鼻咽癌紫杉醇耐药中FOLR1相互作用蛋白的筛选及机制的初步探索
|
摘要
叶酸受体a (FOLR1)是细胞摄取叶酸的高亲和性受体,课题组前期研究发现FOLR1的表达与鼻咽癌的发生及紫杉醇耐药表型密切相关,而FOLR1引起的鼻咽癌紫杉醇耐药表型似乎与其具有叶酸转运的功能无关。本文将以鼻咽癌亲本细胞系和紫杉醇耐药细胞系为研究对象,从蛋白质之间的相互作用为切入点,探索FOLR1的作用通路与鼻咽癌紫杉醇耐药之间的相关性。首先以FOLR1多克隆抗体为诱饵通过免疫共沉淀技术筛选其相互作用蛋白,初步确定了在鼻咽癌紫杉醇耐药细胞中FOLR1的相互作用蛋白——角蛋白17(Cytokeratin17,CK17),接着用免疫共沉淀、Western Blot、免疫荧光共定位等技术鉴定相互作用蛋白质,确定在鼻咽癌亲本细胞和紫杉醇耐药细胞中FOLR1与CK17存在功能上的蛋白质间相互作用。通过生物信息学网络分析相互作用蛋白的作用机制,分析FOLR1可能的作用通路,发现二者之间有一个共同的相互作用蛋白——泛素C(ubiquitin C,UBC),二者的相互作用蛋白涉及细胞分化、细胞周期、DNA修饰、信号转导等功能。然后再通过siRNA干扰技术沉默FOLR1或CK17,检测作用通路分子的活化情况,发现沉默FOLR1基因,CK17在转录与蛋白水平表达均下调,而沉默CK17基因,FOLR1的表达无变化,分析FOLR1引起的鼻咽癌紫杉醇耐药表型可能通过FOLR1与CK17间的相互作用这条作用通路,而二者间的相互作用可能通过UBC起作用。我们推断鼻咽癌紫杉醇耐药细胞中FOLR1表达的增高,可能是通过蛋白质的相互作用,诱导和调节与肿瘤细胞生长或凋亡相关的信号分子而发挥作用。图45幅,表21个,参考文献87篇
1FOLR1的相互作用蛋白筛选
目的：筛选人鼻咽癌紫杉醇耐药细胞中FOLR1的相互作用蛋白。
方法：以免疫共沉淀、SDS-PAGE电泳和凝胶染色方法筛选体外培养的正常鼻咽上皮细胞NP69和三株鼻咽癌紫杉醇耐药细胞(CNE-1/Taxol、CNE-2/Taxol、HNE-2/Taxol)中FOLR1的相互作用蛋白,质谱分析方法鉴定相互作用蛋白。
结果：CNE-2/taxol细胞蛋白质经过FOLR1的抗原抗体复合物及Protein A琼脂糖珠的共沉淀后,与对照比较,有5条差异条带,分子量分别约为120kD,58kD,50kD,44kD,30kD; CNE-1/taxol10细胞蛋白质经免疫共沉淀后电泳,与对照比较,有3差异条带,分子量分别约为60kD,55kD,50kD; CNE-1/taxol13细胞蛋白质经免疫共沉淀后电泳,与自身对照比较,有2差异条带,分子量分别约为50kD,36kD。结合3次免疫共沉淀实验结果,不同凝胶上都显示出-50kD的差异条带,预示SDS-PAGE凝胶上-50kD的蛋白质可能是与FOLR1相互作用的蛋白质。通过对差异条带进行飞行质谱分析,结果显示该蛋白质为cytokeratin17。
结论：人鼻咽癌紫杉醇耐药细胞中FOLR1蛋白可能与CK17蛋白有相互作用。
2FOLR1与CK17蛋白相互作用的验证
目的：验证筛选出来的FOLR1的相互作用蛋白CK17,确定二者在生理条件下存在相互作用。
方法：以免疫共沉淀、Western blot方法验证鼻咽癌亲本细胞(CNE-1)及鼻咽癌紫杉醇耐药细胞(CNE-1/Taxol)中FOLR1与CK17是否存在相互作用；免疫荧光双标法分析FOLR1与CK17的共定位关系；运用Visant软件对生物信息网络数据库进行检索和分析,确定FOLR1和CK17已知的可能相互作用蛋白。
结果：1.以FOLR1抗体对鼻咽癌紫杉醇耐药细胞CNE-1/taxol的总蛋白进行免疫共沉淀后,复合物中可以检测到CK17的表达,阴性对照中没有检测到CK17的表达。
2.以CK17抗体对鼻咽癌紫杉醇耐药细胞CNE-1/taxol的总蛋白进行免疫共沉淀后,复合物中可以检测到FOLR1的表达,而在对照细胞NP69中没有检测到FOLR1的表达。
3.免疫荧光激光共聚焦显微镜观察到FOLR1蛋白在细胞浆及细胞膜中均有表达,CK17蛋白在细胞浆中较强表达,两种蛋白在胞浆中融合。
4.生物信息网络Visant软件搜索发现,FOLR1的相互作用蛋白有5个,分别是LYN、UBC、NCAPH2、IRAK3、CUL3、CK17的相互作用蛋白有16个,分别是UBC、YWHAQ、KRT8、KRT72、SNAPAP、 KRT7、EGFR、CCDC85B、KRT6A、APC、GABARAP1、GRB2、 USP1、UCHL1、COPS5、SUM02。2种蛋白质具有共同的相互作用蛋白质,泛素C (Ubiquitin C)
结论：1.在鼻咽癌细胞和鼻咽癌紫杉醇耐药细胞中FOLR1与CK17存在物理上的相互作用。
2.FOLR1与CK17有一个共同的相互作用蛋白——泛素C。
3FOLR1与CK17的功能相互作用
目的：通过RNA干扰技术抑制FOLR1或CK17基因表达后,观察信号通路的基因表达变化。
方法：采用real time PCR、Western blot方法检测CK17在鼻咽癌亲本细胞(CNE-1)及其紫杉醇耐药细胞(CNE-1/Taxol)中的表达水平；通过RNA干扰技术,沉默CNE-1细胞中CK17的表达,观察FOLR1的变化；沉默CNE-1/Taxol细胞中FOLR1的表达,观察CK17的变化；基因芯片技术分析FOLR1基因沉默后耐药细胞基因组的mRNA表达变化。
结果：CK17mRNA和蛋白在鼻咽癌紫杉醇耐药细胞CNE-1/Taxol中表达明显减弱；鼻咽癌细胞CNE-1的CK17基因表达被降低后,FOLR1基因的表达无显著变化；然而,鼻咽癌紫杉醇耐药细胞CNE-1/Taxol的FOLR1基因被降低后,CK17基因的mRNA及蛋白表达水平也显著下调。cDNA Microarray基因芯片结果显示,FOLR1基因沉默后,与FOLR1有相互作用的5个基因表达均下调1.0-1.7倍,CK17表达下调约2.5倍。
结论：1. Cytokeratin17在人永生化鼻咽上皮细胞、鼻咽癌亲本细胞、鼻咽癌紫杉醇耐药细胞中表达。
2.与鼻咽癌亲本细胞CNE-1比较,CK17在鼻咽癌紫杉醇耐药细胞CNE-1/Taxol中的表达显著降低,可能与鼻咽癌紫杉醇耐药相关。
3. FOLR1在鼻咽癌细胞中与CK17存在蛋白质相互作用,可能通过影响其下游的信号通路,促进肿瘤细胞生长,抑制细胞凋亡,在鼻咽癌紫杉醇耐药中发挥重要作用。
The folate receptor1(FOLR1) is a member of surface glycoprotein with a very high affinity for folates. In the previous study, we reported that FOLR1expression level was closely correlated to both proliferation of nasopharyngeal carcinoma (NPC) cells and taxol-resistant in NPC cells. In this study, both parental NPC cell lines and taxol-resistant NPC cell lines will be used as subjects, and we aim to disclose the mechanism of taxol resistance in NPC cells through investigating the protein interaction of FOLR1. Firstly, screening the interaction proteins of FOLRl using co-immunoprecipitation technique in which FOLR1will be used as a bait protein, and primarily identifying the common interacting proteins and differential interacting proteins of FOLR1between both parental and taxol resistant NPC cells,which is cytokeratin17(CK17). Secondly, the interacting proteins of FOLR1will be verified by co-immunoprecipitation assay and fluorescent subcellular co-localization techniques. Thirdly, we will depict the possible signal pathway of FOLR1, and build protein interaction network through the analysis of interacting proteins with known mechanism of action, and indepth investigation of interacting proteins with unknown function. Then, the FOLR1signal pathway will be confirmed through the detection on activation of FOLRl signal molecules caused by silencing of FOLRl or CK17. Based on the above results, the correlation will be further detected between taxol resistance and FOLR1signal pathway by inhibition of FOLR1or CK17signal molecules using RNA interference. The role that FOLR1playing in the mechanism of taxol resistance will be in detailed elucidated in nasopharyngeal carcinoma.
1Screening of the interaction proteins of FOLR1
Objectives:To screen the interacting protein with FOLR1in human Taxol-resistant nasopharyngeal carcinoma cells(NPC).
