USP11抑制TNFα介导的NF-κB激活途径及其在转移性肾透明细胞癌中的作用
摘要
[研究背景]
正常状态下IκBα在细胞质中与转录因子NF-κB结合。在上游信号的刺激下,泛素化的IκBα的降解使NF-κB得到释放、进入细胞核促进基因转录的关键事件。然而,目前关于IκBα的去泛素化的调节机制尚无清楚认识。
转移性肾透明细胞癌(clear cell renal cell carcinoma, ccRCC)患者预后较差,而且对放化疗不敏感。因此探索ccRCC转移过程涉及的分子遗传背景和主要的信号转导途径对于ccRCC早期发现、转移预测、开发新的药物治疗靶点至关重要。[研究方法]
建立USPs(Ubquitin-specific proteases, USPs)表达文库。采用蛋白组学及报告基因分析的方法初步筛选出抑制NF-KB信号转导途径的候选去泛素化酶。通过免疫沉淀、免疫印记方法检测内源性或过表达候选去泛素化酶在体内体外条件下与IκBα的物理结合及去泛素化IκBα的功能。建立持续沉默去泛素化酶的细胞株,检测该细胞株中TNFα介导的NF-KB信号转导途径的激活情况,以及从mRNA及蛋白水平检测NF-κB下游基因IL6的转录和表达情况。
通过本实验室建立的转移性、非转移性ccRCC细胞株(RCC05TXJ,转移性；RCC05ZYJ,非转移性),采用低代数细胞通过cDNA microarray横向对比分析与转移相关的差异表达基因,通过生物信息学的方法分析差异表达基因富集的信号转导途径,实时荧光定量PCR纵向对比检测两株细胞中不同时间点与富集的信号转导途径的相关分子的动态表达情况,并通过沉默USP11在非转移性ccRCC细胞株的表达、观察相关分子的表达改变。
[研究结果]
USP11在体内或体外均与IκBα结合在一起,它是与IκBα结合的去泛素化酶。过表达USP11可以强烈的抑制IκBα的泛素化程度和NF-κB的转录活性。体外重组蛋白USPll在体外条件下可以发挥去泛素化IκBα的作用。进一步,抑制USP11的表达,可以提高TNFα介导的NF-κB信号转导途径的激活程度,同时提高TNFα介导的依赖于NF-κB转录的IL6的基因表达。
差异表达基因谱中CA9、VEGF、MMP2、LAMA4、TNF家族成员、IL成员等的上调表达反映了ccRCC自身及肿瘤浸润转移的相关特征。细胞色素P450家族成员上调表达,它在某种程度上反映了肾癌的发生发展始终与环境因素在体内代谢过程密切有关。VEGF信号转导途径、缺氧诱导以及新血管形成的过程富集了表达谱芯片的差异表达基因(p<0.05, Benjamini<1)。RhoC在RCC05TXJ细胞传代后48小时较RCC05ZYJ细胞上调表达(p<0.05),反映了肾细胞癌转移的分子遗传背景。两株细胞同时传代培养72小时后,HIFlα表达均有不同程度的升高,但在两株细胞之间不存在明显差异；TNFα、IL6、VEGF、MMP2等基因在转移性肾细胞癌RCC05TXJ较非转移性肾细胞癌RCC05ZYJ明显上调表达(p＜0.05)；沉默USP11在非转移性肾细胞癌RCC05ZYJ中的表达后,TNFα、IL6、VEGF表达上调(p<0.05)上述均提示NF-κB的激活、VEGF信号途径与转移性ccRCC密切相关。NF-κB的激活途径与VEGF途径的相互作用的机制需要进一步探讨。
[结论]
USPll通过去泛素化IκBα负向调节TBFα介导的NF-κB的激活途径；NF-κB激活途径及VEGF、缺氧诱导途径在ccRCC浸润转移中起着重要作用。
Background
IκBαserves as a central anchoring molecule in the sequestration of NF-κB transcription factor in the cytoplasm. Upon the signal of upstream, ubiquitination-mediated IκBαdegradation immediatedly precedes and is required for NF-κB nuclear translocation and activiation. However, the precise mechanism for the deubuiquitination of IκBαis still not fully understood.
Metastatic clear cell renal cell carcinoma (ccRCC) has a poor prognosis and unpredictable course, and resistant to radiotherapy and chemotherapy. A full understanding of the molecular genetics and signaling pathways involved in the metastatic process of ccRCC is important for early detection of ccRCC, prediction of metastasis and the development of innovative treatment options.
Methods
Ubquitin-specific proteases (USPs) expressional library was established. Using proteomic approach and reporter gene assay, we screened this library and got the potential candidate, which can inhibit NF-κB activation and bind with IκBα. Either for the endogenous or overexpression of USP, the physical binding with and functional deubiquitination of IκBαwere detected in vivo and in vitro. In stable knockdown of USP 11 cells, the expression and modification of the protein related to TNFa induced IKBa ubiquitination and NF-κB activation were detected. Moreover, IL6, the NF-κB target gene, were detected at the transcriptional and expressional level.
