形成和生长进展均被显著抑制,说明FTO是乳腺癌的潜在治疗靶点,FTO抑制剂是有前景的乳腺癌治疗药物。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
1.FTO抑制剂在制备防治乳腺癌产品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述FTO抑制剂包括但不限于大黄酸。
3.根据权利要求1所述的应用,其特征在于,所述防治乳腺癌的产品包括但不限于防治乳腺癌的药品和防治乳腺癌的保健功能食品。
4.根据权利要求1所述的应用,其特征在于,所述防治乳腺癌为抑制乳腺癌FTO的表达。
5.一种防治乳腺癌的药物,其特征在于,包括FTO抑制剂。
6.根据权利要求5所述的一种防治乳腺癌的药物,其特征在于,还包括药学上可接受的载体和/或辅料。
7.根据权利要求5所述的一种防治乳腺癌的药物,其特征在于,所述防治乳腺癌药物的剂型包括但不限于口服液、冲剂、胶囊剂、片剂、颗粒剂、丸剂、膏剂和注射剂。
8.一种防治乳腺癌的保健功能食品,其特征在于,包括FTO抑制剂。
9.根据权利要求8所述的一种防治乳腺癌的保健功能食品,其特征在于,还包括食品上可接受的载体和/或辅料。
10.根据权利要求8所述的一种防治乳腺癌的保健功能食品,其特征在于,所述防治乳腺癌保健功能食品的剂型包括但不限于口服液、胶囊剂、片剂和粉剂。
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