Methods:The interacting proteins of FOLR1were screened by co-immunoprecipitation and SDS-PAGE gel staining techiqiue in parental NPC and taxol-resistant NPC cells (CNE-1/Taxol, CNE-2/Taxol, HNE-2/Taxol), and identified by mass spectrometry analysis. Results:Compared with the control, there were5different bands on SDS-PAGE gel after electrophoresis of complexes which FOLR1antibody was co-immunoprecipitated with total CNE-2/taxol cell protein, and the molecular weight was about120kD,58kD,50kD,44kD,30kD,respectively;3differences bands were found on gel which FOLR1antibody co-immunoprecipitated with total CNE-1/taxo110cell protein, and the molecular weight was about60kD,55kD,50kD, respectively; Also,2different bands were detected on gel which anti-FOLR1antibody co-immunoprecipitated with CNE-1/taxol13cell protein, the molecular weight was about50kD,36kD, repectively. Combined with the3experimental results of different precipitation, a constand differential band showed on gel and its molecular weight was about50kD. It indicated that α～50kD protein on SDS-PAGE gel of FOLR1co-immunoprecipitation may be the proteins interacting with FOLR1. Through the flight mass spectrometry analysis of differential bands, it showed that the protein of differential bands was cytokeratin17.
Conclusion:The FOLR1protein may be interacting with CK17protein in taxol-resistant NPC cells.
2Verification of Protein Interaction between FOLR1and CK17proteins
Objective:To verify the FOLR1protein interacting with CK17protein, which was screened by Co-immunoprecipitation and MACS analysis, and identified if both of them existing interactions under physiological conditions.
Methods:Both parental NPC cells (CNE-1) and Taxol-resistant NPC cells (CNE-1/Taxol) were analyzed for protein interaction between FOLR1and CK17proteins by co-immunoprecipitation and Western blot using anti-FOLR1and Anti-CK17antibody; Co-localization of FOLR1and CK17proteins was determined by immunofluorescence assay; The known possible interacting proteins of FOLR1and CK17were retrieved and analyzed by using Visant biological information database network and its software.
Results:1The protein expression of CK17can be detected in the protein complexes of co-immunoprecipitation of FOLR1antibodies with total protein of Taxol-resistant NPC cells (CNE-1/taxol).It was not detectable in negattive controls.
2The protein expression of FOLR1can be detected in the protein complexes of co-immunoprecipitation of CK17antibodies with total protein of Taxol-resistant NPC cells (CNE-1/taxol).It was not detectable in NP69cells.
3The FOLR1expression was observed in the cytoplasm and cell membrane, and a strong expression of CK17protein was observed in the cytoplasm by using immunofluorescence laser confocal microscopy. A fusion of both proteins in the cytoplasm was detected.
4Analysis of Visant biological information network demonstrated that five proteins might be interacted with FOLR1protein (LYN, UBC, NCAPH2, IRAK3, CUL3), and sixteen proteins might be interacted with CK17proteins (UBC, YWHAQ, KRT8, KRT72, SNAPAP, KRT7, EGFR, CCDC85B, KRT6A, APC, GABARAPL1, GRB2, USP1, UCHL1, COPS5, SUM02). There is a common interacting protein for both FOLR1and CK17proteins, and it is Ubiquitin C.
Conclusion:1There is a physical interaction between FOLR1and CK17 proteins in both parental NPC cells and Taxol-resistant NPC cells.2Ubiquitin C is a common interacting protein between FOLR1and CK17proteins.
3The functional interaction of FOLRl and CK17proteins
Objectives:To observe the expressional changes of FOLR1, CK17and related signal transduction genes after inhibition of FOLR1or CK17.
Methods:The knock-down of genes was carried out by siRNA technique. mRNA and protein expression level of CK17and FOLR1genes were detected by real time PCR and Western blot in NPC cells (CNE-1) and taxol-resistant cells (CNE-1/Taxol). The expressional changes of signal transduction genes after FOLRl inhibition was conducted by cDNA microarray.
Results:Expression of CK17mRNA and protein were decreased in Taxol-resistant NPC cells (CNE-1/Taxol) compared with parental cells. No significant change was observed in the expression of the FOLR1gene after knocked-down of CK17gene; However, mRNA and protein expression level of CK17gene was significantly down-regulated after the knocked-down of the FOLR1gene in taxol-resistant NPC cells (CNE-1/Taxol). cDNA Microarray analysis showed that, after FOLR1gene silencing, expression of5genes which known possible interacting with FOLR1, were down-regulated1.0-1.7times, and CK17expression was decreased2.5times.
Conclusion:1.Cytokeratin17expression was detected in nasopharyngeal epithelial cells of human, parental NPC cells, and taxol-resistant NPC cells.
2.Comparison with parental CNE-1cells, the expression of CK17were significantly decreased in taxol-resistant NPC cells, and it may be associated with Taxol-resistant nasopharyngeal carcinoma.
3.The FOLR1protein can be interacting with CK17protein in NPC cells, and promote the growth of tumor cells, inhibit cell apoptosis, and play an important role in taxol resistance in NPC. The role may be playing through signaling pathway and its downstream effects.
1FOLR1的相互作用蛋白筛选
目的：筛选人鼻咽癌紫杉醇耐药细胞中FOLR1的相互作用蛋白。
方法：以免疫共沉淀、SDS-PAGE电泳和凝胶染色方法筛选体外培养的正常鼻咽上皮细胞NP69和三株鼻咽癌紫杉醇耐药细胞(CNE-1/Taxol、CNE-2/Taxol、HNE-2/Taxol)中FOLR1的相互作用蛋白,质谱分析方法鉴定相互作用蛋白。
结果：CNE-2/taxol细胞蛋白质经过FOLR1的抗原抗体复合物及Protein A琼脂糖珠的共沉淀后,与对照比较,有5条差异条带,分子量分别约为120kD,58kD,50kD,44kD,30kD; CNE-1/taxol10细胞蛋白质经免疫共沉淀后电泳,与对照比较,有3差异条带,分子量分别约为60kD,55kD,50kD; CNE-1/taxol13细胞蛋白质经免疫共沉淀后电泳,与自身对照比较,有2差异条带,分子量分别约为50kD,36kD。结合3次免疫共沉淀实验结果,不同凝胶上都显示出-50kD的差异条带,预示SDS-PAGE凝胶上-50kD的蛋白质可能是与FOLR1相互作用的蛋白质。通过对差异条带进行飞行质谱分析,结果显示该蛋白质为cytokeratin17。
结论：人鼻咽癌紫杉醇耐药细胞中FOLR1蛋白可能与CK17蛋白有相互作用。
2FOLR1与CK17蛋白相互作用的验证
目的：验证筛选出来的FOLR1的相互作用蛋白CK17,确定二者在生理条件下存在相互作用。
方法：以免疫共沉淀、Western blot方法验证鼻咽癌亲本细胞(CNE-1)及鼻咽癌紫杉醇耐药细胞(CNE-1/Taxol)中FOLR1与CK17是否存在相互作用；免疫荧光双标法分析FOLR1与CK17的共定位关系；运用Visant软件对生物信息网络数据库进行检索和分析,确定FOLR1和CK17已知的可能相互作用蛋白。
结果：1.以FOLR1抗体对鼻咽癌紫杉醇耐药细胞CNE-1/taxol的总蛋白进行免疫共沉淀后,复合物中可以检测到CK17的表达,阴性对照中没有检测到CK17的表达。
2.以CK17抗体对鼻咽癌紫杉醇耐药细胞CNE-1/taxol的总蛋白进行免疫共沉淀后,复合物中可以检测到FOLR1的表达,而在对照细胞NP69中没有检测到FOLR1的表达。
3.免疫荧光激光共聚焦显微镜观察到FOLR1蛋白在细胞浆及细胞膜中均有表达,CK17蛋白在细胞浆中较强表达,两种蛋白在胞浆中融合。
4.生物信息网络Visant软件搜索发现,FOLR1的相互作用蛋白有5个,分别是LYN、UBC、NCAPH2、IRAK3、CUL3、CK17的相互作用蛋白有16个,分别是UBC、YWHAQ、KRT8、KRT72、SNAPAP、 KRT7、EGFR、CCDC85B、KRT6A、APC、GABARAP1、GRB2、 USP1、UCHL1、COPS5、SUM02。2种蛋白质具有共同的相互作用蛋白质,泛素C (Ubiquitin C)
结论：1.在鼻咽癌细胞和鼻咽癌紫杉醇耐药细胞中FOLR1与CK17存在物理上的相互作用。
2.FOLR1与CK17有一个共同的相互作用蛋白——泛素C。
3FOLR1与CK17的功能相互作用
目的：通过RNA干扰技术抑制FOLR1或CK17基因表达后,观察信号通路的基因表达变化。
方法：采用real time PCR、Western blot方法检测CK17在鼻咽癌亲本细胞(CNE-1)及其紫杉醇耐药细胞(CNE-1/Taxol)中的表达水平；通过RNA干扰技术,沉默CNE-1细胞中CK17的表达,观察FOLR1的变化；沉默CNE-1/Taxol细胞中FOLR1的表达,观察CK17的变化；基因芯片技术分析FOLR1基因沉默后耐药细胞基因组的mRNA表达变化。
结果：CK17mRNA和蛋白在鼻咽癌紫杉醇耐药细胞CNE-1/Taxol中表达明显减弱；鼻咽癌细胞CNE-1的CK17基因表达被降低后,FOLR1基因的表达无显著变化；然而,鼻咽癌紫杉醇耐药细胞CNE-1/Taxol的FOLR1基因被降低后,CK17基因的mRNA及蛋白表达水平也显著下调。cDNA Microarray基因芯片结果显示,FOLR1基因沉默后,与FOLR1有相互作用的5个基因表达均下调1.0-1.7倍,CK17表达下调约2.5倍。
结论：1. Cytokeratin17在人永生化鼻咽上皮细胞、鼻咽癌亲本细胞、鼻咽癌紫杉醇耐药细胞中表达。
2.与鼻咽癌亲本细胞CNE-1比较,CK17在鼻咽癌紫杉醇耐药细胞CNE-1/Taxol中的表达显著降低,可能与鼻咽癌紫杉醇耐药相关。
3. FOLR1在鼻咽癌细胞中与CK17存在蛋白质相互作用,可能通过影响其下游的信号通路,促进肿瘤细胞生长,抑制细胞凋亡,在鼻咽癌紫杉醇耐药中发挥重要作用。
The folate receptor1(FOLR1) is a member of surface glycoprotein with a very high affinity for folates. In the previous study, we reported that FOLR1expression level was closely correlated to both proliferation of nasopharyngeal carcinoma (NPC) cells and taxol-resistant in NPC cells. In this study, both parental NPC cell lines and taxol-resistant NPC cell lines will be used as subjects, and we aim to disclose the mechanism of taxol resistance in NPC cells through investigating the protein interaction of FOLR1. Firstly, screening the interaction proteins of FOLRl using co-immunoprecipitation technique in which FOLR1will be used as a bait protein, and primarily identifying the common interacting proteins and differential interacting proteins of FOLR1between both parental and taxol resistant NPC cells,which is cytokeratin17(CK17). Secondly, the interacting proteins of FOLR1will be verified by co-immunoprecipitation assay and fluorescent subcellular co-localization techniques. Thirdly, we will depict the possible signal pathway of FOLR1, and build protein interaction network through the analysis of interacting proteins with known mechanism of action, and indepth investigation of interacting proteins with unknown function. Then, the FOLR1signal pathway will be confirmed through the detection on activation of FOLRl signal molecules caused by silencing of FOLRl or CK17. Based on the above results, the correlation will be further detected between taxol resistance and FOLR1signal pathway by inhibition of FOLR1or CK17signal molecules using RNA interference. The role that FOLR1playing in the mechanism of taxol resistance will be in detailed elucidated in nasopharyngeal carcinoma.
