蛋白质组学方法识别RKIP作为鼻咽癌的转移抑制蛋白
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摘要
鼻咽癌(nasopharyngeal carcinoma,NPC)是我国南方地区(广东、广西、湖南、福建、江西)常见的恶性肿瘤,其发病率和死亡率均居世界首位,是一种中国特色癌,严重危害国人的生命和健康。NPC几乎均为低分化鳞癌和未分化癌,恶性程度高,易早期发生颈部淋巴结和远处转移,而且NPC放疗后局部残灶复发、远处转移亦是制约其疗效和预后的瓶颈。因此,转移是NPC患者死亡的主要原因,但NPC转移的分子机制至今仍然不清楚,发现NPC转移相关分子对于揭示NPC转移机制、指导NPC治疗、改善NPC预后具有十分重要的作用。
高通量的组学技术是发现肿瘤相关分子的重要手段。如cDNA芯片分析NPC的基因表达谱已发现一些与NPC发病有关的异常表达基因。蛋白质是细胞的功能分子,因此,蛋白质组学技术在识别肿瘤发生发展相关蛋白质、发现肿瘤分子标志物和治疗靶标方面具有独特的优势。
为筛选NPC发病相关的蛋白质,本研究开展了如下3个方面的研究工作:
1、NPC组织与癌旁正常鼻咽上皮组织(adjacent normal nasopharyngealepithelial tissue,ANNET)的差异蛋白质组学研究:以10例配对的NPC组织和ANNET为样本,采用二维凝胶电泳(two-dimensional gelelectrophoresis,2-DE)技术分离组织的总蛋白质,图像分析识别NPC组织和ANNET差异表达的蛋白质点,基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)和电喷雾电离-四极杆-串联质谱(ESI-Q-TOF MS/MS)鉴定差异表达的蛋白质。结果共鉴定了21个差异蛋白质,其中Raf激酶抑制蛋白(Raf kinase inhibitor protein,RKIP)等9个蛋白质在NPC组织中的表达水平显著低于ANNET。
2、NPC组织与正常鼻咽上皮组织(normal nasopharyngeal epithelialtissue,NNET)的差异磷酸化蛋白质组学研究:以10例NPC组织和10例NNET为样本,采用2-DE分离组织的总蛋白质,蛋白质转膜后与抗酪氨酸磷酸化抗体进行2D Western blotting分析,图像分析识别差异磷酸化蛋白质点,ESI-Q-TOF MS/MS鉴定差异酪氨酸磷酸化蛋白质,采用NetPhos软件预测蛋白质的酪氨酸磷酸化位点,采用1-D Westernblotting对差异磷酸化蛋白质RKIP进行验证。结果共鉴定了13个差异酪氨酸磷酸化蛋白质,其中RKIP等6个蛋白质在NPC组织中的磷酸化水平显著低于NNET。
3、RKIP在NPC转移中的作用和机制研究:为探讨RKIP在NPC转移中的作用和机制,采用Western blotting检测RKIP在不同转移潜能的5-8F和6-10B NPC细胞中的表达水平;采用免疫组化方法检察RKIP在石蜡包埋NPC组织、NNET及颈淋巴结转移NPC组织(lymphnode metastaticNPC,LMNPC)中的表达水平;采用脂质体转染方法将正义、反义RKIP表达质粒及其相应空白载体分别转染5-8F和6-10B细胞,建立相应的稳定转染细胞系,分析RKIP表达水平改变对NPC细胞体外侵袭能力以及Raf-1/MEK/ERK和NF-κB信号通路活性的影响。结果显示:RKIP在高转移5-8F细胞中的表达水平低于非转移6-10B细胞、在NPC组织中的表达水平低于NNET、在LMNPC中表达缺失。上调RKIP表达能抑制5-8F细胞的体外侵袭能力,而下调RKIP表达能增强6-10B细胞的体外侵袭能力;上调RKIP表达能降低5-8F细胞Raf-1/MEK/ERK和NF-κB信号通路活性,而下调RKIP表达能增强6-10B细胞Raf-1/MEK/ERK和NF-κB信号通路活性。
研究结果表明,RKIP可能是NPC的转移抑制蛋白,RKIP表达下调/缺失可能通过活化化Raf-1/MEK/ERK和NF-κB信号通路促进NPC转移,本研究初步揭示了RKIP在NPC侵袭和转移中的作用和机制,为RKIP作为防治NPC转移的靶标提供了实验依据。
Nasopharyngeal carcinoma(NPC) is one of the most common malignant tumors in southern China,with an incidence rate ranging from 20 to 50/100,000,and it poses one of the most serious public health problems in southern China.Early metastasis is one of distinctive characteristics of NPC and the main cause of death for NPC patients. Although numerous efforts have been made to reveal the molecular mechanism of NPC metastasis,it remains poorly understood. Identification of NPC metastasis-related molecules will be helpful for diagnosis and treatment of NPC,and may provide new insights into its metastasis.
