DLK1基因异常表达及其促进肺癌细胞侵袭的分子机制
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摘要
肺癌是严重威胁人类生命健康的恶性肿瘤之一,具有高发病率和高死亡率。肿瘤的侵袭与转移是影响肺癌病人生存率的重要因素。本实验室前期以基因芯片分析获得中国人肺鳞癌基因表达谱,进而利用生物信息学方法构建了肺癌转移相关共表达分子网络,从中筛选出肺癌相关基因DLK1(Delta-like1himolog)。随后采用实时定量PCR技术(Realtime PCR),在30例肺癌样品中验证了DLK1基因在肿瘤组织中mRNA水平表达升高,体外实验初步显示其促进肺癌细胞转移的生物学功能。
本课题承接研究组前期工作,围绕DLK1基因在肺癌中的功能以及其作用机制进行深入研究。首先在较大样本非小细胞肺癌(non-small cell lung cancer, NSCLC)中检测DLK1蛋白的表达情况,并分析其临床意义。同时,以人肺癌细胞系为研究对象,通过体外实验对DLK1基因促进肿瘤细胞侵袭的功能研究分析；目的为揭示DLK1基因异常表达调控肺癌发生发展的分子机制。
首先,对204例NSCLC患者手术切除组织进行DLK1蛋白免疫组织化学染色,以显示DLK1在肿瘤组织中的表达情况；并结合病例的临床信息,分析DLK1表达水平与疾病分期、肿瘤大小、分化程度,以及淋巴结转移等的关系。结果发现,DLK1蛋白在癌组织中的表达水平显著高于癌旁正常组织,并且与肺鳞癌分期和肿瘤大小显著相关。
体外实验主要以肺癌细胞系H1299和A549为研究对象,先利用基因转染和RNA干扰技术,分别构建DLK1基因外源过表达或敲降细胞株。通过体外侵袭实验,分析DLKl基因对肺癌细胞侵袭能力的影响,发现DLK1促进肺癌细胞侵袭。而以qPCR(Realtime quantitative PCR)和Western blot分别分析mRNA和蛋白表达,均表明在肺癌细胞中DLK1基因可以上调侵袭相关蛋白MMP9(Matrix metallaproteins9)的表达；提示DLK1可能作用于Notch信号通路来发挥作用。后续分析证实,DLK1基因的表达影响了细胞内NOTCH1蛋白及其下游效应因子HES1基因的表达水平,说明DLK1基因能够激活Notch信号通路。
为探究DLK1基因在NSCLC中异常表达的原因,先后采用qPCR、MSP (Methylation specific PCR),以及亚硫酸测序等技术,分别检测了DLK1基因的拷贝数改变情况、基因印迹情况和启动子区DNA甲基化水平。分析发现,在肺癌组织中,DLK1基因几乎不存在DNA拷贝数改变和印迹缺失情况。DLK1基因启动子区的DNA甲基化水平与DLK1蛋白表达水平呈负相关,DLK1基因异常高表达的肿瘤组织中存在DLK1基因启动子区异常低甲基化。研究结果提示,DLK1基因在NSCLC中的异常表达主要由启动子区DNA甲基化水平降低而引起。
由于前述NSCLC免疫组化阅片结果提示,DLK1蛋白有核转位现象,为此我们利用Western blot和激光共聚焦分析技术检测了肺癌细胞内的DLK1蛋白定位情况；首次证实肺癌细胞内存在DLK1蛋白核定位现象。因此,进一步应用Co-IP联合质谱技术寻找DLKl相互作用蛋白,结合生物信息学分析,希望从中获得DLK1蛋白入核的途径及其参与的生物学功能的提示。我们从质谱鉴定数据中筛选出12个具有较高可信度的DLK1相互作用候选蛋白,参与调控包括Notch和NF-κB信号在内的多条信号通路。
综上所述,本项研究发现DLK1基因在非小细胞肺癌患者的肿瘤组织中异常高表达；DLK1基因通过激活Notch信号通路,上调MMP9的表达水平,促进肺癌细胞侵袭；DNA甲基化水平异常是造成非小细胞肺癌中DLK1基因表达异常的主要原因；DLK1蛋白在肺癌细胞中具有异常核定位,可能参与细胞分化调控；筛选获得12个潜在的DLK1相互作用蛋白,有待后期验证。
Lung cancer is one of the most common malignancies with high morbidity and mortality around the world. Tumor invasion and metastasis is strongly associated with the overall survival of the cancer patients. Previous investigations in this laboratory had found that DLKl (Delta-like1homolog) was one of metastasis-associated genes, according to the global expression profiling on lung squamous cell carcinomas and the bioinformatic analysis. Preliminary results revealed that DLK1could promote lung cancer cell invasion in vitro, but the mechanism still remained to be explored. The aims of present study are to discover the role(s) of DLK1in non-small cell lung cancers (NSCLCs) and to explore the molecular mechanisms.