1Screening of the interaction proteins of FOLR1
Objectives:To screen the interacting protein with FOLR1in human Taxol-resistant nasopharyngeal carcinoma cells(NPC).
Methods:The interacting proteins of FOLR1were screened by co-immunoprecipitation and SDS-PAGE gel staining techiqiue in parental NPC and taxol-resistant NPC cells (CNE-1/Taxol, CNE-2/Taxol, HNE-2/Taxol), and identified by mass spectrometry analysis. Results:Compared with the control, there were5different bands on SDS-PAGE gel after electrophoresis of complexes which FOLR1antibody was co-immunoprecipitated with total CNE-2/taxol cell protein, and the molecular weight was about120kD,58kD,50kD,44kD,30kD,respectively;3differences bands were found on gel which FOLR1antibody co-immunoprecipitated with total CNE-1/taxo110cell protein, and the molecular weight was about60kD,55kD,50kD, respectively; Also,2different bands were detected on gel which anti-FOLR1antibody co-immunoprecipitated with CNE-1/taxol13cell protein, the molecular weight was about50kD,36kD, repectively. Combined with the3experimental results of different precipitation, a constand differential band showed on gel and its molecular weight was about50kD. It indicated that α～50kD protein on SDS-PAGE gel of FOLR1co-immunoprecipitation may be the proteins interacting with FOLR1. Through the flight mass spectrometry analysis of differential bands, it showed that the protein of differential bands was cytokeratin17.
Conclusion:The FOLR1protein may be interacting with CK17protein in taxol-resistant NPC cells.
2Verification of Protein Interaction between FOLR1and CK17proteins
Objective:To verify the FOLR1protein interacting with CK17protein, which was screened by Co-immunoprecipitation and MACS analysis, and identified if both of them existing interactions under physiological conditions.
Methods:Both parental NPC cells (CNE-1) and Taxol-resistant NPC cells (CNE-1/Taxol) were analyzed for protein interaction between FOLR1and CK17proteins by co-immunoprecipitation and Western blot using anti-FOLR1and Anti-CK17antibody; Co-localization of FOLR1and CK17proteins was determined by immunofluorescence assay; The known possible interacting proteins of FOLR1and CK17were retrieved and analyzed by using Visant biological information database network and its software.
Results:1The protein expression of CK17can be detected in the protein complexes of co-immunoprecipitation of FOLR1antibodies with total protein of Taxol-resistant NPC cells (CNE-1/taxol).It was not detectable in negattive controls.
2The protein expression of FOLR1can be detected in the protein complexes of co-immunoprecipitation of CK17antibodies with total protein of Taxol-resistant NPC cells (CNE-1/taxol).It was not detectable in NP69cells.
3The FOLR1expression was observed in the cytoplasm and cell membrane, and a strong expression of CK17protein was observed in the cytoplasm by using immunofluorescence laser confocal microscopy. A fusion of both proteins in the cytoplasm was detected.
4Analysis of Visant biological information network demonstrated that five proteins might be interacted with FOLR1protein (LYN, UBC, NCAPH2, IRAK3, CUL3), and sixteen proteins might be interacted with CK17proteins (UBC, YWHAQ, KRT8, KRT72, SNAPAP, KRT7, EGFR, CCDC85B, KRT6A, APC, GABARAPL1, GRB2, USP1, UCHL1, COPS5, SUM02). There is a common interacting protein for both FOLR1and CK17proteins, and it is Ubiquitin C.
Conclusion:1There is a physical interaction between FOLR1and CK17 proteins in both parental NPC cells and Taxol-resistant NPC cells.2Ubiquitin C is a common interacting protein between FOLR1and CK17proteins.
3The functional interaction of FOLRl and CK17proteins
Objectives:To observe the expressional changes of FOLR1, CK17and related signal transduction genes after inhibition of FOLR1or CK17.
Methods:The knock-down of genes was carried out by siRNA technique. mRNA and protein expression level of CK17and FOLR1genes were detected by real time PCR and Western blot in NPC cells (CNE-1) and taxol-resistant cells (CNE-1/Taxol). The expressional changes of signal transduction genes after FOLRl inhibition was conducted by cDNA microarray.
Results:Expression of CK17mRNA and protein were decreased in Taxol-resistant NPC cells (CNE-1/Taxol) compared with parental cells. No significant change was observed in the expression of the FOLR1gene after knocked-down of CK17gene; However, mRNA and protein expression level of CK17gene was significantly down-regulated after the knocked-down of the FOLR1gene in taxol-resistant NPC cells (CNE-1/Taxol). cDNA Microarray analysis showed that, after FOLR1gene silencing, expression of5genes which known possible interacting with FOLR1, were down-regulated1.0-1.7times, and CK17expression was decreased2.5times.
Conclusion:1.Cytokeratin17expression was detected in nasopharyngeal epithelial cells of human, parental NPC cells, and taxol-resistant NPC cells.
2.Comparison with parental CNE-1cells, the expression of CK17were significantly decreased in taxol-resistant NPC cells, and it may be associated with Taxol-resistant nasopharyngeal carcinoma.
3.The FOLR1protein can be interacting with CK17protein in NPC cells, and promote the growth of tumor cells, inhibit cell apoptosis, and play an important role in taxol resistance in NPC. The role may be playing through signaling pathway and its downstream effects.
引文
[1]方宁,农晓琳.肿瘤多药耐药机制研究现状[J].实用肿瘤学杂志：2008,22：553-556.
[2]Nobili S, Landini I, Giglioni B, et al. Pharmacological Strategies for Overcoming multidrug Resistance[J]. Current Drug Targets:2006,7:861-879.
[3]Garcia-Martin E, Pizarro RM, Martinez C, et al. Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8[J]. Pharrmacogenomics:2006,7:575-585.
[4]王鑫,王洁,张燕,等(综述).肿瘤细胞耐药机制的研究进展[J].癌症进展杂志：2007,5：73-78,47.
[5]Xing H, Wang S, Weng D, et al. Knock-down of P-glycoprotein reverses taxol resistance in ovarian cancer multicellular spheroids[J]. Oncol Rep:2007,17:117-122.
[6]Stone R.Surpris! A fungus factory for taxol?[J] Science:1993,260:154-155.
[7]Holmes FA,Walters RS,Theriault RL, et al. Phase Ⅱ trial of taxol, an active drug in the treatment of metastatic breast cancer[J]. Natl.Cancer Inst:1991,83:1797-1805.
[8]Pinedo HM, Longo DL, Chabner BA. Cancer chemotherapy and biological response modifiers annual 16 Amsterdam:Elsevier Science B.V.,1996, p.57-67.
[9]Yusuf RZ, Duan Z, Lamendola DE, et al. Paclitaxel resistance:molecular mechanisms and pharmacologic manipulation[J]. Curr Cancer Targets:2003,3:1-19.
[10]Pires MM, Emmert D, Hrycyna CA, et al. Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers[J]. Mol Pharmacol:2009,75:92-100.
[11]Quan F, Pan C, Ma Q, et al. Reversal effect of resveratrol on multidrug resistance in KBv200 cell line[J]. Biomed Pharmacother:2008,62:622-629.
[12]褚玉敏,谭国林,马艳红.人鼻咽癌紫杉醇耐药细胞株CNE-1/Taxol的建立及其机制初探[J].中国耳鼻咽喉颅底外科杂志：2007,13：411-14.
[13]彭小伟,贺广湘,李维,等.ATP结合盒转运体基因在鼻咽癌紫杉醇耐药细胞中的表达[J].中国耳鼻咽喉颅底外科杂志：2008,14：15-20.
[14]李维,谭国林,马艳红,等.叶酸受体1在鼻咽癌细胞抵抗紫杉醇化疗药物中的作用[J].中华耳鼻咽喉头颈外科杂志：2010,12：1035-1039.