High throughput omics technologies such as microarrays and proteomics offer the potential ability to find alterations previously unidentified in cancer.Analyses for gene expression profiles of NPC have been reported using a cDNA array,found the genes with aberrant expressions possibly contributed to pathogenesis of NPC.Because the functional molecules in cells are proteins,proteome analysis is believed to have an advantage over cDNA microarray for clinical use.Proteomics has introduced a new approach to cancer research which aims at identifying differential expression proteins associated with the development and progression of cancer,providing new opportunities to uncover biomarkers and therapeutic targets for cancer.
To screen for NPC associated proteins,we carried out the following 3 parts of research in this study.
1.Differential proteome study of NPC and adjacent non-cancerous nasopharyngeal epithelial tissue(ANNET).2-DE was performed to separate the total proteins from 10 paired NPC and ANNET,image analysis was used to fine the differential protein spots between the two types of tissues,and both MALDI-TOF-MS and ESI-Q-TOF MS/MS were performed to identify the differential proteins.As a result,21 differential proteins were identified.Among them,nine proteins including Raf kinase inhibitor protein(RKIP) were significantly downregulated in NPC as compared ANNET.
2.Differential phosphoproteome study of NPC and non-cancerous nasopharyngeal epithelial tissue(NNET).2-DE was used to separate the total proteins from 10 NPC and 10 NNET.After transferring the proteins to PVDF membranes,2-D Western blotting was did to find the differential tyrosine-phosphorylated proteins between the two types of tissues by using monoclonal anti-phosphotyrosine antibody,and ESI-Q-TOF MS/MS was performed to identify the differential tyrosine-phosphorylated proteins.And then NetPhos software was used to predict the tyrosin-phosphorylation sites of the identified proteins,and 1-D Western blotting was did to verify the differential tyrosine-phosphorylated protein RKIP.As a result,13 differential tyrosine-phosphorylated proteins were identified,and tyrosine-phosphorylated levels of six proteins including RKIP were significantly downregulated in NPC as compared NNET.
3.Study on the roles and mechanisms of RKIP in NPC metastasis.To explore the roles and mechanisms of RKIP in NPC metastasis,Western blotting analysis and immunohistochemistry was respectively used to detect RKIP expression in 5-8F and 6-10B NPC cell lines with the different metastatic potentials,and in NNET,primary NPC and NPC metastasis.Furthermore,high metastatic 5-8F with low RKIP expression and non-metastatic 6-10B with high RKIP expression were stably transfected with plasmids that expressed sense and antisense RKIP cDNA, respectively,or with empty vector.The effects of RKIP expression on in vitro cell invasion,and the activity of Raf-1/MEK/ERK and NF-κB signaling pathway were analyzed in the transfected cells.The results showed that RKIP was significantly downregulated in 5-8F compared with 6-10B,in NPC compared with NNET,and not detectable in NPC metastasis.Overexpressed RKIP in 5-8F could decrease its in vitro cell invasion,whereas downregulated RKIP in 6-10B could increased its in vitro cell invasion.RKIP negatively regulated Raf-1/MEK/ERK and NF-κB signaling pathway in NPC cells,and activation of the two signaling pathways by RKIP downregulation increased in vitro invasion of NPC cells.
