CN112870364B - circ-RNF13-TRIM41-p53复合体作为靶位点检测制剂的应用 - Google Patents
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Abstract
本发明公开了circ‑RNF13‑TRIM41‑p53复合体作为靶位点检测制剂在制备鼻咽癌紫杉醇增敏药物中的应用。本发明研究表明,鼻咽癌紫杉醇耐药细胞株中circ‑RNF13可与泛素连接酶TRIM41和p53蛋白结合形成复合体调控鼻咽癌紫杉醇敏感性。机制研究表明,p53蛋白主要结合在circ‑RNF13的1‑176 nt区域上,TRIM41蛋白主要结合在circ‑RNF13的301‑425 nt区域上,阻断circ‑RNF13的相关区域可使p53蛋白与TRIM41蛋白的结合能力减弱,减弱了TRIM41对p53的泛素化降解,进而导致鼻咽癌细胞对紫杉醇的敏感性增加。因此,circ‑RNF13‑TRIM41‑p53复合体可在制备鼻咽癌紫杉醇增敏药物中作为靶位点。
Description
技术领域
本发明属于生物医药技术领域,具体涉及circ-RNF13-TRIM41-p53复合体作为靶位点检测制剂在制备鼻咽癌紫杉醇增敏药物中的应用。
背景技术
鼻咽癌(Nasopheryngeal cancer, NPC)是一种高度侵袭性的鳞状细胞癌,常见于东亚(尤其是我国南部)、东南亚以及北非地区。除遗传和环境因素外,EB病毒(Epstein-Barr virus, EBV)在鼻咽癌的发生发展中也起着重要的作用。由于鼻咽部解剖结构复杂,且鼻咽癌细胞对放射线高度敏感,因此放射治疗是鼻咽癌的主要治疗方法。但是,由于鼻咽癌起病隐匿,约有 60%~70%的患者就诊时已处于 III 期或 IV 期。最新的 NCCN 指南(2020.V1)指出,对于非早期鼻咽癌患者,同步放化疗或是辅助化疗是主要的治疗手段。紫杉醇是鼻咽癌常用的化疗药物,无论是联合治疗还是单药化疗,都在临床中广泛使用[3]。然而,部分患者在治疗过程中对紫杉醇原发或获得性耐药从而导致预后欠佳,因此,探讨鼻咽癌紫杉醇耐药新机制具有重大的临床意义。
环状RNA(Circular RNA,circRNA)是非编码RNA的一种特殊成员,在细胞分化和代谢等生命活动中发挥非常重要的作用。深入探讨circRNA的相关功能,极有可能挖掘疾病诊断的新型标志物及潜在的药物靶点,具有非常重要的潜在临床应用价值。研究表明circRNA除了可海绵吸附miRNA的作用外,还能与蛋白质结合调节蛋白质的细胞定位、功能和稳定性,并影响蛋白质-蛋白质和蛋白质-DNA的相互作用。例如,circ-Amotl1可以与PDK1和AKT1相互作用,促进它们的核易位,并促进AKT1的磷酸化; circYAP可以通过结合翻译起始蛋白eIF4G和PABP,抑制母基因YAP的mRNA翻译起始,调控YAP蛋白的表达量;circ1662可与YAP1结合促进其入核,进而抑制SMAD3和E-Cadherin的活性,提高结肠癌细胞的迁移侵袭能力。
我们前期以鼻咽癌CNE-1亲本株/紫杉醇耐药株与HNE-2亲本株/紫杉醇耐药株为研究对象,行circRNA芯片筛查,结果发现hsa_circ_0067717的差异表达最明显(由RNF13的2-5外显子形成,我们将其称为circ-RNF13。我们通过体内外实验已证实circ-RNF13可通过结合泛素连接酶TRIM41蛋白和p53蛋白,并介导p53的泛素化降解,进而可促进鼻咽癌细胞紫杉醇。但是circ-RNF13上TRIM41蛋白和p53蛋白的结合区域是否发挥了促进鼻咽癌细胞对紫杉醇耐药的作用仍需进一步深入探究。
发明内容