[15]Kelemen LE. The role of folate receptor aincancer development, progression and treatment:cause,consequence or innocent by stander[J]? Int J Cancer:2006,119:243-250.
[16]Weitman SD, Weinberg AG, Coney LR, et al. Cellular localization of the folate receptor:potential role in drug toxicity and folate homeostasis[J]. Cancer Res: 1992,52:6708-6711.
[17]Odin E,Wettergren Y, Nilsson S, et al. Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients[J]. Clin Cancer Res:2003,9(16 Pt 1):6012-6019.
[18]Toffoli G, Cernigoi C, Russo A, et al. Overexpression of folate binding protein in ovarian cancer[J]. Int J Cancer:1997,74:193-198.
[19]Iwakiri S, Sonobe M, Nagai S, et al. Expression status of folate receptor alpha is significantly correlated with prognosis in non-small-cell lung cancers[J]. Ann Surg Oncol:2008,15:889-899.
[20]Jhaveri MS, Rait AS, Chung KN, et al. Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment[J]. Mol Cancer Ther:2004,3:1505-1512.
[21]Miotti S, Bagnoli M, Tomassetti A, et al. Interaction of folate receptor with signaling molecules lyn and G(a)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1[J]. J Cell Sci:2000,113:349-357.
[22]Rwei-Fen S. Huang, Yun-Hsiu Ho, Huei-Li Lin, et al. Folate Deficiency Induces a Cell Cycle-Specific Apoptosis in HepG2 Cells[J].The Journal of Nutrition:1999,129:25-31.
[23]刘里.鼻咽癌紫杉醇耐药细胞系的生物学特性及多药耐药性检测[D].长沙：中南大学,2010.
[24]唐刘君,王建,杨晓明.规模化蛋白质相互作用的研究技术[J].医学分子生物学杂志：2009,6：347-352.
[25]向波,王理,李桂源,等.鼻咽癌下调新基因NOR1相互作用蛋白的筛选和鉴定[J].生物化学与生物物理进展：2009,36.709-714.
[26]Cellai E, Chiavacci A, Olmi P, et al. Carcinoma of the nasopharynx:results of radiation therapy[J]. Acta Radiol Oncol:1982,21(2):87-95.
[27]闵华庆,洪明晃,郭翔,等.鼻咽癌研究进展[J].中国肿 瘤：1999，12：558-561.
[28]Cheng S H, Tsai S Y, Yen K L, et al. Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma[J]. J Clin Oncol:2000,18(10):2040-2045.
[29]Serin M, Erkal H S, Cakmak A. Radiation therapy and concurrent cisplatin in management of locoregionally advanced nasopharyngeal carcinomas[J]. Acta Oncol:1999,38(8):1031-1035.
[30]Li W,Tan G,Ma Y,et al.Inhibition of a Folate Receptor Resulting in a Reversal of Taxol Resistance in Nasopharyngeal Carcinoma. [J] Otolaryngology Head and Neck Surgery:2012,146:250-258.
[31]Brzezinska A, Winska P, Balinska M. Cellular aspects of folate and antifolate membrane transport[J]. Acta Biochim Pol:2000,47(3):735-749.
[32]Shen F, Wu M, Ross J F, et al. Folate receptor type gamma is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification:protein characterization and cell type specificity[J]. Biochemistry:1995,34(16):5660-5665.
[33]Eisenberg D, Marcotte EM, Xenarios I,et al. Protein function in the post-genomic era[J].Nature:2000,405(6788):823-826.
[34]. Auerbach D, Thaminy S, Hottiger MO,et al. The post-genomic era of interactive proteomics:facts and perspectives[J]. Proteomics:2002,2(6):611-623.
[35].Wang,J. Protein recognition by cell surface receptors:physiological receptors versus virus interactions[J]. Trends Biochem Sci:2002,27(3):122-126.
[36]Kone BC, Kuncewicz T, Zhang W, et al. Protein interactions with nitric oxide synthases:controlling the right time, the right place,and the right amount of nitric oxide[J]. Am J Physiol Renal Physiol:2003,285 (2):F178-190.
[37]Cohen FE, Prusiner SB. Pathologic conformations of prion proteins[J]. Annu Rev Biochem:1998,67:793-819.
[38].Loregian, A., H. S. Marsden, G Palu. Protein-protein interactions as targets for antiviral chemotherapy[J]. Rev Med Virol:2002,12(4):239-262.
[39].Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease[J]. Trends Cell Biol:1998,8(11):447-453.
[40]Fields S, Song O. A novel genetic system to detect protein-protein interactions[J]. Nature:1989,340(6230):245-246.
[41]Stahlhut M, van Deurs B. Identification of filamin as a novel ligand for caveolin-1:evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton[J]. Mol Biol Cell.:2000,11(1):325-337.
[42]Angermayr M, Hochleitner E, Lottspeich F,et al. Protein kinase CK2 activates the atypical Riolp kinase and promotes its cell-cycle phase-dependent degradation in yeast[J]. FEBS J.:2007,274(17):4654-4667.
[43]Leung KM, Feng DX, Lou J,et al. Development of human single-chain antibodies against SARS-associated coronavirus[J]. Intervirology: 2008,51(3):173-181.
[44]Zhu H, Snyder M. Protein chip technology[J]. Curr Opin Chem Biol.:2003,7(1):55-63.
[45]Zhou X, Kao M C, Wong W H. Transitive functional annotation by shortest-path analysis of gene expression data[J]. Proc Natl Acad Sci USA:2002, 99(20):12783-12788.
[46]Karaoz U, Murali T M, Letovsky S, et al. Whole-genome annota-tion by using evidence integration in functional-linkage networks[J]. Proc Natl Acad Sci USA:2004,101(9):2888-2893.
[47]Legrain P, Wojcik J, Gauthier JM. Protein--protein interaction maps:a lead towards cellular functions[J]. Trends Genet:2001,17(6):346-352.
[48]Von Mering,C.,et al.Comparative assessment of large-scale data sets of protein-protein interactions[J]. Nature:2002,417(6887):399-403.
[49]彭小伟,谭国林.基因芯片技术检测鼻咽癌紫杉醇耐药及耐药逆转相关基因的表达[J].中南大学学报：医学版,2012,37(1)：48-52.
[50]孙林潮,王刚,王岩,等.K17反义寡核苷酸对角质形成细胞增殖和K17表达的影响[J].中华皮肤科杂志：2006,11：642-644.
[51]Abbott A. A post-genomic challenge:learning to read patterns of protein synthesis[J]. Nature:1999,402(6763):715-720.
[52]孙宇,贾凌云,任军.蛋白质相互作用的研究方法[J].分析化学医学期刊(新)：2007,5：760-766.
[53]Tomita S, Ozaki T, Taru H,et al. Interaction of a Neuron-specific protein containing PDZ domains with Alzheimer's Amyloid precursor protein[J]. J. Biol. Chem:1999,274(4):2243-2254.
[54]Kong M, Barnes EA, Ollendorff V, et al. Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction[J]. The EMBO J:2000,19(6):1378-1388.
[55]Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27kip1 is instigated by Jab1[J].Nature:1999,398:160-164.
[56]Aronheim A, Zandi E, Hennemann H, et al. Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions[J]. Mol. Cell. Biol:1997,17(6):3094-3102.
[57]Dressel U, Thormeyer D, Renkawitz R, et al. Alien, a highly conserved protein with characteristics of a corepressor for membranes of the nuclear hormone receptor superfamily[J]. Mol. Cell. Biol:1999,19(5):3383-3394.
[58]Bosnar M H, Gunzburg de J, Bago R, et al. Subcellular localization of A and B Nm23/NDPK subunits [J]. Exp Cell Res:2004,298:275-284.
[59]Fuchs E, Cleveland DW. A structural scaffolding of intermediate filaments in health and disease[J]. Science:1998,279:514-519.
[60]Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins[J]. J Cell Biol:2006,174:169-174.
[61]Coulombe PA, Omary MB.'Hard' and' soft' principles defining the structure, function and regulation of keratin intermediate filaments[J]. Curr Opin Cell Biol:2002,14:110-122.
[62]Gu LH, Coulombe PA. Keratin function in skin epithelia:A broadening palette with surprising shades[J]. Curr Opin Cell Biol:2007,19(1):13-23.
[63]Oriolo AS, Wald FA, Ramsauer VP, Salas PJ. Intermediate filaments:a role in epithelial polarity[J]. Exp Cell Res:2007,313:2255-2264.
[64]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[65]Vijayaraj P, Kroger C, Reuter U,et al. Keratins regulate protein biosynthesis through localization of GLUT1 and-3 upstream of AMP kinase and Raptor[J]. J Cell Biol:2009,187:175-184.
[66]Styers ML, Kowalczyk AP, Faundez V. Intermediate filaments and vesicular membrane traffic:the odd couple's first dance[J]? Traffic:2005,6:359-365.
[67]Toivola DM, Tao GZ, Habtezion A, et al. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments[j]. Trends Cell Biol:2005,15:608-617.
[68]Chu YW, Seftor EA, Romer LH, et al Experimental coexpression of vimentin and keratin intermediate filaments in human melanoma cells augments motility[J]. Am. J. Pathol:1996,148(1):63-69.
[69]Moll R, Divo M, Langbein L. The human keratins:Biology and pathology[J]. Histochem Cell Biol:2008,129(6):705-733.
[70]Hsu TM, Kwok PY. Advances in molecular medicine[J]. J Am Acad Dermatol:2001,44(5):847-855.
[71]McGowan KM, Coulombe PA. Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development[J]. J Cell Biol:1998,143:469-486.