Taken together,our results suggest that RKIP may be a NPC metastasis suppressor,and decreased RKIP expression is associated with the increased invasive capability of NPC cells possibly through the activation of Raf-1/MEK/ERK and NF-κB signaling pathway.
高通量的组学技术是发现肿瘤相关分子的重要手段。如cDNA芯片分析NPC的基因表达谱已发现一些与NPC发病有关的异常表达基因。蛋白质是细胞的功能分子,因此,蛋白质组学技术在识别肿瘤发生发展相关蛋白质、发现肿瘤分子标志物和治疗靶标方面具有独特的优势。
为筛选NPC发病相关的蛋白质,本研究开展了如下3个方面的研究工作:
1、NPC组织与癌旁正常鼻咽上皮组织(adjacent normal nasopharyngealepithelial tissue,ANNET)的差异蛋白质组学研究:以10例配对的NPC组织和ANNET为样本,采用二维凝胶电泳(two-dimensional gelelectrophoresis,2-DE)技术分离组织的总蛋白质,图像分析识别NPC组织和ANNET差异表达的蛋白质点,基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)和电喷雾电离-四极杆-串联质谱(ESI-Q-TOF MS/MS)鉴定差异表达的蛋白质。结果共鉴定了21个差异蛋白质,其中Raf激酶抑制蛋白(Raf kinase inhibitor protein,RKIP)等9个蛋白质在NPC组织中的表达水平显著低于ANNET。
2、NPC组织与正常鼻咽上皮组织(normal nasopharyngeal epithelialtissue,NNET)的差异磷酸化蛋白质组学研究:以10例NPC组织和10例NNET为样本,采用2-DE分离组织的总蛋白质,蛋白质转膜后与抗酪氨酸磷酸化抗体进行2D Western blotting分析,图像分析识别差异磷酸化蛋白质点,ESI-Q-TOF MS/MS鉴定差异酪氨酸磷酸化蛋白质,采用NetPhos软件预测蛋白质的酪氨酸磷酸化位点,采用1-D Westernblotting对差异磷酸化蛋白质RKIP进行验证。结果共鉴定了13个差异酪氨酸磷酸化蛋白质,其中RKIP等6个蛋白质在NPC组织中的磷酸化水平显著低于NNET。
3、RKIP在NPC转移中的作用和机制研究:为探讨RKIP在NPC转移中的作用和机制,采用Western blotting检测RKIP在不同转移潜能的5-8F和6-10B NPC细胞中的表达水平;采用免疫组化方法检察RKIP在石蜡包埋NPC组织、NNET及颈淋巴结转移NPC组织(lymphnode metastaticNPC,LMNPC)中的表达水平;采用脂质体转染方法将正义、反义RKIP表达质粒及其相应空白载体分别转染5-8F和6-10B细胞,建立相应的稳定转染细胞系,分析RKIP表达水平改变对NPC细胞体外侵袭能力以及Raf-1/MEK/ERK和NF-κB信号通路活性的影响。结果显示:RKIP在高转移5-8F细胞中的表达水平低于非转移6-10B细胞、在NPC组织中的表达水平低于NNET、在LMNPC中表达缺失。上调RKIP表达能抑制5-8F细胞的体外侵袭能力,而下调RKIP表达能增强6-10B细胞的体外侵袭能力;上调RKIP表达能降低5-8F细胞Raf-1/MEK/ERK和NF-κB信号通路活性,而下调RKIP表达能增强6-10B细胞Raf-1/MEK/ERK和NF-κB信号通路活性。
研究结果表明,RKIP可能是NPC的转移抑制蛋白,RKIP表达下调/缺失可能通过活化化Raf-1/MEK/ERK和NF-κB信号通路促进NPC转移,本研究初步揭示了RKIP在NPC侵袭和转移中的作用和机制,为RKIP作为防治NPC转移的靶标提供了实验依据。
Nasopharyngeal carcinoma(NPC) is one of the most common malignant tumors in southern China,with an incidence rate ranging from 20 to 50/100,000,and it poses one of the most serious public health problems in southern China.Early metastasis is one of distinctive characteristics of NPC and the main cause of death for NPC patients. Although numerous efforts have been made to reveal the molecular mechanism of NPC metastasis,it remains poorly understood. Identification of NPC metastasis-related molecules will be helpful for diagnosis and treatment of NPC,and may provide new insights into its metastasis.
