EB病毒潜伏膜蛋白LMP1通过转录因子EGFR和STAT3调控cyclin D1基因的分子机制研究
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摘要
鼻咽癌(nasopharyngeal carcinoma, NPC)是一种具有地域特异性的恶性肿瘤,在中国南部居恶性肿瘤发病率的第三位,与EB病毒(Epstein-Barr virus, EBV)感染密切相关。LMP1是EBV编码的瘤蛋白,其生物学功能涉及细胞转化、凋亡、分化、细胞周期行进以及参与恶性肿瘤的侵袭和转移。以鼻咽癌为切入点,我们多年的研究工作一直致力于LMP1介导的信号转导通路的研究,系统地研究了LMP1介导的信号转导通路异常以及由此产生的一系列生物学效应。
转录因子是参与调节靶基因转录的的反式作用因子,能直接或间接识别或结合在各顺式作用元件核心序列上,参与调控转录效率。转录因子是上游信号传导事件与下游功能基因表达改变的联系纽带,也是信号传导研究的重要核心。表皮生长因子受体(epidermal growth factor receptor, EGFR)是一个170kDa的跨膜糖蛋白,属于受体酪氨酸激酶(receptor tyrosine kinases, RTKs)家族成员。传统的受体学说认为,细胞膜受体作为第一信使,在细胞膜上与其配体结合发挥其生物学效应,但细胞膜受体不能进入核内而不能直接影响基因转录。但近年来,在许多肿瘤如皮肤癌、乳腺癌、宫颈癌、膀胱癌、卵巢癌等的细胞核内发现高水平的EGFR表达,其作为一种新型转录因子在核内独立或作为转录共活化子与其他转录因子相互作用于与细胞周期行进或细胞增殖密切相关的靶基因,促进肿瘤的发生发展。转录因子STAT3 (signal transducer and activation of transcription3, STAT3)是多种细胞因子和生长因子发挥作用的关键信号分子,其通过酪氨酸磷酸化的STAT之间形成同源二聚体或异源二聚体而活化,活化后移位至细胞核,激活多种相关下游靶基因的表达。STAT3蛋白能识别靶基因启动子区的保守序列成分并通过该序列激活靶基因转录。
本室的前期研究首先发现在鼻咽癌细胞中LMP1通过其CTAR1 (carboxyterminal activating region 1,CTAR1)募集肿瘤坏死因子受体相关因子(Tumor Necrosis Factor Receptor Associated Factors, TRAFs)精细调控EGFR表达和上调EGFR磷酸化水平,进而促进细胞增殖,继首次发现LMP1可以调控EGFR核移位,并呈EGF配体非依赖性。据报道用EGF刺激细胞后应用激光共聚焦检查观察,10分钟即可细胞核内发现核EGFR的存在。同时,不少作者认为EGFR需与其他能直接结合于靶基因DNA的转录因子相互作用方能发挥促进细胞增殖的生物学作用。本室前期研究还发现在鼻咽癌细胞中存在LMP1激活的JAK/STAT信号通路,并且LMP1激活STAT途径的结构基础在于其CTAR2和CTAR3的协同作用。进一步发现LMP1通过JAK3促进STAT3酪氨酸705位磷酸化,磷酸化活化后的STAT3即核移位并核内积聚,并且LMP1调控磷酸化STAT3核移位呈705位酪氨酸磷酸化依赖性。我们推测LMP1有可能通过诱导转录因子EGFR和STAT3核移位调节其相互作用。为观察在LMP1调控下转录因子EGFR和STAT3在鼻咽癌细胞核内是否存在共定位,选择激光共聚焦扫描显微镜进行检测,以LMP1阴性表达的鼻咽癌细胞CNE1细胞为阴性对照,发现在LMP1阳性表达的鼻咽癌细胞CNE1-LMP1细胞内存在EGFR和STAT3蛋白的共定位；应用免疫共沉淀[Co-immunoprecipitation (CO-IP)-western blot(WB)]方法检测,显示LMP1可调控鼻咽癌细胞内转录因子EGFR和STAT3呈复合物结合；再分别用胞浆和核蛋白做免疫共沉淀及western-blot检测表明EGFR和STAT3复合物结合的主要亚细胞定位是细胞核。以上结果为LMP1调控转录因子EGFR和STAT3在鼻咽癌细胞核内的作用机制提供了重要的实验基础。
肿瘤作为一类细胞周期病,G1/S检测点常在癌变多阶段,甚至在癌前阶段就已失调。细胞周期调节系统是肿瘤发生过程中常发生改变的调节网络,尤其是cyclin D,作为一种调节G1/S期行进的重要正性调节蛋白,是连接外界生长因子、信号转导与细胞周期调控机制的纽带,常成为肿瘤发生过程中的分子靶。Cyclin D1是肿瘤细胞的细胞周期中G1期向S期行进必不可少的蛋白质之一,cyclin D1基因已被证实是重要瘤基因,cyclinD1的主要功能是促进细胞的增殖,而其基因转录受多种因素的调节。本室的前期研究发现LMP1可以活化cyclinD1的表达,EGFR可直接结合于细胞周期G1/S期调节分子cyclinD1和cyclin E启动子区,并反式激活cyclinD1和cyclin E启动子活性,文献证实STAT3可以通过与cyclin D1启动子区结合位点结合并调节其转录功能。
为探讨LMP1调控转录因子EGFR/STAT3作用的靶基因是否是cyclin D1基因,以LMP1表达阴性的鼻咽癌细胞CNE1和LMP1阳性表达的CNE1-LMP1细胞为模型,采用脂质体瞬时转染方法将cyclin D1报道基因质粒转染至CNE1、CNE1-LMP1细胞系后,进行荧光素酶报告基因分析。同时利用特异性靶向LMP1的脱氧核酶DZ1阻断LMP1的表达后,进行报告基因分析,发现CNE1-LMP1细胞的cyclin D启动子活性明显高于CNE1,转染了特异性靶向LMP1的脱氧核酶DZ1的CNE1-LMP1细胞系的报告基因活性显著低于未经DZ1转染的细胞。结果提示了LMP1能够有效地分别调节转录因子EGFR和STAT3反式激活cyclinD1的活性。进一步通过小干扰RNA(small interfering RNA, siRNA)沉寂靶基因RNA策略,将EGFRsiRNA,STAT3siRNA分别和共同与cyclinD1报道质粒及转染试剂转染CNE1-LMP1细胞后,进行报告基因检测,并与加入非特异性siRNA的对照组比较,发现前组各自的cyclinD1报道基因活性都明显降低,T'检验,P值<0.05,差异有显著性意义；共转染EGFRsiRNA和STAT3siRNA组的cyclinD1报道基因活性比各单独转染组更降低。提示不论独立或同时沉寂cyclinD1启动子区EGFR和STAT3mRNA均可降低LMP1调控的cyclinD1启动子活性,从另一方面证明LMP1通过转录因子EGFR和STAT3调节cyclin D1启动子活性。为探讨LMP1是否可经调控转录因子EGFR/STAT3而调节cyclin D1 mRNA的转录水平,通过GeneBank和Primer3引物设计软件搜索和设计合成人Cyclin D1的cDNA引物序列进行了real-time PCR检测,经分别转染EGFRsiRNA和STAT3siRNA与非特异性对照siRNA于CNE1-LMP1细胞,提取其mRNA进行real-time PCR实验,显示LMP1可通过转录因子EGFR. STAT3对CyclinD1 mRNA表达水平进行不同程度的调节；但是同时沉寂EGFR、STAT3转录因子并未显示其抑制作用强于两转录因子的分别沉寂的抑制作用,表现了CyclinD1 mRNA表达调控的复杂性。