[72]Achtsttter T, Moll R, Moore B, et al. Cytokeratin polypeptide patterns of different epithelia of the human male urogenital tract:Immunofluorescence and gel electrophoretic studies[J]. J Histochem Cytochem:1985,33:415-426.
[73]Komine M, Freedberg IM, Blumberg PM. Regulation of epidermal expression of keratin 17 in inflammatory skin diseases[J]. J Invest Dermatol:1996,107:569-575.
[74]Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the keratinocyte activation cycle[J]. J Invest Dermatol:2001,116:633-640.
[75]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[76]Cohen-Kerem R, Madah W, Sabo E, et al. Cytokeratin-17 as a potential marker for squamous cell carcinoma of the larynx[J]. Ann Otol Rhinol Laryngol:2004,113(10):821-827.
[77]Van de Rijn M, Perou CM, Tibshirani R, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome[J]. Am J Pathol:2002,161(6):1991-1996.
[78]Carrilho C, Alberto M, Buane L, et al. Keratins 8,10,13, and 17 are useful markers in the diagnosis of human cervix carcinomas [J]. Hum Pathol:2004,35(5):546-551.
[79]Wetzels RH, Schaafsma HE, Leigh IM, et al. Laminin and type Ⅶ collagen distribution in different types of human lung carcinoma:Correlation with expression of keratins 14,16,17 and 18[J]. Histopathology:1992,20(4):295-303.
[80]Smedts F, Ramaekers F C, Hopman A H. CK17 and p16 expression patterns distinguish(atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia [J].Histopathology:2008,52(4):515-516.
[81]李晓梅,赵玉兰,王洪梅.ck17和ck18在肺低分化鳞癌及腺癌鉴别诊断中的应用[J].伤残医学杂志：2003,11(3)：73-75.
[82]Steinert PM, Parry DA, Racoosin EL, et al. The complete cDNA and deduced amino acid sequence of a type II mouse epidermal keratin of 60 000 Da: analysis of sequence differences between type I and type II keratins[J]. Proc Natl Acad Sci USA:1984,81:5709-5713.
[83]Tong X, Coulombe PA. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion[J]. Genes Dev.:2006,20(10):1353-1364.
[84]Lei DS, Yu J, Tong XL, et al. Diagnostic value of cytokeratin 19 fragment in nasopharyngeal carcinoma[J]. Zhonghua Bing Li Xue Za Zhi.:2012,41(7):461-465.
[85]Li XM, Huang WG, Yi H,et al. Proteomic analysis to identify cytokeratin 18 as a novel biomarker of nasopharyngeal carcinoma[J]. J Cancer Res Clin Oncol.:2009,135(12):1763-1775.
[86]Huang WG, Cheng AL, Chen ZC,et al. Targeted proteomic analysis of 14-3-3sigma in nasopharyngeal carcinoma[J]. Int J Biochem Cell Biol.:2010,42(1):137-147.
[87]Tang S, Huang W, Zhong M, et al. Identification Keratin 1 as a cDDP-resistant protein in nasopharyngeal carcinoma cell lines[J]. J Proteomics.:2012,75(8):2352-2360.
[1]Pollard TD, Cooper JA. Actin, a central player in cell shape and movement[J]. Science:2009,326:1208-1212.
[2]Herrmann H, Strelkov SV, Burkhard P, et al. Intermediate filaments: primary determinants of cell architecture and plasticity[J]. J Clin Invest:2009,119:1772-1783.
[3]Glotzer M. The 3Ms of central spindle assembly:microtubules, motors and MAPs[J]. Nat Rev Mol Cell Biol:2009,10:9-20.
[4]Herrmann H, Bar H, Kreplak L, et al. Intermediate filaments:from cell architecture to nanomechanics[J]. Nat Rev Mol Cell Biol:2007,8:562-573.
[5]Steinert PM, Marekov LN, Parry DA. Conservation of the structure of keratin intermediate filaments:molecular mechanism by which different keratin molecules integrate into preexisting keratin intermediate filaments during differentiation[J]. Biochemistry:1993,32:10046-10056.
[6]Moll R, Franke WW, Schiller DL, et al. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells[J]. Cell:1982,31:11-24.
[7]Quinlan RA, Cohlberg JA, Schiller DL, et al. Heterotypic tetramer (A2D2) complexes of non-epidermal keratins isolated from cytoskeletons of rat hepatocytes and hepatoma cells[J]. J Mol Biol:1984,178:365-388.
[8]Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins[J]. J Cell Biol:2006,174:169-174.
[9]Bragulla HH, Homberger DG. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia[J]. J Anat:2009,214:516-559.
[10]Moll R, Divo M, Langbein L. The human keratins:biology and pathology[J]. Histochem Cell Biol:2008,129:705-733.
[11]Coulombe PA, Omary MB.'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments[J]. Curr Opin Cell Biol:2002,14:110-122.
[12]Omary MB, Ku NO, Strnad P, et al. Toward unraveling the complexity of simple epithelial keratins in human disease[J]. J Clin Invest:2009,119:1794-1805.
[13]Vijayaraj P, Sohl G, Magin TM. Keratin transgenic and knockout mice: functional analysis and validation of disease-causing mutations[J]. Methods Mol Biol:2007,360:203-251.
[14]Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering[J]. Nature:1992,356:244-246.
[15]Coulombe PA, Hutton ME, Letai A, et al. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients:genetic and functional analyses[J]. Cell:1991,66:1301-1311.
[16]Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy [J]. Nat Genet:1997,16:184-187.
[17]Ku NO, Gish R, Wright TL, et al. Keratin 8 mutations in patients with cryptogenic liver disease[J]. N Engl J Med:2001,344:1580-1587.
[18]Ku NO, Wright TL, Terrault NA, et al. Mutation of human keratin 18 in association with cryptogenic cirrhosis[J]. J Clin Invest:1997,99:19-23.
[19]Omary MB, Ku NO, Tao GZ, et al.'Heads and tails' of intermediate filament phosphorylation:multiple sites and functional insights[J]. Trends Biochem Sci:2006,31:383-394.
[20]Strnad P, Zhou Q, Hanada S, et al. Keratin variants predispose to acute liver failure and adverse outcome:race and ethnic associations[J]. Gastroenterology:2010,139:828-835.835 el-e3.
[21]Peters B, Kirfel J, Bussow H, et al. Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex[J]. Mol Biol Cell:2001,12:1775-1789.
[22]Lloyd C, Yu QC, Cheng J, et al. The basal keratin network of stratified squamous epithelia:defining K15 function in the absence of K14[J]. J Cell Biol:1995,129:1329-1344.
[23]Kao WW, Liu CY, Converse RL, et al. Keratin 12-deficient mice have fragile corneal epithelia[J]. Invest Ophthalmol Vis Sci:1996,37:2572-2584.
[24]Baribault H, Price J, Miyai K,et al. Mid-gestational lethality in mice lacking keratin 8[J]. Genes Dev:1993,7:1191-1202.
[25]Baribault H, Penner J, Iozzo RV, et al. Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice[J]. Genes Dev:1994,8:2964-2973.
[26]Magin TM, Schroder R, Leitgeb S, et al. Lessons from keratin 18 knockout mice:formation of novel keratin filaments, secondary loss of keratin 7 and accumulation of liver-specific keratin 8-positive aggregates[J]. J Cell Biol:1998,140:1441-1451.
[27]Ku NO, Michie S, Oshima RG, et al. Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant[J]. J Cell Biol:1995,131:1303-1314.
[28]Zatloukal K, Stumptner C, Lehner M, et al. Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies[J]. Am J Pathol:2000,156:1263-1274.
[29]Ku NO, Omary MB. A disease-and phosphorylation-related nonmechanical function for keratin 8[J]. J Cell Biol:2006,174:115-125.
[30]Oriolo AS, Wald FA, Ramsauer VP, et al. Intermediate filaments:a role in epithelial polarity[J]. Exp Cell Res:2007,313:2255-2264.
[31]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[32]Toivola DM, Tao GZ, Habtezion A, et al. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments[J]. Trends Cell Biol:2005,15:608-617.
[33]Yano S, Komine M, Fujimoto M, et al. Mechanical stretching in vitro regulates signal transduction pathways and cellular proliferation in human epidermal keratinocytes[J]. J Invest Dermatol:2004,122:783-790.
[34]Zatloukal K, French SW, Stumptner C, et al. From Mallory to Mallory-Denk bodies:what, how and why[J]? Exp Cell Res:2007,313:2033-2049.
[35]Fickert P, Trauner M, Fuchsbichler A, et al. Mallory body formation in primary biliary cirrhosis is associated with increased amounts and abnormal phosphorylation and ubiquitination of cytokeratins[J]. J Hepatol:2003,38:387-394.
[36]Sivaramakrishnan S, DeGiulio JV, Lorand L, et al. Micromechanical properties of keratin intermediate filament networks[J]. Proc Natl Acad Sci USA:2008,105:889-894.
[37]Na N, Chandel NS, Litvan J, et al. Mitochondrial reactive oxygen species are required for hypoxia-induced degradation of keratin intermediate filaments[J]. FASEB J:2010,24:799-809.
[38]Nelson DA, Tan TT, Rabson AB, et al. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis[J]. Genes Dev:2004,18:2095-2107.
[39]Sivaramakrishnan S, Schneider JL, Sitikov A, et al. Shear stress induced reorganization of the keratin intermediate filament network requires phosphorylation by protein kinase C zeta[J]. Mol Biol Cell:2009,20:2755-2765.
[40]Liao J, Ku NO, Omary MB. Stress, apoptosis, and mitosis induce phosphorylation of human keratin 8 at Ser-73 in tissues and cultured cells[J]. J Biol Chem:1997,272:17565-17573.