We first examined the expressive status of DLK1protein in the tumor tissues of NSCLC with immunohistochemical (IHC) analysis. IHC staining was applied on formalin fixed paraffin embedded sections derived from204cases of NSCLCs, including102squamous cell carcinomas (SCCs) and102adenocarcinomas (ADCs). The expression of DLK1was significantly higher in the tumor tissues in comparing with that in the corresponding adjacent normal tissues. Moreover, the level of the DLK1were associated with the tumor size and stage in patients with SCCs according to the clinical characters.
Meanwhile, we investigated the molecular mechanism of DLK1on promoting lung cancer cells invasion through classic cell biologic methods. Human lung cancer cell lines H1299and A549were taken for in vitro investigations, and the cells that over-express exogenous DLK1or in that the endogenous DLK1was knocked down were generated. Over-expression of DLK1promoted invasion of the lung cancer cells, based on the results of Transwell assay. On the other hand, over-expressed DLK1was associated with up-regulation of MMP9and could also increase NOTCH1expression. Together with the up-regulated expression of the effector gene HES1, the data indicate that DLK1could activate Notch signaling pathway. On the contrary, knocking down DLK1with siRNA could down-regulate expression of MMP9, NOTCH1and HES1in the lung cancer cells.
To discover the mechanism for abnormal expression of DLK1in NSCLCs, we compared DNA copy number of DLK1gene in the tumor tissues with their paired adjacent non-cancerous tissues by realtime PCR. Using methylation specific PCR (MSP), we determined the methylation status at DLK1imprinting control elements. The results suggested that the causation of DLK1over-expression in lung cancers is neither gene amplification nor loss of imprint. In vitro,5-aza-dC treatment increased DLK1expression in lung cancer cells, indicating that expression of the gene was regulated by DNA methylation. Results obtained by bisulfite sequencing showed that CpG island within the promoter region was hypo-methylated in the tumor samples with over-expressed DLK1.
By the IHC analysis described above, nucleus staining of DLK1was observed. Then we confirmed the nuclear translocation of DLK1by Western blot and immunofluorecence approach. Co-immunoprecipitation/mass spectrum (Co-IP/MS) assay was performed to identify DLK1interacting proteins in order to provide clues on the mechanism and function of DLK1nuclear translocation. A total of12proteins with high confidence were selected for further identification; and those candidate proteins participate in various cell signaling pathways, including Notch signaling and NF-κB signaling.
In conclusions, this study reveal that DLK1was over-expressed in the tumor tissues of NSCLC patients. In vitro the DLK1could promote cancer cell invasion by up-regulating MMP9expression via activating Notch signaling pathway. DNA hypo-methylation on DLK1promoter was the primary cause for its aberrant expression in lung cancer. In addition, DLK1has nuclear translocation in lung cancer cells, which indicates an undiscovered function of this gene.
本课题承接研究组前期工作,围绕DLK1基因在肺癌中的功能以及其作用机制进行深入研究。首先在较大样本非小细胞肺癌(non-small cell lung cancer, NSCLC)中检测DLK1蛋白的表达情况,并分析其临床意义。同时,以人肺癌细胞系为研究对象,通过体外实验对DLK1基因促进肿瘤细胞侵袭的功能研究分析；目的为揭示DLK1基因异常表达调控肺癌发生发展的分子机制。
首先,对204例NSCLC患者手术切除组织进行DLK1蛋白免疫组织化学染色,以显示DLK1在肿瘤组织中的表达情况；并结合病例的临床信息,分析DLK1表达水平与疾病分期、肿瘤大小、分化程度,以及淋巴结转移等的关系。结果发现,DLK1蛋白在癌组织中的表达水平显著高于癌旁正常组织,并且与肺鳞癌分期和肿瘤大小显著相关。
体外实验主要以肺癌细胞系H1299和A549为研究对象,先利用基因转染和RNA干扰技术,分别构建DLK1基因外源过表达或敲降细胞株。通过体外侵袭实验,分析DLKl基因对肺癌细胞侵袭能力的影响,发现DLK1促进肺癌细胞侵袭。而以qPCR(Realtime quantitative PCR)和Western blot分别分析mRNA和蛋白表达,均表明在肺癌细胞中DLK1基因可以上调侵袭相关蛋白MMP9(Matrix metallaproteins9)的表达；提示DLK1可能作用于Notch信号通路来发挥作用。后续分析证实,DLK1基因的表达影响了细胞内NOTCH1蛋白及其下游效应因子HES1基因的表达水平,说明DLK1基因能够激活Notch信号通路。
为探究DLK1基因在NSCLC中异常表达的原因,先后采用qPCR、MSP (Methylation specific PCR),以及亚硫酸测序等技术,分别检测了DLK1基因的拷贝数改变情况、基因印迹情况和启动子区DNA甲基化水平。分析发现,在肺癌组织中,DLK1基因几乎不存在DNA拷贝数改变和印迹缺失情况。DLK1基因启动子区的DNA甲基化水平与DLK1蛋白表达水平呈负相关,DLK1基因异常高表达的肿瘤组织中存在DLK1基因启动子区异常低甲基化。研究结果提示,DLK1基因在NSCLC中的异常表达主要由启动子区DNA甲基化水平降低而引起。
由于前述NSCLC免疫组化阅片结果提示,DLK1蛋白有核转位现象,为此我们利用Western blot和激光共聚焦分析技术检测了肺癌细胞内的DLK1蛋白定位情况；首次证实肺癌细胞内存在DLK1蛋白核定位现象。因此,进一步应用Co-IP联合质谱技术寻找DLKl相互作用蛋白,结合生物信息学分析,希望从中获得DLK1蛋白入核的途径及其参与的生物学功能的提示。我们从质谱鉴定数据中筛选出12个具有较高可信度的DLK1相互作用候选蛋白,参与调控包括Notch和NF-κB信号在内的多条信号通路。