文献报道大量的细胞膜受体可以核移位,如EGFR, HER-2, FGFR(Fibroblast growth factor receptor, FGFR), HER-3。膜受体核移位后如何作用于靶基因的分子机制至今尚未完全明了。据报道EGFR核移位后能识别并结合至cyclinDl启动子区富含AT的保守序列(AT-rich consensus sequence, ATRS)并反式激活cyclinDl基因的表达,但并未研究清楚EGFR是否能直接结合于cyclinD1启动子ATRS;另有作者认为EGFR缺乏DNA结合域,需与其他能直接结合于DNA的转录因子相互作用方能发挥促进细胞增殖的生物学作用。激活后的STAT3即可核移位,通过识别靶基因上STAT3特异性的DNA结合成分而与其结合,并激活靶基因的转录。有作者发现STAT3蛋白的转录活性需要募集共活化子共同作用,如需与EGFR共同靶向iNOS启动子才能最大程度地促进iNOS基因表达。鼻咽癌细胞cyclin D1启动子区是否存在EGFR与STAT3共结合DNA序列,LMP1通过转录因子EGFR和STAT3调控cyclin D1转录的作用机制是通过对cyclinD1启动子区EGFR、STAT3各自独立结合位点或EGFR/STAT3共结合位点而发挥生物调控作用?首先分析LMP1通过诱导EGFR、STAT3分别与cyclinD1基因启动子区各自的结合位点结合并反式激活作用,通过电泳迁移率变动分析(electrophoretic mobility shift assay, EMSA),并且基于已证实的某些小分子抑制剂可阻断LMP1诱导EGFR/STAT3的主要磷酸化位点激活,而抑制其核移位的实验基础,采用小分子阻断策略观察抑制EGFR/STAT3核移位后对其与CyclinD1启动子区结合能力的影响。结果显示LMP1阳性细胞核蛋白与生物素标记野生型EGFR形成的结合带明显强于LMP1阴性表达细胞,提示LMP1能够调控EGFR与CyclinD1启动子区EGFR结合位点DNA的结合。利用酪氨酸激酶小分子抑制剂AG1478阻断EGFR磷酸化途径后,其与CyclinD1启动子区DNA结合能力降低,表明酪氨酸激酶抑制剂AG1478能够降低LMP1调控的EGFR与CyclinD1启动子区DNA结合的能力,这从另一方面证实LMP1可调控EGFR与CyclinD1启动子区结合。同时发现LMP1能够调控STAT3与CyclinD1启动子区STAT3结合位点的结合能力,利用小分子阻断剂WHI-p131, PD98059,阻断STAT3磷酸化后,可以降低STAT3与CyclinD1启动子DNA结合能力,证实LMP1可调控STAT3与CyclinD1启动子区的结合能力。进一步通过报告基因检测发现LMP1通过EGFR和STAT3诱导上调的cylinD1启动子活性能被EGFRTry1173位磷酸化,STAT3酪氨酸705位磷酸化和STAT3丝氨酸727位磷酸化的小分子阻断剂分别不同程度地抑制。这些结果从正反两方面证明了LMP1可通过调控转录因子EGFR和STAT3结合于cyclinD1启动子区各自的结合位点而调节cyclin D1启动子活性的作用机制。
根据分子生物学信息技术及参考文献,我们推测在cyclin D1启动子区存在EGFR和STAT3共结合(consensus)潜在的位点,分析其序列为TTCTATGAA.经分析在CYCLIND1启动子区只有一个EGFR和STAT3潜在的共结合位点TTCTATGAA。根据该序列设计PCR引物,采用CHIP(Chromatin immunoprecipitation, CHIP、PCR及琼脂糖凝胶电泳分析,显示CNE1-LMP1活体细胞内Cyclin D1启动子区存在EGFR、STAT3结合的共结合序列；不能忽略的是CNE1细胞内CyclinD1启动子区也存在与EGFR、STAT3结合的共序列,这个共序列的存在也可能是鼻咽癌细胞的共同生物结构特征；通过设计并合成包含EGFR/STAT3共结合序列的生物素标记探针,采用EMSA分析发现CNE1-LMP1细胞核蛋白与生物素标记野生型探针结合能力显著高于CNE1细胞,提示LMP1可以调控转录因子STAT3和EGFR与cyclinD1基因启动子区结合位点共序列的结合能力。运用点突变原则将cyclin D1启动子报道基因质粒推测的EGFR和STAT3共序列的部分关键核苷酸进行点突变,使转录因子EGFR和STAT3不能与cyclinD 1启动子区的共结合序列结合,从而不能反式激活cyclinD1,再转染CNE1和CNE1-LMP1细胞进行报告基因检测,结果发现点突变后LMP1细胞cylin D1启动子转录活性明显降低,约1倍,t'检验,P<0.05,差异有显著性意义；而CNE1细胞点突变前后无明显改变。这些结果表明LMP1可以通过调控转录因子EGFR和STAT3结合至cyclinD1启动子区的其结合位点共序列,并通过该位点协同反式激活cyclinD1启动子的活性。
综上所述,本研究发现了在LMP1阳性表达的鼻咽癌细胞核存在转录因子EGFR和STAT3的核移位和共定位,及LMP1可诱导EGFR/STAT3相互呈复合物结合并且其结合的主要部位为胞核；LMP1调控EGFR和STAT3作用的主要靶基因是cyclin D1;LMP1既可以通过调控EGFR、STAT3结合于cyclin D1启动子区各自的结合位点调节cyclin D1启动子活性,又可通过调控EGFR、STAT3结合于cyclin D1启动子区EGFR/STAT3共结合序列而激活cyclin D1启动子。
本项目首次观察到LMP1可调控转录因子EGFR和STAT3共定位于鼻咽癌细胞核,为LMP1激活的转录因子EGFR和STAT3两条不同的信号通路的整合提供了结构基础的依据；也同样首次发现鼻咽癌细胞cyclin D1启动子区存在EGFR/STAT3共结合位点序列,LMP1可调控EGFR/STAT3与该共结合位点的结合能力,并通过EGFR/STAT3与其结合位点的结合而激活cyclin D1启动子。这一新发现从蛋白质间相互作用的新视野阐明了EGFR和STAT3参与细胞周期异常演进的新机制,对EBV重要瘤蛋白LMP1的功能进行了拓展,也为鼻咽癌分子靶向治疗研发新的靶点提供了实验依据。
Nasopharyngeal carcinoma (NPC) is a malignant tumor with remarkably distinctive geographic distribution and thirdly high morbility in south china. One of the unique features of NPC is its strong association with infection of Epstein-Barr Virus (EBV). Latent membrane protein 1 (LMP1) is the only one with oncogenic properties among EBV encoded proteins and its biological functions has involved in cell transformation, apoptosis, cell cycle locomotion and participating in invasion and metastasis of carcinomas. Our previous studies have been focused on signaling transduction pathways mediated by LMP1, we elucidated that LMP1 was involved in abnormal signaling pathway and by which multiple tumor biological functions brought about.