[41]Toivola DM, Zhou Q, English LS, et al. Type Ⅱ keratins are phosphorylated on a unique motif during stress and mitosis in tissues and cultured cells[J]. Mol Biol Cell:2002,13:1857-1870.
[42]Kongara S, Kravchuk O, Teplova I, et al. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors[J]. Mol Cancer Res:2010,8:873-884.
[43]Ku NO, Azhar S, Omary MB. Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization:modulation by a keratin 1-like disease causing mutation[J]. J Biol Chem:2002,277:10775-10782.
[44]He T, Stepulak A, Holmstrom TH, et al. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase[J]. J Biol Chem:2002,277:10767-10774.
[45]Ridge KM, Linz L, Flitney FW, et al. Keratin 8 phosphorylation by protein kinase C delta regulates shear stress-mediated disassembly of keratin intermediate filaments in alveolar epithelial cells[J]. J Biol Chem:2005,280:30400-30405.
[46]Omary MB, Ku NO, Liao J, et al. Keratin modifications and solubility properties in epithelial cells and in vitro[J]. Subcell Biochem:1998,31:105-140.
[47]Ku NO, Omary MB. Keratins turn over by ubiquitination in a phosphorylation-modulated fashion[J]. J Cell Biol:2000,149:547-552.
[48]Ku NO, Michie S, Resurreccion EZ, et al. Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression[J]. Proc Natl Acad Sci USA:2002,99:4373-4378.
[49]Hernandez BY, Frierson HF, Moskaluk CA, et al. CK20 and CK7 protein expression in colorectal cancer:demonstration of the utility of a population-based tissue microarray[J]. Hum Pathol:2005,36:275-281.
[50]Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms:a survey of 435 cases[J]. Mod Pathol:2000,13:962-972.
[51]Chu PG, Weiss LM. Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases[J]. Mod Pathol:2002,15:6-10.
[52]Nikitakis NG, Tosios KI, Papanikolaou VS, et al. Immunohistochemical expression of cytokeratins 7 and 20 in malignant salivary gland tumors[J], Mod Pathol:2004,17:407-415.
[53]Yaziji H, Battifora H, Barry TS, et al. Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma:identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity[J]. Mod Pathol:2006,19:514-523.
[54]Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms[J]. Histopathology:2002,40:403-439.
[55]Lehr HA, Folpe A, Yaziji H, et al. Cytokeratin 8 immunostaining pattern and E-cadherin expression distinguish lobular from ductal breast carcinoma[J]. Am J Clin Pathol:2000,114:190-196.
[56]Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[J]. Proc Natl Acad Sci USA:2001,98:10869-10874.
[57]Liu L, Qian J, Singh H, et al. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma:an optimal and practical panel for differential diagnosis[J]. Arch Pathol Lab Med:2007,131:1290-1297.
[58]Moll R, Lowe A, Laufer J, et al. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies[J]. Am J Pathol:1992,140:427-447.
[59]Knosel T, Emde V, Schluns K, et al. Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays[J]. Cell Oncol:2006,28:167-175.
[60]Ausch C, Buxhofer-Ausch V, Olszewski U, et al. Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients[J]. Eur J Surg Oncol:2009,35:1164-1168.
[61]Ulukaya E, Yilmaztepe A, Akgoz S, et al. The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival[J]. Lung Cancer:2007,56:399-404.
[62]Linder S, Olofsson MH, Herrmann R, et al. Utilization of cytokeratin-based biomarkers for pharmacodynamic studies[J]. Expert Rev Mol Diagn:2010,10:353-359.
[63]Uenishi T, Yamazaki O, Tanaka H, et al. Serum cytokeratin 19 fragment (CYFRA21-1) as a prognostic factor in intrahepatic cholangiocarcinoma[J]. Ann Surg Oncol:2008,15:583-589.
[64]Matros E, Bailey G, Clancy T, et al. Cytokeratin 20 expression identifies a subtype of pancreatic adenocarcinoma with decreased overall survival[J]. Cancer.2006,106:693-702.
[65]Katsuragi K, Yashiro M, Sawada T, et al. Prognostic impact of PCR-based identification of isolated tumour cells in the peritoneal lavage fluid of gastric cancer patients who underwent a curative R0 resection[J]. Br J Cancer:2007,97:550-556.
[66]Yang XR, Xu Y, Shi GM, et al. Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection[J]. Clin Cancer Res:2008,14:3850-3859.
[67]Stefansson IM, Salvesen HB, Akslen LA. Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients[J]. Int J Cancer:2006,118:1227-1233.
[68]Mertz KD, Demichelis F, Sboner A, et al. Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer[J]. Int J Cancer:2008,123:569-576.
[69]Bluemke K, Bilkenroth U, Meye A, et al. Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis[J]. Cancer Epidemiol Biomarkers Prev:2009,18:2190-2194.
[70]Weckermann D, Polzer B, Ragg T, et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer[J]. J Clin Oncol:2009,27:1549-1556.
[71]Chen N, Gong J, Chen X, et al. Cytokeratin expression in malignant melanoma:potential application of in-situ hybridization analysis of Mrna[J]. Melanoma Res:2009,19:87-93.
[72]Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype[J]. Clin Cancer Res:2008,14:1368-1376.
[73]Van de Rijn M, Perou CM, Tibshirani R, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome[J]. Am J Pathol:2002,161:1991-1996.
[74]Ignatiadis M, Xenidis N, Perraki M, et al. Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer[J]. J Clin Oncol:2007,25:5194-5202.
[75]Xenidis N, Ignatiadis M, Apostolaki S, et al. Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer[J]. J Clin Oncol:2009,27:2177-2184.
[76]Zajchowski DA, Bartholdi MF, Gong Y, et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells[J]. Cancer Res:2001,61:5168-5178.
[77]Woelfle U, Sauter G, Santjer S, et al. Down-regulated expression of cytokeratin 18 promotes progression of human breast cancer[J]. Clin Cancer Res:2004,10:2670-2674.
[78]Iwaya K, Ogawa H, Mukai Y, et al. Ubiquitin-immunoreactive degradation products of cytokeratin 8/18 correlate with aggressive breast cancer [J]. Cancer Sci:2003,94:864-870.
[79]Casanova ML, Bravo A, Ramirez A, et al. Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8[J]. J Clin Invest:1999,103:1587-1595.
[80]Casanova ML, Bravo A, Martinez-Palacio J, et al. Epidermal abnormalities and increased malignancy of skin tumors in human epidermal keratin 8-expressing transgenic mice[J]. FASEB J:2004,18:1556-1558.
[81]Chu YW, Runyan RB, Oshima RG, et al. Expression of complete keratin filaments in mouse L cells augments cell migration and invasion[J]. Proc Natl Acad Sci USA:1993,90:4261-4265.
[82]Chu YW, Seftor EA, Romer LH, et al. Experimental coexpression of vimentin and keratin intermediate filaments in human melanoma cells augments motility[J]. Am J Pathol:1996,148:63-69.
[83]Hendrix MJ, Seftor EA, Seftor RE, et al. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior[J]. Am J Pathol:1997,150:483-495.
[84]Beil M, Micoulet A, von Wichert G, et al. Sphingosylphosphorylcholine regulates keratin network architecture and visco-elastic properties of human cancer cells[J]. Nat Cell Biol:2003,5:803-811.
[85]Rolli CG, Seufferlein T, Kemkemer R, et al. Impact of tumor cell cytoskeleton organization on invasiveness and migration:a microchannel-based approach[J]. PLoS One:2010,5:e8726.
[86]Mizuuchi E, Semba S, Kodama Y, et al. Down-modulation of keratin 8 phosphorylation levels by PRL-3 contributes to colorectal carcinoma progression[J]. Int J Cancer:2009,124:1802-1810.
[87]Meng Y, Wu Z, Yin X, et al. Keratin 18 attenuates estrogen receptor alpha-mediated signaling by sequestering LRP16 in cytoplasm[J]. BMC Cell Biol:2009,10:96.
[88]Harada M, Strnad P, Toivola DM, et al. Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion[J]. Exp Cell Res:2008,314:1753-1764.
[89]Vijayaraj P, Kroger C, Reuter U, et al. Keratins regulate protein biosynthesis through localization of GLUT1 and-3 upstream of AMP kinase and Raptor[J]. J Cell Biol:2009,187:175-184.
[90]Fortier AM, Van Themsche C, Asselin E, et al. Akt isoforms regulate intermediate filament protein levels in epithelial carcinoma cells[J]. FEBS Lett:2010,584:984-988.
[91]Fields AP, Regala RP. Protein kinase C iota:human oncogene, prognostic marker and therapeutic target[J]. Pharmacol Res:2007,55:487-497.
[92]Mashukova A, Oriolo AS, Wald FA, et al. Rescue of atypical protein kinase C in epithelia by the cytoskeleton and Hsp70 family chaperones[J]. J Cell Sci:2009,122:2491-2503.
[93]Van den IP, Norman DG, Quinlan RA. Molecular chaperones:small heat shock proteins in the limelight[J]. Curr Biol:1999,9:R103-R105.
[94]Gilbert S, Loranger A, Daigle N, et al. Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation[J]. J Cell Biol:2001,154:763-773.
[95]Ku NO, Soetikno RM, Omary MB. Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury[J]. Hepatology:2003,37:1006-1014.
[96]Ashkenazi A. Directing cancer cells to self-destruct with proapoptotic receptor agonists[J]. Nat Rev Drug Discov:2008,7:1001-1012.