本发明旨在提供一种可以用于制备鼻咽癌紫杉醇增敏药物的新靶点。在本研究中,我们首次发现在鼻咽癌紫杉醇耐药细胞中circ-RNF13可与p53蛋白、TRIM41蛋白结合形成circ-RNF13-TRIM41-p53复合体,增强TRIM41对p53的泛素化降解,并降低p53蛋白的稳定性,从而导致鼻咽癌细胞中紫杉醇的化学耐药性。本研究促进了我们对circRNA与蛋白结合机制的理解,并提供了抑制鼻咽癌紫杉醇耐药的潜在治疗新靶点。
本发明提供了circ-RNF13-TRIM41-p53复合体作为靶位点检测制剂在制备治疗鼻咽癌紫杉醇增敏药物中的应用,所述circ-RNF13-TRIM41-p53复合体是p53蛋白结合在circ-RNF13的1-176 nt区域上,TRIM41蛋白结合在circ-RNF13的301-425 nt区域上所形成的复合体。
本发明提供了circ-RNF13-TRIM41-p53复合体作为靶位点检测制剂在制备治疗鼻咽癌紫杉醇敏感性分子标志物中的应用。
本发明还提供了circ-RNF13的1-176 nt和301-425 nt区域的阻断制剂在制备治疗鼻咽癌紫杉醇敏感性分子标志物中的应用。
我们预测发现circ-RNF13上TRIM41蛋白和p53蛋白具有相似的高得分结合区域:301-376 nt,125-176 nt和250-301 nt区域,针对这三个区域设计了circ-RNF13全长探针、circ-RNF13反义探针和4种不同的circ-RNF13截短探针,行RNA pull down实验。结果表明在circ-RNF13-p53-TRIM41复合体中p53蛋白主要结合在circ-RNF13的1-176 nt区域,而TRIM41蛋白主要结合circ-RNF13的301-425 nt区域。
为进一步确证Circ-RNF13与p53蛋白及TRIM41蛋白具体结合区域,我们利用未标记反义寡核苷酸探针竞争性的封闭circ-RNF13上目的蛋白的结合位点,设计了阻断p53结合位点的寡核苷酸(block-p53)——circ-RNF13的1-176nt区域的反向互补序列,阻断TRIM41结合位点的寡核苷酸(block-p53)——circ-RNF13的301-425nt区域的反向互补序列,行RNA pull down实验。结果表明Circ-RNF13中p53蛋白和TRIM41蛋白的主要结合区域的阻断有效地降低了TRIM41蛋白与p53蛋白的结合,抑制了p53蛋白泛素化降解,从而使p53蛋白表达水平上升。我们进一步行MTT实验、EdU增殖检测、细胞侵袭实验、细胞划痕修复实验和细胞凋亡实验,结果表明block-p53或block-TRIM41可有效逆转过表达circ-RNF13所导致的鼻咽癌紫杉醇耐药。
总之,本发明首次发现circ-RNF13-TRIM41-p53复合体的存在促进了鼻咽癌细胞紫杉醇耐药,阻断circ-RNF13中p53蛋白和TRIM41蛋白的主要结合区域,可减弱TRIM41蛋白与p53蛋白的结合,减缓p53蛋白泛素化降解,进而逆转circ-RNF13所导致的鼻咽癌紫杉醇耐药。circ-RNF13-TRIM41-p53复合体可在制备鼻咽癌紫杉醇增敏药中作为靶位点,也是临床上预测鼻咽癌患者紫杉醇药物敏感性的的分子标志物,可能是一种新的改善鼻咽癌患者治疗和生存的策略。
附图说明
图1: circ-RNF13可以与TRIM41蛋白和p53蛋白结合。(a)RIP实验结合银染检测结果显示circ-RNF13可与TRIM41蛋白和p53蛋白结合。(b)RIP实验表明,与对照组相比,高表达的circ-RNF13使得TRIM41蛋白和p53蛋白都沉淀了更多circ-RNF13。(c)RNA pull down实验表明过表达circ-RNF13可以沉淀更多的TRIM41和p53。 (d)当过表达TRIM41或敲低TRIM41时,RIP实验检测circ-RNF13与p53的结合情况。IgG用作阴性对照。Bars表示标准差;* P <0.05,** P <0.01。