Transcription factor (TF) is important core of signaling transduction research. Epidermal growth factor receptor (EGFR) is a 170 kDa transmembrane protein and belongs to receptor tyrosine kinases (RTKs). Recently, studies on nuclear translocation of the EGFR family (erbB-1/EGFR, erbB-3, and erbB-4) have greatly improved the knowledge of the biological function of cell surface receptors. It is reported that high level EGFR have been detected in the nucleus of many cancer cells, including those of skin, breast, cervix, bladder, and ovaries, and EGFR acting as a new transcriptional factor or co-activator affect on the target genes which closely related to cell cycle progressing or cell proliferation, and promote tumorigenesis and development. Signal transducer and activation of transcription 3 (STAT3) is a key molecule through which receptors of multiple cytokines and growth factors perform their function. After its activation with the phosphorylation of tyrosine 705(tyr 705), STAT3 forms dimmers with itself or with STAT1, translocates to nuclei and binds to specific DNA sequences, then, starts the transcription of multiple related downstream genes.
Our previous research first found that LMP1 can finely regulated EGFR expression and increased phosphorylation of EGFR by recruiting tumor necrosis factor receptor associated factors (TRAFs) through its carboxterminal activating region 1(CTAR1) in NPC cells; then, discovered that LMP1 could regulate nuclear translocation of EGFR. It is reported that after epidermal growth factor (EGF) stimulate 10 minutes, EGFR could be found in nucleus with laser cofocal microscopy (LCFM). Meanwhile, some authors consider that EGFR educe its promoting proliferation needing to interact with other transcription factors which can directly bind to DNA. It has been previously reported that LMP1 can promote STAT3 705 phosphorylation then to be activated, and activated STAT3 translocate to nuclear immediately and accumulate in nuclear. Therefore, we presume LMP1 may regulate TF EGFR and STAT3 interaction through inducing them nuclear translocation. We chose LCFM to observe whether TF EGFR and STAT3 co-localization exists in NPC cells nuclear controlled under LMP1. The results showed EGFR and STAT3 co-localization was discovered in LMP1 positive expression cells CNE1-LMP1; and by co-immunoprecipitation (COIP)-western blot (WB) assay, it displayed that LMP1 can facilitate the complex combination of EGFR and STAT3; We performed COIP-WB again to part with kytoplasm and nuclear protein, and found that the main subcellular localization of EGFR and STAT3 complex combination together was in nuclei. The results above provided important experiment foundation for understanding the mechanism how LMP1 regulate NF EGFR and STAT3 in NPC cells.
Regulatory system of cell cycle is the network in which changes often occur in tumorigenesis, especially for cyclin D1 which always become one of the commonest molecular targets. Cyclin D1 is one of the most important proteins during cell cycle from G1 to S phase in cancer cells. Currently, there is conclusive evidence that cyclin D1 is oncogene which can promote cell proliferation, but its gene transcription was regulated by many factors. Our previous studies showed that LMP1 can activate cyclin D1 expression, and found that EGFR could bind to directly cyclin D1 and cyclin E promoters and trans-activate the transcription of cyclin D1 and cyclin E.