[97]Bauman PA, Dalton WS, Anderson JM, et al. Expression of cytokeratin confers multiple drug resistance[J]. Proc Natl Acad Sci USA:1994,91:5311-5314.
[98]Anderson JM, Heindl LM, Bauman PA, et al. Cytokeratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents [J]. Clin Cancer Res:1996,2:97-105.
[99]Liu F, Fan D, Qi J, et al. Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line[J]. Life Sci:2008,83:496-501.
[100]Liu F, Chen Z, Wang J, et al. Overexpression of cell surface cytokeratin 8 in multidrug-resistant MCF-7/MX cells enhances cell adhesion to the extracellular matrix[J]. Neoplasia:2008,10:1275-1284.
[2]Nobili S, Landini I, Giglioni B, et al. Pharmacological Strategies for Overcoming multidrug Resistance[J]. Current Drug Targets:2006,7:861-879.
[3]Garcia-Martin E, Pizarro RM, Martinez C, et al. Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8[J]. Pharrmacogenomics:2006,7:575-585.
[4]王鑫,王洁,张燕,等(综述).肿瘤细胞耐药机制的研究进展[J].癌症进展杂志：2007,5：73-78,47.
[5]Xing H, Wang S, Weng D, et al. Knock-down of P-glycoprotein reverses taxol resistance in ovarian cancer multicellular spheroids[J]. Oncol Rep:2007,17:117-122.
[6]Stone R.Surpris! A fungus factory for taxol?[J] Science:1993,260:154-155.
[7]Holmes FA,Walters RS,Theriault RL, et al. Phase Ⅱ trial of taxol, an active drug in the treatment of metastatic breast cancer[J]. Natl.Cancer Inst:1991,83:1797-1805.
[8]Pinedo HM, Longo DL, Chabner BA. Cancer chemotherapy and biological response modifiers annual 16 Amsterdam:Elsevier Science B.V.,1996, p.57-67.
[9]Yusuf RZ, Duan Z, Lamendola DE, et al. Paclitaxel resistance:molecular mechanisms and pharmacologic manipulation[J]. Curr Cancer Targets:2003,3:1-19.
[10]Pires MM, Emmert D, Hrycyna CA, et al. Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers[J]. Mol Pharmacol:2009,75:92-100.
[11]Quan F, Pan C, Ma Q, et al. Reversal effect of resveratrol on multidrug resistance in KBv200 cell line[J]. Biomed Pharmacother:2008,62:622-629.
[12]褚玉敏,谭国林,马艳红.人鼻咽癌紫杉醇耐药细胞株CNE-1/Taxol的建立及其机制初探[J].中国耳鼻咽喉颅底外科杂志：2007,13：411-14.
[13]彭小伟,贺广湘,李维,等.ATP结合盒转运体基因在鼻咽癌紫杉醇耐药细胞中的表达[J].中国耳鼻咽喉颅底外科杂志：2008,14：15-20.
[14]李维,谭国林,马艳红,等.叶酸受体1在鼻咽癌细胞抵抗紫杉醇化疗药物中的作用[J].中华耳鼻咽喉头颈外科杂志：2010,12：1035-1039.
[15]Kelemen LE. The role of folate receptor aincancer development, progression and treatment:cause,consequence or innocent by stander[J]? Int J Cancer:2006,119:243-250.
[16]Weitman SD, Weinberg AG, Coney LR, et al. Cellular localization of the folate receptor:potential role in drug toxicity and folate homeostasis[J]. Cancer Res: 1992,52:6708-6711.
[17]Odin E,Wettergren Y, Nilsson S, et al. Altered gene expression of folate enzymes in adjacent mucosa is associated with outcome of colorectal cancer patients[J]. Clin Cancer Res:2003,9(16 Pt 1):6012-6019.
[18]Toffoli G, Cernigoi C, Russo A, et al. Overexpression of folate binding protein in ovarian cancer[J]. Int J Cancer:1997,74:193-198.
[19]Iwakiri S, Sonobe M, Nagai S, et al. Expression status of folate receptor alpha is significantly correlated with prognosis in non-small-cell lung cancers[J]. Ann Surg Oncol:2008,15:889-899.
[20]Jhaveri MS, Rait AS, Chung KN, et al. Antisense oligonucleotides targeted to the human alpha folate receptor inhibit breast cancer cell growth and sensitize the cells to doxorubicin treatment[J]. Mol Cancer Ther:2004,3:1505-1512.
[21]Miotti S, Bagnoli M, Tomassetti A, et al. Interaction of folate receptor with signaling molecules lyn and G(a)(i-3) in detergent-resistant complexes from the ovary carcinoma cell line IGROV1[J]. J Cell Sci:2000,113:349-357.
[22]Rwei-Fen S. Huang, Yun-Hsiu Ho, Huei-Li Lin, et al. Folate Deficiency Induces a Cell Cycle-Specific Apoptosis in HepG2 Cells[J].The Journal of Nutrition:1999,129:25-31.
[23]刘里.鼻咽癌紫杉醇耐药细胞系的生物学特性及多药耐药性检测[D].长沙：中南大学,2010.
[24]唐刘君,王建,杨晓明.规模化蛋白质相互作用的研究技术[J].医学分子生物学杂志：2009,6：347-352.
[25]向波,王理,李桂源,等.鼻咽癌下调新基因NOR1相互作用蛋白的筛选和鉴定[J].生物化学与生物物理进展：2009,36.709-714.
[26]Cellai E, Chiavacci A, Olmi P, et al. Carcinoma of the nasopharynx:results of radiation therapy[J]. Acta Radiol Oncol:1982,21(2):87-95.
[27]闵华庆,洪明晃,郭翔,等.鼻咽癌研究进展[J].中国肿 瘤：1999，12：558-561.
[28]Cheng S H, Tsai S Y, Yen K L, et al. Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma[J]. J Clin Oncol:2000,18(10):2040-2045.
[29]Serin M, Erkal H S, Cakmak A. Radiation therapy and concurrent cisplatin in management of locoregionally advanced nasopharyngeal carcinomas[J]. Acta Oncol:1999,38(8):1031-1035.
[30]Li W,Tan G,Ma Y,et al.Inhibition of a Folate Receptor Resulting in a Reversal of Taxol Resistance in Nasopharyngeal Carcinoma. [J] Otolaryngology Head and Neck Surgery:2012,146:250-258.
[31]Brzezinska A, Winska P, Balinska M. Cellular aspects of folate and antifolate membrane transport[J]. Acta Biochim Pol:2000,47(3):735-749.
[32]Shen F, Wu M, Ross J F, et al. Folate receptor type gamma is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification:protein characterization and cell type specificity[J]. Biochemistry:1995,34(16):5660-5665.
[33]Eisenberg D, Marcotte EM, Xenarios I,et al. Protein function in the post-genomic era[J].Nature:2000,405(6788):823-826.
[34]. Auerbach D, Thaminy S, Hottiger MO,et al. The post-genomic era of interactive proteomics:facts and perspectives[J]. Proteomics:2002,2(6):611-623.
[35].Wang,J. Protein recognition by cell surface receptors:physiological receptors versus virus interactions[J]. Trends Biochem Sci:2002,27(3):122-126.
[36]Kone BC, Kuncewicz T, Zhang W, et al. Protein interactions with nitric oxide synthases:controlling the right time, the right place,and the right amount of nitric oxide[J]. Am J Physiol Renal Physiol:2003,285 (2):F178-190.
[37]Cohen FE, Prusiner SB. Pathologic conformations of prion proteins[J]. Annu Rev Biochem:1998,67:793-819.
[38].Loregian, A., H. S. Marsden, G Palu. Protein-protein interactions as targets for antiviral chemotherapy[J]. Rev Med Virol:2002,12(4):239-262.
[39].Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease[J]. Trends Cell Biol:1998,8(11):447-453.
[40]Fields S, Song O. A novel genetic system to detect protein-protein interactions[J]. Nature:1989,340(6230):245-246.
[41]Stahlhut M, van Deurs B. Identification of filamin as a novel ligand for caveolin-1:evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton[J]. Mol Biol Cell.:2000,11(1):325-337.
[42]Angermayr M, Hochleitner E, Lottspeich F,et al. Protein kinase CK2 activates the atypical Riolp kinase and promotes its cell-cycle phase-dependent degradation in yeast[J]. FEBS J.:2007,274(17):4654-4667.
[43]Leung KM, Feng DX, Lou J,et al. Development of human single-chain antibodies against SARS-associated coronavirus[J]. Intervirology: 2008,51(3):173-181.
[44]Zhu H, Snyder M. Protein chip technology[J]. Curr Opin Chem Biol.:2003,7(1):55-63.
[45]Zhou X, Kao M C, Wong W H. Transitive functional annotation by shortest-path analysis of gene expression data[J]. Proc Natl Acad Sci USA:2002, 99(20):12783-12788.
[46]Karaoz U, Murali T M, Letovsky S, et al. Whole-genome annota-tion by using evidence integration in functional-linkage networks[J]. Proc Natl Acad Sci USA:2004,101(9):2888-2893.
[47]Legrain P, Wojcik J, Gauthier JM. Protein--protein interaction maps:a lead towards cellular functions[J]. Trends Genet:2001,17(6):346-352.
[48]Von Mering,C.,et al.Comparative assessment of large-scale data sets of protein-protein interactions[J]. Nature:2002,417(6887):399-403.
[49]彭小伟,谭国林.基因芯片技术检测鼻咽癌紫杉醇耐药及耐药逆转相关基因的表达[J].中南大学学报：医学版,2012,37(1)：48-52.
[50]孙林潮,王刚,王岩,等.K17反义寡核苷酸对角质形成细胞增殖和K17表达的影响[J].中华皮肤科杂志：2006,11：642-644.