Metastatic (RCC05TXJ) or non-metastatic (RCC05ZYJ) ccRCC cell lines were established by our lab. Differentially expressed genes and significant signal pathway, which was related to metastatic process and differentially expressed genes were involved in, were analyzed by cDNA microarray and bioinformatics approach. The expression of the molecule of our interest, which were related to the key signal pathway relative to metastatic process, were detected at different time point by real time quantitative PCR. After knocking down USP11 expression in RCC05ZYJ cells, the expression of molecule of interest were detected.
Results
USP11 is associated with IκBαin vivo and in vitro. USP11 is an IκBαassociated deubiquitinase. Overexpression of USP11 strongly inhibits IκBαubiquitination and NF-κB activation. Recombinant of USP11 catalyzes deubiquitination of IκBαin vitro. Further, suppression of USP11 expression of enhances TNFa induced IκBαubiquitination and NF-κB activation. Suppression of USP11 enhances TNFa induced NF-κB-dependent IL6 gene expression.
In the differentially expressed gene profile, up-regulation of CA9,VEGF, MMP2, LAMA4,TNF reflected the characteristics of ccRCC and tumor invasion and metastatics. Up-regulation of cytochrome P450 family members indicated the association of metabolism of environmental agents and ccRCC progression. VEGF, Hypoxia and angiogenesis signal pathway enriched the differentially expressed genes (p<0.05, Benjamini<1). RhoC was up-regulated at 48h after passage in RCC05TXJ cells compared to RCC05ZYJ cells (p<0.05), which indicated the genetic background of metastatic ccRCC. The expression of HIF1αwas up-regulated in RCC05TXJ and RCC05ZYJ cells, but no significant difference was detected in these two cell lines. The expression of TNFa,IL6,VEGF, MMP2 at 72h after passage was up-regulated in RCC05TXJ cells compared to RCC05ZYJ cells (p<0.05), and the up-regulated expression of TNFa,IL6,VEGF was also detected (p＜0.05) in RCC05ZYJ cells of which USP11 expression was knocked down to-50%. It strongly indicates the NF-κB signaling pathway and VEGF pathway is related to the progression of ccRCC invasion and metastatics. Further study will be focused on the interaction of these two pathways.
Conclusion
USP11 negatively regulates TNFa induced NF-κB activation by deubiquitination of IκBα; NF-κB signal pathway and VEGF, Hypoxia signal pathway play an important role in the process of ccRCC invasion and metastatics.
正常状态下IκBα在细胞质中与转录因子NF-κB结合。在上游信号的刺激下,泛素化的IκBα的降解使NF-κB得到释放、进入细胞核促进基因转录的关键事件。然而,目前关于IκBα的去泛素化的调节机制尚无清楚认识。
转移性肾透明细胞癌(clear cell renal cell carcinoma, ccRCC)患者预后较差,而且对放化疗不敏感。因此探索ccRCC转移过程涉及的分子遗传背景和主要的信号转导途径对于ccRCC早期发现、转移预测、开发新的药物治疗靶点至关重要。[研究方法]
建立USPs(Ubquitin-specific proteases, USPs)表达文库。采用蛋白组学及报告基因分析的方法初步筛选出抑制NF-KB信号转导途径的候选去泛素化酶。通过免疫沉淀、免疫印记方法检测内源性或过表达候选去泛素化酶在体内体外条件下与IκBα的物理结合及去泛素化IκBα的功能。建立持续沉默去泛素化酶的细胞株,检测该细胞株中TNFα介导的NF-KB信号转导途径的激活情况,以及从mRNA及蛋白水平检测NF-κB下游基因IL6的转录和表达情况。
通过本实验室建立的转移性、非转移性ccRCC细胞株(RCC05TXJ,转移性；RCC05ZYJ,非转移性),采用低代数细胞通过cDNA microarray横向对比分析与转移相关的差异表达基因,通过生物信息学的方法分析差异表达基因富集的信号转导途径,实时荧光定量PCR纵向对比检测两株细胞中不同时间点与富集的信号转导途径的相关分子的动态表达情况,并通过沉默USP11在非转移性ccRCC细胞株的表达、观察相关分子的表达改变。
[研究结果]
USP11在体内或体外均与IκBα结合在一起,它是与IκBα结合的去泛素化酶。过表达USP11可以强烈的抑制IκBα的泛素化程度和NF-κB的转录活性。体外重组蛋白USPll在体外条件下可以发挥去泛素化IκBα的作用。进一步,抑制USP11的表达,可以提高TNFα介导的NF-κB信号转导途径的激活程度,同时提高TNFα介导的依赖于NF-κB转录的IL6的基因表达。
差异表达基因谱中CA9、VEGF、MMP2、LAMA4、TNF家族成员、IL成员等的上调表达反映了ccRCC自身及肿瘤浸润转移的相关特征。细胞色素P450家族成员上调表达,它在某种程度上反映了肾癌的发生发展始终与环境因素在体内代谢过程密切有关。VEGF信号转导途径、缺氧诱导以及新血管形成的过程富集了表达谱芯片的差异表达基因(p<0.05, Benjamini<1)。RhoC在RCC05TXJ细胞传代后48小时较RCC05ZYJ细胞上调表达(p<0.05),反映了肾细胞癌转移的分子遗传背景。两株细胞同时传代培养72小时后,HIFlα表达均有不同程度的升高,但在两株细胞之间不存在明显差异；TNFα、IL6、VEGF、MMP2等基因在转移性肾细胞癌RCC05TXJ较非转移性肾细胞癌RCC05ZYJ明显上调表达(p＜0.05)；沉默USP11在非转移性肾细胞癌RCC05ZYJ中的表达后,TNFα、IL6、VEGF表达上调(p<0.05)上述均提示NF-κB的激活、VEGF信号途径与转移性ccRCC密切相关。NF-κB的激活途径与VEGF途径的相互作用的机制需要进一步探讨。
[结论]
USPll通过去泛素化IκBα负向调节TBFα介导的NF-κB的激活途径；NF-κB激活途径及VEGF、缺氧诱导途径在ccRCC浸润转移中起着重要作用。
Background