In order to investigate whether the target gene is cyclin D1 which LMP1 effect on by modulation of EGFR and STAT3, we used the CNE1 and CNE1-LMP1 NPC cells with LMP1 negative and positive expression as model, transferred cyclin D1 reporter plasmids to CNE1 and CNE1-LMP1 cells with liposome transient transfection methods, and luciferase reporter assays were carried out. Meanwhile, we also performed another reporter assays after transfering DZ1 which is deoxyribozyme /DNAzyme specificity for LMP1 to block LMP1 expression. It was exhibited that cyclin D1 promoter activity in CNE1-LMP1 was obviously higher than in CNE1 cells; the luciferase reporter activity transfected with DZ1 significantly lower than without transfection in CNE1-LMP1 cells. The results revealed that LMP1 could effectively control TF EGFR and STAT3 to trans-activate cyclin D1. Further reporter analysis showed that each group of reporter activity was markedly lower after transfection with EGFR siRNA and STAT3 siRNA into CNE1-LMP1 cells, compared with controlled group, P value<0.05. To explore whether LMP1 can regulate the transcription of cyclinD1 mRNA via modulating EGFR/STAT3, we designed and synthetized the cDNA primers of cyclin D1 and real-time PCR were carried out. The results suggested that LMP1 can impact the expression of cyclin Dl mRNA via EGFR and STAT3.
Emerging evidences indicated that many membrane receptors can nuclear translocation, such as EGFR, HER-2, Fibroblast growth factor receptor (FGFR), HER-3. The mechanisms of how membrane receptors affect on gene targets have not been fully elucidate. Recent advances and our research let us think about:Is there the existence of EGFR and STAT3 consensus sequence in cyclin D1 promoter in NPC cells? What are the mechanisms in which LMP1 regulate cyclin D1 transcription through inducing EGFR and STAT3 bind to their respective binding site or consensus binding site in cyclin D1 promoter? We first analyzed the role that EGFR、STAT3 bind to each binding site of the promoter region in cyclin D1 and trans-activation of cyclin D1 modulated by LMP1. We found that LMP1 can enhance the EGFR and DNA binding activity of the promoter region of cyclin D1 only in CNE1-LMP1 cells detected by electrophoretic mobility shift assay(EMSA); Because previous works have confirmed that some small molecular inhibitors can block the activation of main location of phosphorylation of EGFR and STAT3, and nuclear translocation modulated by LMP1, we used small molecular inhibitors to aim directly at RTK AG1478 to obstruct EGFR phophorylation pathway and to restrict EGFR nuclear translocation, and the data showed that EGFR-DNA binding activity of the promoter region of cyclin Dl attenuated after being treated with AG1478 with EMS A in same cells. Likewise, we identified that STAT3-DNA binding activity of the promoter region of cyclin D1 was increased regulated by LMP1, and decreased after being treated with small molecular inhibitors aimed to STAT3, WHI-P131 and PD98059, to inhibit its phophorylation with EMS A in CNE1-LMP1 cells. Then, further reporter tests displayed that the cyclinDl promoter activity induced by LMP1 via EGFR and STAT3 could be inhibited differently degree by small molecular inhibitors which repressed the phophorylation of EGFR Tyr 1173, STAT3 Tyr 705 and Ser 727. These finding from right and reverse sides indicated the mechanism that LMP1 can enhance EGFR/STAT3 binding activity to their respective DNA site in the region of cyclin D1 promoter, and increase cycin D1 transcription.
According to molecular biology and information technology, and referring to literatures, we presume that there is a putative consensus DNA sequence of EGFR/STAT3 in the region of cyclin D1 promoter. We conjectured that the nucleotides, TTCTATGAA was the putative consensus sequence and only found one such nucleotides sequence after checking promoter region of cyclin D1. PCR primers were designed according to the nucleotides sequence and Chromatin immunoprecipitation (CHIP), PCR, agarose gel electrophoresis assays were performed. The data suggested that the consensus DNA sequence of EGFR/STAT3 existed in the promoter region of cyclin D1 in CNE1-LMP1 and CNE1 cells in vivo. This consensus sequences may be the common feature of biological structure in NPC cells. To further understanding the LMP1 effect on the EGFR/STAT3 binding with consensus DNA sequences in cyclin D1 promoter region, we designed and synthesized biotin labeled probes containing consensus sequences with EGFR/STAT3 binding in cyclin D1 promoter region. Results showed that the binding activity of neucleoprotein with wild biotin labeled probes in CNE1-LMP1 cells was markedly higher than in CNE1 cells, and it revealed that LMP1 can regulate EGFR/STAT3 binding ability with consensus DNA in cyclin D1 promoter region through inducing EGFR cooperation with STAT3. To further confirm the role of consensus DNA in cyclin D1 promoter region, applying reporter test and point mutation technique in which we mutated the key nucleotides in the consensus sequence of EGFR/STAT3 in the region of cyclin D1 promoter to lead to TF EGFR/STAT3 could not bind with, the reporter results displayed that transcription activity of cyclin D1 promoter after point mutation obviously decreased about 1 fold compared with point mutation before, P value<0.05. The data suggested that LMP1 can induce the synergism of EGFR and STAT3 to trans-activate the activation of cyclin D1 promoter.
In conclusion, the present study demonstrate that the co-localization of EGFR and STAT3 in the LMP1 positive expression NPC cells; it mainly occurred in nuclei of NPC cells in which the association of complex combination between EGFR and STAT3 was modulated by EBV-encoded oncoprotein LMP1; The main target gene that LMP1 effects on by regulating EGFR and STAT3 is cyclin D1; and LMP1 can activate the promoter activity of cyclinDl through mediating EGFR,STAT3 to bind to their consensus sequence DNA site, as well as to bind to their respective sites in promoter region of cyclin D1.