综上所述,本项研究发现DLK1基因在非小细胞肺癌患者的肿瘤组织中异常高表达；DLK1基因通过激活Notch信号通路,上调MMP9的表达水平,促进肺癌细胞侵袭；DNA甲基化水平异常是造成非小细胞肺癌中DLK1基因表达异常的主要原因；DLK1蛋白在肺癌细胞中具有异常核定位,可能参与细胞分化调控；筛选获得12个潜在的DLK1相互作用蛋白,有待后期验证。
Lung cancer is one of the most common malignancies with high morbidity and mortality around the world. Tumor invasion and metastasis is strongly associated with the overall survival of the cancer patients. Previous investigations in this laboratory had found that DLKl (Delta-like1homolog) was one of metastasis-associated genes, according to the global expression profiling on lung squamous cell carcinomas and the bioinformatic analysis. Preliminary results revealed that DLK1could promote lung cancer cell invasion in vitro, but the mechanism still remained to be explored. The aims of present study are to discover the role(s) of DLK1in non-small cell lung cancers (NSCLCs) and to explore the molecular mechanisms.
We first examined the expressive status of DLK1protein in the tumor tissues of NSCLC with immunohistochemical (IHC) analysis. IHC staining was applied on formalin fixed paraffin embedded sections derived from204cases of NSCLCs, including102squamous cell carcinomas (SCCs) and102adenocarcinomas (ADCs). The expression of DLK1was significantly higher in the tumor tissues in comparing with that in the corresponding adjacent normal tissues. Moreover, the level of the DLK1were associated with the tumor size and stage in patients with SCCs according to the clinical characters.
Meanwhile, we investigated the molecular mechanism of DLK1on promoting lung cancer cells invasion through classic cell biologic methods. Human lung cancer cell lines H1299and A549were taken for in vitro investigations, and the cells that over-express exogenous DLK1or in that the endogenous DLK1was knocked down were generated. Over-expression of DLK1promoted invasion of the lung cancer cells, based on the results of Transwell assay. On the other hand, over-expressed DLK1was associated with up-regulation of MMP9and could also increase NOTCH1expression. Together with the up-regulated expression of the effector gene HES1, the data indicate that DLK1could activate Notch signaling pathway. On the contrary, knocking down DLK1with siRNA could down-regulate expression of MMP9, NOTCH1and HES1in the lung cancer cells.
To discover the mechanism for abnormal expression of DLK1in NSCLCs, we compared DNA copy number of DLK1gene in the tumor tissues with their paired adjacent non-cancerous tissues by realtime PCR. Using methylation specific PCR (MSP), we determined the methylation status at DLK1imprinting control elements. The results suggested that the causation of DLK1over-expression in lung cancers is neither gene amplification nor loss of imprint. In vitro,5-aza-dC treatment increased DLK1expression in lung cancer cells, indicating that expression of the gene was regulated by DNA methylation. Results obtained by bisulfite sequencing showed that CpG island within the promoter region was hypo-methylated in the tumor samples with over-expressed DLK1.
By the IHC analysis described above, nucleus staining of DLK1was observed. Then we confirmed the nuclear translocation of DLK1by Western blot and immunofluorecence approach. Co-immunoprecipitation/mass spectrum (Co-IP/MS) assay was performed to identify DLK1interacting proteins in order to provide clues on the mechanism and function of DLK1nuclear translocation. A total of12proteins with high confidence were selected for further identification; and those candidate proteins participate in various cell signaling pathways, including Notch signaling and NF-κB signaling.
In conclusions, this study reveal that DLK1was over-expressed in the tumor tissues of NSCLC patients. In vitro the DLK1could promote cancer cell invasion by up-regulating MMP9expression via activating Notch signaling pathway. DNA hypo-methylation on DLK1promoter was the primary cause for its aberrant expression in lung cancer. In addition, DLK1has nuclear translocation in lung cancer cells, which indicates an undiscovered function of this gene.
引文
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