IκBαserves as a central anchoring molecule in the sequestration of NF-κB transcription factor in the cytoplasm. Upon the signal of upstream, ubiquitination-mediated IκBαdegradation immediatedly precedes and is required for NF-κB nuclear translocation and activiation. However, the precise mechanism for the deubuiquitination of IκBαis still not fully understood.
Metastatic clear cell renal cell carcinoma (ccRCC) has a poor prognosis and unpredictable course, and resistant to radiotherapy and chemotherapy. A full understanding of the molecular genetics and signaling pathways involved in the metastatic process of ccRCC is important for early detection of ccRCC, prediction of metastasis and the development of innovative treatment options.
Methods
Ubquitin-specific proteases (USPs) expressional library was established. Using proteomic approach and reporter gene assay, we screened this library and got the potential candidate, which can inhibit NF-κB activation and bind with IκBα. Either for the endogenous or overexpression of USP, the physical binding with and functional deubiquitination of IκBαwere detected in vivo and in vitro. In stable knockdown of USP 11 cells, the expression and modification of the protein related to TNFa induced IKBa ubiquitination and NF-κB activation were detected. Moreover, IL6, the NF-κB target gene, were detected at the transcriptional and expressional level.
Metastatic (RCC05TXJ) or non-metastatic (RCC05ZYJ) ccRCC cell lines were established by our lab. Differentially expressed genes and significant signal pathway, which was related to metastatic process and differentially expressed genes were involved in, were analyzed by cDNA microarray and bioinformatics approach. The expression of the molecule of our interest, which were related to the key signal pathway relative to metastatic process, were detected at different time point by real time quantitative PCR. After knocking down USP11 expression in RCC05ZYJ cells, the expression of molecule of interest were detected.
Results
USP11 is associated with IκBαin vivo and in vitro. USP11 is an IκBαassociated deubiquitinase. Overexpression of USP11 strongly inhibits IκBαubiquitination and NF-κB activation. Recombinant of USP11 catalyzes deubiquitination of IκBαin vitro. Further, suppression of USP11 expression of enhances TNFa induced IκBαubiquitination and NF-κB activation. Suppression of USP11 enhances TNFa induced NF-κB-dependent IL6 gene expression.
In the differentially expressed gene profile, up-regulation of CA9,VEGF, MMP2, LAMA4,TNF reflected the characteristics of ccRCC and tumor invasion and metastatics. Up-regulation of cytochrome P450 family members indicated the association of metabolism of environmental agents and ccRCC progression. VEGF, Hypoxia and angiogenesis signal pathway enriched the differentially expressed genes (p<0.05, Benjamini<1). RhoC was up-regulated at 48h after passage in RCC05TXJ cells compared to RCC05ZYJ cells (p<0.05), which indicated the genetic background of metastatic ccRCC. The expression of HIF1αwas up-regulated in RCC05TXJ and RCC05ZYJ cells, but no significant difference was detected in these two cell lines. The expression of TNFa,IL6,VEGF, MMP2 at 72h after passage was up-regulated in RCC05TXJ cells compared to RCC05ZYJ cells (p<0.05), and the up-regulated expression of TNFa,IL6,VEGF was also detected (p＜0.05) in RCC05ZYJ cells of which USP11 expression was knocked down to-50%. It strongly indicates the NF-κB signaling pathway and VEGF pathway is related to the progression of ccRCC invasion and metastatics. Further study will be focused on the interaction of these two pathways.
Conclusion
USP11 negatively regulates TNFa induced NF-κB activation by deubiquitination of IκBα; NF-κB signal pathway and VEGF, Hypoxia signal pathway play an important role in the process of ccRCC invasion and metastatics.
引文
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