This project for the first time observed that LMP1 can induce TF EGFR and STAT3 co-localization in the nuclei of NPC cells, and provides structure foundation for the integration of EGFR and STAT3 which are two different pathways activated by LMP1; it for also the firs time discovered that there is a consensus sequences binding site of EGFR/STAT3 in cyclin D1 promoter region in NPC cells, by which LMP1 can enhance EFGR/STAT3 binding ability with this binding site and trans-activating promoter activity of cyclin D1. These new discoveries elucidate the new mechanisms of EGFR and STAT3 participating in the abnormal progression of cell cycle from a new field of view of proteins interaction, hence, it also provides experimental evidences for understanding the function of EBV important oncoprotein LMP1, and for finding new treating targets of molecular treatment of NPC.
转录因子是参与调节靶基因转录的的反式作用因子,能直接或间接识别或结合在各顺式作用元件核心序列上,参与调控转录效率。转录因子是上游信号传导事件与下游功能基因表达改变的联系纽带,也是信号传导研究的重要核心。表皮生长因子受体(epidermal growth factor receptor, EGFR)是一个170kDa的跨膜糖蛋白,属于受体酪氨酸激酶(receptor tyrosine kinases, RTKs)家族成员。传统的受体学说认为,细胞膜受体作为第一信使,在细胞膜上与其配体结合发挥其生物学效应,但细胞膜受体不能进入核内而不能直接影响基因转录。但近年来,在许多肿瘤如皮肤癌、乳腺癌、宫颈癌、膀胱癌、卵巢癌等的细胞核内发现高水平的EGFR表达,其作为一种新型转录因子在核内独立或作为转录共活化子与其他转录因子相互作用于与细胞周期行进或细胞增殖密切相关的靶基因,促进肿瘤的发生发展。转录因子STAT3 (signal transducer and activation of transcription3, STAT3)是多种细胞因子和生长因子发挥作用的关键信号分子,其通过酪氨酸磷酸化的STAT之间形成同源二聚体或异源二聚体而活化,活化后移位至细胞核,激活多种相关下游靶基因的表达。STAT3蛋白能识别靶基因启动子区的保守序列成分并通过该序列激活靶基因转录。
本室的前期研究首先发现在鼻咽癌细胞中LMP1通过其CTAR1 (carboxyterminal activating region 1,CTAR1)募集肿瘤坏死因子受体相关因子(Tumor Necrosis Factor Receptor Associated Factors, TRAFs)精细调控EGFR表达和上调EGFR磷酸化水平,进而促进细胞增殖,继首次发现LMP1可以调控EGFR核移位,并呈EGF配体非依赖性。据报道用EGF刺激细胞后应用激光共聚焦检查观察,10分钟即可细胞核内发现核EGFR的存在。同时,不少作者认为EGFR需与其他能直接结合于靶基因DNA的转录因子相互作用方能发挥促进细胞增殖的生物学作用。本室前期研究还发现在鼻咽癌细胞中存在LMP1激活的JAK/STAT信号通路,并且LMP1激活STAT途径的结构基础在于其CTAR2和CTAR3的协同作用。进一步发现LMP1通过JAK3促进STAT3酪氨酸705位磷酸化,磷酸化活化后的STAT3即核移位并核内积聚,并且LMP1调控磷酸化STAT3核移位呈705位酪氨酸磷酸化依赖性。我们推测LMP1有可能通过诱导转录因子EGFR和STAT3核移位调节其相互作用。为观察在LMP1调控下转录因子EGFR和STAT3在鼻咽癌细胞核内是否存在共定位,选择激光共聚焦扫描显微镜进行检测,以LMP1阴性表达的鼻咽癌细胞CNE1细胞为阴性对照,发现在LMP1阳性表达的鼻咽癌细胞CNE1-LMP1细胞内存在EGFR和STAT3蛋白的共定位；应用免疫共沉淀[Co-immunoprecipitation (CO-IP)-western blot(WB)]方法检测,显示LMP1可调控鼻咽癌细胞内转录因子EGFR和STAT3呈复合物结合；再分别用胞浆和核蛋白做免疫共沉淀及western-blot检测表明EGFR和STAT3复合物结合的主要亚细胞定位是细胞核。以上结果为LMP1调控转录因子EGFR和STAT3在鼻咽癌细胞核内的作用机制提供了重要的实验基础。
肿瘤作为一类细胞周期病,G1/S检测点常在癌变多阶段,甚至在癌前阶段就已失调。细胞周期调节系统是肿瘤发生过程中常发生改变的调节网络,尤其是cyclin D,作为一种调节G1/S期行进的重要正性调节蛋白,是连接外界生长因子、信号转导与细胞周期调控机制的纽带,常成为肿瘤发生过程中的分子靶。Cyclin D1是肿瘤细胞的细胞周期中G1期向S期行进必不可少的蛋白质之一,cyclin D1基因已被证实是重要瘤基因,cyclinD1的主要功能是促进细胞的增殖,而其基因转录受多种因素的调节。本室的前期研究发现LMP1可以活化cyclinD1的表达,EGFR可直接结合于细胞周期G1/S期调节分子cyclinD1和cyclin E启动子区,并反式激活cyclinD1和cyclin E启动子活性,文献证实STAT3可以通过与cyclin D1启动子区结合位点结合并调节其转录功能。
为探讨LMP1调控转录因子EGFR/STAT3作用的靶基因是否是cyclin D1基因,以LMP1表达阴性的鼻咽癌细胞CNE1和LMP1阳性表达的CNE1-LMP1细胞为模型,采用脂质体瞬时转染方法将cyclin D1报道基因质粒转染至CNE1、CNE1-LMP1细胞系后,进行荧光素酶报告基因分析。同时利用特异性靶向LMP1的脱氧核酶DZ1阻断LMP1的表达后,进行报告基因分析,发现CNE1-LMP1细胞的cyclin D启动子活性明显高于CNE1,转染了特异性靶向LMP1的脱氧核酶DZ1的CNE1-LMP1细胞系的报告基因活性显著低于未经DZ1转染的细胞。结果提示了LMP1能够有效地分别调节转录因子EGFR和STAT3反式激活cyclinD1的活性。进一步通过小干扰RNA(small interfering RNA, siRNA)沉寂靶基因RNA策略,将EGFRsiRNA,STAT3siRNA分别和共同与cyclinD1报道质粒及转染试剂转染CNE1-LMP1细胞后,进行报告基因检测,并与加入非特异性siRNA的对照组比较,发现前组各自的cyclinD1报道基因活性都明显降低,T'检验,P值<0.05,差异有显著性意义；共转染EGFRsiRNA和STAT3siRNA组的cyclinD1报道基因活性比各单独转染组更降低。提示不论独立或同时沉寂cyclinD1启动子区EGFR和STAT3mRNA均可降低LMP1调控的cyclinD1启动子活性,从另一方面证明LMP1通过转录因子EGFR和STAT3调节cyclin D1启动子活性。为探讨LMP1是否可经调控转录因子EGFR/STAT3而调节cyclin D1 mRNA的转录水平,通过GeneBank和Primer3引物设计软件搜索和设计合成人Cyclin D1的cDNA引物序列进行了real-time PCR检测,经分别转染EGFRsiRNA和STAT3siRNA与非特异性对照siRNA于CNE1-LMP1细胞,提取其mRNA进行real-time PCR实验,显示LMP1可通过转录因子EGFR. STAT3对CyclinD1 mRNA表达水平进行不同程度的调节；但是同时沉寂EGFR、STAT3转录因子并未显示其抑制作用强于两转录因子的分别沉寂的抑制作用,表现了CyclinD1 mRNA表达调控的复杂性。