High throughput omics technologies such as microarrays and proteomics offer the potential ability to find alterations previously unidentified in cancer.Analyses for gene expression profiles of NPC have been reported using a cDNA array,found the genes with aberrant expressions possibly contributed to pathogenesis of NPC.Because the functional molecules in cells are proteins,proteome analysis is believed to have an advantage over cDNA microarray for clinical use.Proteomics has introduced a new approach to cancer research which aims at identifying differential expression proteins associated with the development and progression of cancer,providing new opportunities to uncover biomarkers and therapeutic targets for cancer.
To screen for NPC associated proteins,we carried out the following 3 parts of research in this study.
1.Differential proteome study of NPC and adjacent non-cancerous nasopharyngeal epithelial tissue(ANNET).2-DE was performed to separate the total proteins from 10 paired NPC and ANNET,image analysis was used to fine the differential protein spots between the two types of tissues,and both MALDI-TOF-MS and ESI-Q-TOF MS/MS were performed to identify the differential proteins.As a result,21 differential proteins were identified.Among them,nine proteins including Raf kinase inhibitor protein(RKIP) were significantly downregulated in NPC as compared ANNET.
2.Differential phosphoproteome study of NPC and non-cancerous nasopharyngeal epithelial tissue(NNET).2-DE was used to separate the total proteins from 10 NPC and 10 NNET.After transferring the proteins to PVDF membranes,2-D Western blotting was did to find the differential tyrosine-phosphorylated proteins between the two types of tissues by using monoclonal anti-phosphotyrosine antibody,and ESI-Q-TOF MS/MS was performed to identify the differential tyrosine-phosphorylated proteins.And then NetPhos software was used to predict the tyrosin-phosphorylation sites of the identified proteins,and 1-D Western blotting was did to verify the differential tyrosine-phosphorylated protein RKIP.As a result,13 differential tyrosine-phosphorylated proteins were identified,and tyrosine-phosphorylated levels of six proteins including RKIP were significantly downregulated in NPC as compared NNET.
3.Study on the roles and mechanisms of RKIP in NPC metastasis.To explore the roles and mechanisms of RKIP in NPC metastasis,Western blotting analysis and immunohistochemistry was respectively used to detect RKIP expression in 5-8F and 6-10B NPC cell lines with the different metastatic potentials,and in NNET,primary NPC and NPC metastasis.Furthermore,high metastatic 5-8F with low RKIP expression and non-metastatic 6-10B with high RKIP expression were stably transfected with plasmids that expressed sense and antisense RKIP cDNA, respectively,or with empty vector.The effects of RKIP expression on in vitro cell invasion,and the activity of Raf-1/MEK/ERK and NF-κB signaling pathway were analyzed in the transfected cells.The results showed that RKIP was significantly downregulated in 5-8F compared with 6-10B,in NPC compared with NNET,and not detectable in NPC metastasis.Overexpressed RKIP in 5-8F could decrease its in vitro cell invasion,whereas downregulated RKIP in 6-10B could increased its in vitro cell invasion.RKIP negatively regulated Raf-1/MEK/ERK and NF-κB signaling pathway in NPC cells,and activation of the two signaling pathways by RKIP downregulation increased in vitro invasion of NPC cells.
Taken together,our results suggest that RKIP may be a NPC metastasis suppressor,and decreased RKIP expression is associated with the increased invasive capability of NPC cells possibly through the activation of Raf-1/MEK/ERK and NF-κB signaling pathway.
引文
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