图2:circ-RNF13与TRIM41蛋白和p53蛋白的结合区域。(a)RPIseq网站预测显示TRIM41蛋白和P53蛋白与circ-RNF13具有较高的结合评分。(b)catRAPID网站显示出TRIM41、p53蛋白可能结合circ-RNF13的前20个评分最高的片段区域。(c)根据预测的circ-RNF13结合区域进行部分缺失,设计circ-RNF13的截断探针。(d)p53蛋白主要结合在circ-RNF13的1-176 nt区域,TRIM41蛋白主要结合circ-RNF13的301-425 nt区域。
图3:circ-RNF13与TRIM41蛋白和p53蛋白的结合区域。(a)在CNE-1 / T和HNE-2 /T细胞中,用6个不同circ-RNF13的截断探针下拉TRIM41和p53蛋白,western blot检测TRIM41和p53蛋白的表达水平。(b)RNA pull down实验表明,block-p53减弱了p53蛋白与circ-RNF13的结合,但不影响TRIM41蛋白与circ-RNF13的结合,同理block-TRIM41也是如此。(c)将CHX(10μg/ mL)添加到细胞培养基中,western blot显示block-P53和block-TRIM41可以增强p53的蛋白稳定性,减缓其降解速度。 (d)Co-IP实验表明block-P53和block-TRIM41可以减弱TRIM41与p53的结合,降低p53泛素化水平并提升p53蛋白表达。Bars表示标准差;* P <0.05,** P <0.01。
图4:block-p53和block-TRIM41可促进鼻咽癌细胞的紫杉醇敏感性。 (a)Westernblot显示block-p53或block-TRIM41可以促进p53,p21,Bax和Caspase-3蛋白表达。Bars表示标准差;* P <0.05,** P <0.01。(b)细胞凋亡实验表明在CNE-1/T和HNE-2/T中,IC25浓度紫杉醇处理条件下,block-p53和block-TRIM41组细胞凋亡高于对照组。Taxol:CNE-1/T和HNE-2/T细胞中IC25浓度的紫杉醇。Bars表示标准差;* P <0.05,** P <0.01。
图5:MTT细胞和EdU增殖实验结果进一步表明,block-p53或block-TRIM41可以有效逆转高表达的circ-RNF13引起的鼻咽癌细胞紫杉醇化学耐药性。Bars表示标准差;* P <0.05,** P <0.01。
图6:细胞侵袭实验和细胞划痕修复实验结果进一步表明,block-p53或block-TRIM41可以有效逆转高表达的circ-RNF13引起的鼻咽癌细胞紫杉醇化学耐药性。Bars表示标准差;* P <0.05,** P <0.01。
具体实施方式
下面结合附图和实验数据对本发明做进一步的解释和说明
1、材料及方法
细胞培养及转染,qRT-PCR分析,蛋白质印迹分析,免疫组化测定,MTT测定,流式细胞术,免疫沉淀,免疫荧光,细胞划痕修复实验,寡核苷酸封闭实验以上方法均是现有方法,在此不再累述。
、结果
2.1 Circ-RNF13可以与TRIM41蛋白和p53蛋白结合形成三联复合体
为了进一步分析circ-RNF13的分子机制,我们通过RNA pull down实验结合银染确定了TRIM41和p53均能结合在circ-RNF13上(图1a)。RIP实验结果表明,在过表达circ-RNF13组中,TRIM41蛋白和p53蛋白结合了更多的circ-RNF13(图1b)。RNA pull down结果显示高表达的circ-RNF13富集了更多的TRIM41蛋白和p53蛋白(图1c)。此外,RIP实验表明,TRIM41的过表达或敲低并不影响circ-RNF13与p53的结合(图1d),进一步证实了导致circ-RNF13与p53蛋白结合增强的原因是circ-RNF13的高表达,而与TRIM41无关。