文献报道大量的细胞膜受体可以核移位,如EGFR, HER-2, FGFR(Fibroblast growth factor receptor, FGFR), HER-3。膜受体核移位后如何作用于靶基因的分子机制至今尚未完全明了。据报道EGFR核移位后能识别并结合至cyclinDl启动子区富含AT的保守序列(AT-rich consensus sequence, ATRS)并反式激活cyclinDl基因的表达,但并未研究清楚EGFR是否能直接结合于cyclinD1启动子ATRS;另有作者认为EGFR缺乏DNA结合域,需与其他能直接结合于DNA的转录因子相互作用方能发挥促进细胞增殖的生物学作用。激活后的STAT3即可核移位,通过识别靶基因上STAT3特异性的DNA结合成分而与其结合,并激活靶基因的转录。有作者发现STAT3蛋白的转录活性需要募集共活化子共同作用,如需与EGFR共同靶向iNOS启动子才能最大程度地促进iNOS基因表达。鼻咽癌细胞cyclin D1启动子区是否存在EGFR与STAT3共结合DNA序列,LMP1通过转录因子EGFR和STAT3调控cyclin D1转录的作用机制是通过对cyclinD1启动子区EGFR、STAT3各自独立结合位点或EGFR/STAT3共结合位点而发挥生物调控作用?首先分析LMP1通过诱导EGFR、STAT3分别与cyclinD1基因启动子区各自的结合位点结合并反式激活作用,通过电泳迁移率变动分析(electrophoretic mobility shift assay, EMSA),并且基于已证实的某些小分子抑制剂可阻断LMP1诱导EGFR/STAT3的主要磷酸化位点激活,而抑制其核移位的实验基础,采用小分子阻断策略观察抑制EGFR/STAT3核移位后对其与CyclinD1启动子区结合能力的影响。结果显示LMP1阳性细胞核蛋白与生物素标记野生型EGFR形成的结合带明显强于LMP1阴性表达细胞,提示LMP1能够调控EGFR与CyclinD1启动子区EGFR结合位点DNA的结合。利用酪氨酸激酶小分子抑制剂AG1478阻断EGFR磷酸化途径后,其与CyclinD1启动子区DNA结合能力降低,表明酪氨酸激酶抑制剂AG1478能够降低LMP1调控的EGFR与CyclinD1启动子区DNA结合的能力,这从另一方面证实LMP1可调控EGFR与CyclinD1启动子区结合。同时发现LMP1能够调控STAT3与CyclinD1启动子区STAT3结合位点的结合能力,利用小分子阻断剂WHI-p131, PD98059,阻断STAT3磷酸化后,可以降低STAT3与CyclinD1启动子DNA结合能力,证实LMP1可调控STAT3与CyclinD1启动子区的结合能力。进一步通过报告基因检测发现LMP1通过EGFR和STAT3诱导上调的cylinD1启动子活性能被EGFRTry1173位磷酸化,STAT3酪氨酸705位磷酸化和STAT3丝氨酸727位磷酸化的小分子阻断剂分别不同程度地抑制。这些结果从正反两方面证明了LMP1可通过调控转录因子EGFR和STAT3结合于cyclinD1启动子区各自的结合位点而调节cyclin D1启动子活性的作用机制。
根据分子生物学信息技术及参考文献,我们推测在cyclin D1启动子区存在EGFR和STAT3共结合(consensus)潜在的位点,分析其序列为TTCTATGAA.经分析在CYCLIND1启动子区只有一个EGFR和STAT3潜在的共结合位点TTCTATGAA。根据该序列设计PCR引物,采用CHIP(Chromatin immunoprecipitation, CHIP、PCR及琼脂糖凝胶电泳分析,显示CNE1-LMP1活体细胞内Cyclin D1启动子区存在EGFR、STAT3结合的共结合序列；不能忽略的是CNE1细胞内CyclinD1启动子区也存在与EGFR、STAT3结合的共序列,这个共序列的存在也可能是鼻咽癌细胞的共同生物结构特征；通过设计并合成包含EGFR/STAT3共结合序列的生物素标记探针,采用EMSA分析发现CNE1-LMP1细胞核蛋白与生物素标记野生型探针结合能力显著高于CNE1细胞,提示LMP1可以调控转录因子STAT3和EGFR与cyclinD1基因启动子区结合位点共序列的结合能力。运用点突变原则将cyclin D1启动子报道基因质粒推测的EGFR和STAT3共序列的部分关键核苷酸进行点突变,使转录因子EGFR和STAT3不能与cyclinD 1启动子区的共结合序列结合,从而不能反式激活cyclinD1,再转染CNE1和CNE1-LMP1细胞进行报告基因检测,结果发现点突变后LMP1细胞cylin D1启动子转录活性明显降低,约1倍,t'检验,P<0.05,差异有显著性意义；而CNE1细胞点突变前后无明显改变。这些结果表明LMP1可以通过调控转录因子EGFR和STAT3结合至cyclinD1启动子区的其结合位点共序列,并通过该位点协同反式激活cyclinD1启动子的活性。
综上所述,本研究发现了在LMP1阳性表达的鼻咽癌细胞核存在转录因子EGFR和STAT3的核移位和共定位,及LMP1可诱导EGFR/STAT3相互呈复合物结合并且其结合的主要部位为胞核；LMP1调控EGFR和STAT3作用的主要靶基因是cyclin D1;LMP1既可以通过调控EGFR、STAT3结合于cyclin D1启动子区各自的结合位点调节cyclin D1启动子活性,又可通过调控EGFR、STAT3结合于cyclin D1启动子区EGFR/STAT3共结合序列而激活cyclin D1启动子。
本项目首次观察到LMP1可调控转录因子EGFR和STAT3共定位于鼻咽癌细胞核,为LMP1激活的转录因子EGFR和STAT3两条不同的信号通路的整合提供了结构基础的依据；也同样首次发现鼻咽癌细胞cyclin D1启动子区存在EGFR/STAT3共结合位点序列,LMP1可调控EGFR/STAT3与该共结合位点的结合能力,并通过EGFR/STAT3与其结合位点的结合而激活cyclin D1启动子。这一新发现从蛋白质间相互作用的新视野阐明了EGFR和STAT3参与细胞周期异常演进的新机制,对EBV重要瘤蛋白LMP1的功能进行了拓展,也为鼻咽癌分子靶向治疗研发新的靶点提供了实验依据。
Nasopharyngeal carcinoma (NPC) is a malignant tumor with remarkably distinctive geographic distribution and thirdly high morbility in south china. One of the unique features of NPC is its strong association with infection of Epstein-Barr Virus (EBV). Latent membrane protein 1 (LMP1) is the only one with oncogenic properties among EBV encoded proteins and its biological functions has involved in cell transformation, apoptosis, cell cycle locomotion and participating in invasion and metastasis of carcinomas. Our previous studies have been focused on signaling transduction pathways mediated by LMP1, we elucidated that LMP1 was involved in abnormal signaling pathway and by which multiple tumor biological functions brought about.
Transcription factor (TF) is important core of signaling transduction research. Epidermal growth factor receptor (EGFR) is a 170 kDa transmembrane protein and belongs to receptor tyrosine kinases (RTKs). Recently, studies on nuclear translocation of the EGFR family (erbB-1/EGFR, erbB-3, and erbB-4) have greatly improved the knowledge of the biological function of cell surface receptors. It is reported that high level EGFR have been detected in the nucleus of many cancer cells, including those of skin, breast, cervix, bladder, and ovaries, and EGFR acting as a new transcriptional factor or co-activator affect on the target genes which closely related to cell cycle progressing or cell proliferation, and promote tumorigenesis and development. Signal transducer and activation of transcription 3 (STAT3) is a key molecule through which receptors of multiple cytokines and growth factors perform their function. After its activation with the phosphorylation of tyrosine 705(tyr 705), STAT3 forms dimmers with itself or with STAT1, translocates to nuclei and binds to specific DNA sequences, then, starts the transcription of multiple related downstream genes.
Our previous research first found that LMP1 can finely regulated EGFR expression and increased phosphorylation of EGFR by recruiting tumor necrosis factor receptor associated factors (TRAFs) through its carboxterminal activating region 1(CTAR1) in NPC cells; then, discovered that LMP1 could regulate nuclear translocation of EGFR. It is reported that after epidermal growth factor (EGF) stimulate 10 minutes, EGFR could be found in nucleus with laser cofocal microscopy (LCFM). Meanwhile, some authors consider that EGFR educe its promoting proliferation needing to interact with other transcription factors which can directly bind to DNA. It has been previously reported that LMP1 can promote STAT3 705 phosphorylation then to be activated, and activated STAT3 translocate to nuclear immediately and accumulate in nuclear. Therefore, we presume LMP1 may regulate TF EGFR and STAT3 interaction through inducing them nuclear translocation. We chose LCFM to observe whether TF EGFR and STAT3 co-localization exists in NPC cells nuclear controlled under LMP1. The results showed EGFR and STAT3 co-localization was discovered in LMP1 positive expression cells CNE1-LMP1; and by co-immunoprecipitation (COIP)-western blot (WB) assay, it displayed that LMP1 can facilitate the complex combination of EGFR and STAT3; We performed COIP-WB again to part with kytoplasm and nuclear protein, and found that the main subcellular localization of EGFR and STAT3 complex combination together was in nuclei. The results above provided important experiment foundation for understanding the mechanism how LMP1 regulate NF EGFR and STAT3 in NPC cells.
Regulatory system of cell cycle is the network in which changes often occur in tumorigenesis, especially for cyclin D1 which always become one of the commonest molecular targets. Cyclin D1 is one of the most important proteins during cell cycle from G1 to S phase in cancer cells. Currently, there is conclusive evidence that cyclin D1 is oncogene which can promote cell proliferation, but its gene transcription was regulated by many factors. Our previous studies showed that LMP1 can activate cyclin D1 expression, and found that EGFR could bind to directly cyclin D1 and cyclin E promoters and trans-activate the transcription of cyclin D1 and cyclin E.