RPIseq [27]显示TRIM41蛋白和p53蛋白与circ-RNF13的结合评分很高(图2a)。我们通过catRAPID网站预测发现circ-RNF13上TRIM41蛋白和p53蛋白具有相似的高得分结合区域:301-376 nt,125-176 nt和250-301 nt区域(图2b)。
我们针对这三个区域设计了circ-RNF13全长探针、circ-RNF13反义探针和4种不同的circ-RNF13截短探针用于RNA pull down实验,以确定与p53和TRIM41结合的特定位置(图2c)。如果某段较关键的结合位点缺失可导致后续的western blot分析中不能出现目的蛋白条带,基于此我们确认了p53蛋白主要结合在circ-RNF13的1-176 nt区域,TRIM41蛋白主要结合circ-RNF13的301-425 nt区域(图2d)。
的1-176 nt和301-425 nt区域具有重要作用
为了评估这些结合位点是否发挥了重要的作用,我们利用未标记反义寡核苷酸探针竞争性的封闭circ-RNF13上目的蛋白的结合位点,设计了阻断p53结合位点的寡核苷酸(block-p53)——circ-RNF13的1-176nt区域的反向互补序列,阻断TRIM41结合位点的寡核苷酸(block-p53)——circ-RNF13的301-425nt区域的反向互补序列,并将它们转染至细胞中。qRT-PCR检测显示block-p53,block-TRIM41和block-both(p53和TRIM41)均降低了circ-RNF13的表达(图3a)。
紧接着我们将circ-RNF13探针和对照组寡核苷酸探针与细胞裂解液一起孵育,然后通过RNA pull down下拉了p53蛋白和TRIM41蛋白。结果表明,与对照组相比,鼻咽癌紫杉醇耐药细胞中高表达的circ-RNF13能富集沉淀更多的p53蛋白,而si-circ-RNF13、block-p53和block-both的转染使得circ-RNF13和p53蛋白的结合作用减弱,但block-TRIM41并不影响它俩的结合(图3b)。这些结果表明,阻断p53结合位点可以减少circ-RNF13与p53的结合,但是不影响circ-RNF13与TRIM41的结合。同样,阻断TRIM41结合位点减少了circ-RNF13与TRIM41的结合,但不影响circ-RNF13与p53的结合。
为了评估推定的结合位点对p53稳定性和泛素化的影响,我们在CHX存在的情况下将block-p53或block-TRIM41转染至鼻咽癌紫杉醇耐药细胞中,结果表明阻断circ-RNF13上p53或TRIM41结合位点减慢了p53的降解速率(图3c)。 circ-RNF13中p53和TRIM41的主要结合位点的阻断有效地降低了TRIM41蛋白与p53蛋白的结合,抑制了p53蛋白泛素化降解,从而提高了p53蛋白的水平。 但对TRIM41蛋白的表达没有观察影响(图3d)。
阻断circ-RNF13上的TRIM41或p53结合区域可以促进体内鼻咽癌细胞的紫杉醇敏感性。
Western blot实验结果表明在用IC25剂量的紫杉醇处理的CNE-1 / T和HNE-2 /T细胞中,circ-RNF13的过表达、block-p53、block-TRIM41和block-both均增强了p53,P21,BAX和Caspase-3的表达水平(图 4a)。细胞凋亡实验、MTT实验、EdU增殖检测、细胞侵袭实验和细胞划痕修复实验结果进一步表明,block-p53或block-TRIM41可以有效逆转高表达的circ-RNF13引起的鼻咽癌细胞紫杉醇化学耐药性(图4b和图5-6)。
Claims (1)
1.circ-RNF13上的1-176 nt区域和301-425 nt区域的反向互补序列作为阻断剂在制备治疗紫杉醇耐药的鼻咽癌的药物中的应用。
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