In order to investigate whether the target gene is cyclin D1 which LMP1 effect on by modulation of EGFR and STAT3, we used the CNE1 and CNE1-LMP1 NPC cells with LMP1 negative and positive expression as model, transferred cyclin D1 reporter plasmids to CNE1 and CNE1-LMP1 cells with liposome transient transfection methods, and luciferase reporter assays were carried out. Meanwhile, we also performed another reporter assays after transfering DZ1 which is deoxyribozyme /DNAzyme specificity for LMP1 to block LMP1 expression. It was exhibited that cyclin D1 promoter activity in CNE1-LMP1 was obviously higher than in CNE1 cells; the luciferase reporter activity transfected with DZ1 significantly lower than without transfection in CNE1-LMP1 cells. The results revealed that LMP1 could effectively control TF EGFR and STAT3 to trans-activate cyclin D1. Further reporter analysis showed that each group of reporter activity was markedly lower after transfection with EGFR siRNA and STAT3 siRNA into CNE1-LMP1 cells, compared with controlled group, P value<0.05. To explore whether LMP1 can regulate the transcription of cyclinD1 mRNA via modulating EGFR/STAT3, we designed and synthetized the cDNA primers of cyclin D1 and real-time PCR were carried out. The results suggested that LMP1 can impact the expression of cyclin Dl mRNA via EGFR and STAT3.
Emerging evidences indicated that many membrane receptors can nuclear translocation, such as EGFR, HER-2, Fibroblast growth factor receptor (FGFR), HER-3. The mechanisms of how membrane receptors affect on gene targets have not been fully elucidate. Recent advances and our research let us think about:Is there the existence of EGFR and STAT3 consensus sequence in cyclin D1 promoter in NPC cells? What are the mechanisms in which LMP1 regulate cyclin D1 transcription through inducing EGFR and STAT3 bind to their respective binding site or consensus binding site in cyclin D1 promoter? We first analyzed the role that EGFR、STAT3 bind to each binding site of the promoter region in cyclin D1 and trans-activation of cyclin D1 modulated by LMP1. We found that LMP1 can enhance the EGFR and DNA binding activity of the promoter region of cyclin D1 only in CNE1-LMP1 cells detected by electrophoretic mobility shift assay(EMSA); Because previous works have confirmed that some small molecular inhibitors can block the activation of main location of phosphorylation of EGFR and STAT3, and nuclear translocation modulated by LMP1, we used small molecular inhibitors to aim directly at RTK AG1478 to obstruct EGFR phophorylation pathway and to restrict EGFR nuclear translocation, and the data showed that EGFR-DNA binding activity of the promoter region of cyclin Dl attenuated after being treated with AG1478 with EMS A in same cells. Likewise, we identified that STAT3-DNA binding activity of the promoter region of cyclin D1 was increased regulated by LMP1, and decreased after being treated with small molecular inhibitors aimed to STAT3, WHI-P131 and PD98059, to inhibit its phophorylation with EMS A in CNE1-LMP1 cells. Then, further reporter tests displayed that the cyclinDl promoter activity induced by LMP1 via EGFR and STAT3 could be inhibited differently degree by small molecular inhibitors which repressed the phophorylation of EGFR Tyr 1173, STAT3 Tyr 705 and Ser 727. These finding from right and reverse sides indicated the mechanism that LMP1 can enhance EGFR/STAT3 binding activity to their respective DNA site in the region of cyclin D1 promoter, and increase cycin D1 transcription.
According to molecular biology and information technology, and referring to literatures, we presume that there is a putative consensus DNA sequence of EGFR/STAT3 in the region of cyclin D1 promoter. We conjectured that the nucleotides, TTCTATGAA was the putative consensus sequence and only found one such nucleotides sequence after checking promoter region of cyclin D1. PCR primers were designed according to the nucleotides sequence and Chromatin immunoprecipitation (CHIP), PCR, agarose gel electrophoresis assays were performed. The data suggested that the consensus DNA sequence of EGFR/STAT3 existed in the promoter region of cyclin D1 in CNE1-LMP1 and CNE1 cells in vivo. This consensus sequences may be the common feature of biological structure in NPC cells. To further understanding the LMP1 effect on the EGFR/STAT3 binding with consensus DNA sequences in cyclin D1 promoter region, we designed and synthesized biotin labeled probes containing consensus sequences with EGFR/STAT3 binding in cyclin D1 promoter region. Results showed that the binding activity of neucleoprotein with wild biotin labeled probes in CNE1-LMP1 cells was markedly higher than in CNE1 cells, and it revealed that LMP1 can regulate EGFR/STAT3 binding ability with consensus DNA in cyclin D1 promoter region through inducing EGFR cooperation with STAT3. To further confirm the role of consensus DNA in cyclin D1 promoter region, applying reporter test and point mutation technique in which we mutated the key nucleotides in the consensus sequence of EGFR/STAT3 in the region of cyclin D1 promoter to lead to TF EGFR/STAT3 could not bind with, the reporter results displayed that transcription activity of cyclin D1 promoter after point mutation obviously decreased about 1 fold compared with point mutation before, P value<0.05. The data suggested that LMP1 can induce the synergism of EGFR and STAT3 to trans-activate the activation of cyclin D1 promoter.
In conclusion, the present study demonstrate that the co-localization of EGFR and STAT3 in the LMP1 positive expression NPC cells; it mainly occurred in nuclei of NPC cells in which the association of complex combination between EGFR and STAT3 was modulated by EBV-encoded oncoprotein LMP1; The main target gene that LMP1 effects on by regulating EGFR and STAT3 is cyclin D1; and LMP1 can activate the promoter activity of cyclinDl through mediating EGFR,STAT3 to bind to their consensus sequence DNA site, as well as to bind to their respective sites in promoter region of cyclin D1.
This project for the first time observed that LMP1 can induce TF EGFR and STAT3 co-localization in the nuclei of NPC cells, and provides structure foundation for the integration of EGFR and STAT3 which are two different pathways activated by LMP1; it for also the firs time discovered that there is a consensus sequences binding site of EGFR/STAT3 in cyclin D1 promoter region in NPC cells, by which LMP1 can enhance EFGR/STAT3 binding ability with this binding site and trans-activating promoter activity of cyclin D1. These new discoveries elucidate the new mechanisms of EGFR and STAT3 participating in the abnormal progression of cell cycle from a new field of view of proteins interaction, hence, it also provides experimental evidences for understanding the function of EBV important oncoprotein LMP1, and for finding new treating targets of molecular treatment of NPC.
引文
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