[51]Abbott A. A post-genomic challenge:learning to read patterns of protein synthesis[J]. Nature:1999,402(6763):715-720.
[52]孙宇,贾凌云,任军.蛋白质相互作用的研究方法[J].分析化学医学期刊(新)：2007,5：760-766.
[53]Tomita S, Ozaki T, Taru H,et al. Interaction of a Neuron-specific protein containing PDZ domains with Alzheimer's Amyloid precursor protein[J]. J. Biol. Chem:1999,274(4):2243-2254.
[54]Kong M, Barnes EA, Ollendorff V, et al. Cyclin F regulates the nuclear localization of cyclin B1 through a cyclin-cyclin interaction[J]. The EMBO J:2000,19(6):1378-1388.
[55]Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27kip1 is instigated by Jab1[J].Nature:1999,398:160-164.
[56]Aronheim A, Zandi E, Hennemann H, et al. Isolation of an AP-1 repressor by a novel method for detecting protein-protein interactions[J]. Mol. Cell. Biol:1997,17(6):3094-3102.
[57]Dressel U, Thormeyer D, Renkawitz R, et al. Alien, a highly conserved protein with characteristics of a corepressor for membranes of the nuclear hormone receptor superfamily[J]. Mol. Cell. Biol:1999,19(5):3383-3394.
[58]Bosnar M H, Gunzburg de J, Bago R, et al. Subcellular localization of A and B Nm23/NDPK subunits [J]. Exp Cell Res:2004,298:275-284.
[59]Fuchs E, Cleveland DW. A structural scaffolding of intermediate filaments in health and disease[J]. Science:1998,279:514-519.
[60]Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins[J]. J Cell Biol:2006,174:169-174.
[61]Coulombe PA, Omary MB.'Hard' and' soft' principles defining the structure, function and regulation of keratin intermediate filaments[J]. Curr Opin Cell Biol:2002,14:110-122.
[62]Gu LH, Coulombe PA. Keratin function in skin epithelia:A broadening palette with surprising shades[J]. Curr Opin Cell Biol:2007,19(1):13-23.
[63]Oriolo AS, Wald FA, Ramsauer VP, Salas PJ. Intermediate filaments:a role in epithelial polarity[J]. Exp Cell Res:2007,313:2255-2264.
[64]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[65]Vijayaraj P, Kroger C, Reuter U,et al. Keratins regulate protein biosynthesis through localization of GLUT1 and-3 upstream of AMP kinase and Raptor[J]. J Cell Biol:2009,187:175-184.
[66]Styers ML, Kowalczyk AP, Faundez V. Intermediate filaments and vesicular membrane traffic:the odd couple's first dance[J]? Traffic:2005,6:359-365.
[67]Toivola DM, Tao GZ, Habtezion A, et al. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments[j]. Trends Cell Biol:2005,15:608-617.
[68]Chu YW, Seftor EA, Romer LH, et al Experimental coexpression of vimentin and keratin intermediate filaments in human melanoma cells augments motility[J]. Am. J. Pathol:1996,148(1):63-69.
[69]Moll R, Divo M, Langbein L. The human keratins:Biology and pathology[J]. Histochem Cell Biol:2008,129(6):705-733.
[70]Hsu TM, Kwok PY. Advances in molecular medicine[J]. J Am Acad Dermatol:2001,44(5):847-855.
[71]McGowan KM, Coulombe PA. Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development[J]. J Cell Biol:1998,143:469-486.
[72]Achtsttter T, Moll R, Moore B, et al. Cytokeratin polypeptide patterns of different epithelia of the human male urogenital tract:Immunofluorescence and gel electrophoretic studies[J]. J Histochem Cytochem:1985,33:415-426.
[73]Komine M, Freedberg IM, Blumberg PM. Regulation of epidermal expression of keratin 17 in inflammatory skin diseases[J]. J Invest Dermatol:1996,107:569-575.
[74]Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the keratinocyte activation cycle[J]. J Invest Dermatol:2001,116:633-640.
[75]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[76]Cohen-Kerem R, Madah W, Sabo E, et al. Cytokeratin-17 as a potential marker for squamous cell carcinoma of the larynx[J]. Ann Otol Rhinol Laryngol:2004,113(10):821-827.
[77]Van de Rijn M, Perou CM, Tibshirani R, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome[J]. Am J Pathol:2002,161(6):1991-1996.
[78]Carrilho C, Alberto M, Buane L, et al. Keratins 8,10,13, and 17 are useful markers in the diagnosis of human cervix carcinomas [J]. Hum Pathol:2004,35(5):546-551.
[79]Wetzels RH, Schaafsma HE, Leigh IM, et al. Laminin and type Ⅶ collagen distribution in different types of human lung carcinoma:Correlation with expression of keratins 14,16,17 and 18[J]. Histopathology:1992,20(4):295-303.
[80]Smedts F, Ramaekers F C, Hopman A H. CK17 and p16 expression patterns distinguish(atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia [J].Histopathology:2008,52(4):515-516.
[81]李晓梅,赵玉兰,王洪梅.ck17和ck18在肺低分化鳞癌及腺癌鉴别诊断中的应用[J].伤残医学杂志：2003,11(3)：73-75.
[82]Steinert PM, Parry DA, Racoosin EL, et al. The complete cDNA and deduced amino acid sequence of a type II mouse epidermal keratin of 60 000 Da: analysis of sequence differences between type I and type II keratins[J]. Proc Natl Acad Sci USA:1984,81:5709-5713.
[83]Tong X, Coulombe PA. Keratin 17 modulates hair follicle cycling in a TNFalpha-dependent fashion[J]. Genes Dev.:2006,20(10):1353-1364.
[84]Lei DS, Yu J, Tong XL, et al. Diagnostic value of cytokeratin 19 fragment in nasopharyngeal carcinoma[J]. Zhonghua Bing Li Xue Za Zhi.:2012,41(7):461-465.
[85]Li XM, Huang WG, Yi H,et al. Proteomic analysis to identify cytokeratin 18 as a novel biomarker of nasopharyngeal carcinoma[J]. J Cancer Res Clin Oncol.:2009,135(12):1763-1775.
[86]Huang WG, Cheng AL, Chen ZC,et al. Targeted proteomic analysis of 14-3-3sigma in nasopharyngeal carcinoma[J]. Int J Biochem Cell Biol.:2010,42(1):137-147.
[87]Tang S, Huang W, Zhong M, et al. Identification Keratin 1 as a cDDP-resistant protein in nasopharyngeal carcinoma cell lines[J]. J Proteomics.:2012,75(8):2352-2360.
[1]Pollard TD, Cooper JA. Actin, a central player in cell shape and movement[J]. Science:2009,326:1208-1212.
[2]Herrmann H, Strelkov SV, Burkhard P, et al. Intermediate filaments: primary determinants of cell architecture and plasticity[J]. J Clin Invest:2009,119:1772-1783.
[3]Glotzer M. The 3Ms of central spindle assembly:microtubules, motors and MAPs[J]. Nat Rev Mol Cell Biol:2009,10:9-20.
[4]Herrmann H, Bar H, Kreplak L, et al. Intermediate filaments:from cell architecture to nanomechanics[J]. Nat Rev Mol Cell Biol:2007,8:562-573.
[5]Steinert PM, Marekov LN, Parry DA. Conservation of the structure of keratin intermediate filaments:molecular mechanism by which different keratin molecules integrate into preexisting keratin intermediate filaments during differentiation[J]. Biochemistry:1993,32:10046-10056.
[6]Moll R, Franke WW, Schiller DL, et al. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells[J]. Cell:1982,31:11-24.
[7]Quinlan RA, Cohlberg JA, Schiller DL, et al. Heterotypic tetramer (A2D2) complexes of non-epidermal keratins isolated from cytoskeletons of rat hepatocytes and hepatoma cells[J]. J Mol Biol:1984,178:365-388.
[8]Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins[J]. J Cell Biol:2006,174:169-174.
[9]Bragulla HH, Homberger DG. Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia[J]. J Anat:2009,214:516-559.
[10]Moll R, Divo M, Langbein L. The human keratins:biology and pathology[J]. Histochem Cell Biol:2008,129:705-733.
[11]Coulombe PA, Omary MB.'Hard' and 'soft' principles defining the structure, function and regulation of keratin intermediate filaments[J]. Curr Opin Cell Biol:2002,14:110-122.
[12]Omary MB, Ku NO, Strnad P, et al. Toward unraveling the complexity of simple epithelial keratins in human disease[J]. J Clin Invest:2009,119:1794-1805.
[13]Vijayaraj P, Sohl G, Magin TM. Keratin transgenic and knockout mice: functional analysis and validation of disease-causing mutations[J]. Methods Mol Biol:2007,360:203-251.
[14]Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering[J]. Nature:1992,356:244-246.
[15]Coulombe PA, Hutton ME, Letai A, et al. Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients:genetic and functional analyses[J]. Cell:1991,66:1301-1311.
[16]Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy [J]. Nat Genet:1997,16:184-187.
[17]Ku NO, Gish R, Wright TL, et al. Keratin 8 mutations in patients with cryptogenic liver disease[J]. N Engl J Med:2001,344:1580-1587.
[18]Ku NO, Wright TL, Terrault NA, et al. Mutation of human keratin 18 in association with cryptogenic cirrhosis[J]. J Clin Invest:1997,99:19-23.
[19]Omary MB, Ku NO, Tao GZ, et al.'Heads and tails' of intermediate filament phosphorylation:multiple sites and functional insights[J]. Trends Biochem Sci:2006,31:383-394.
[20]Strnad P, Zhou Q, Hanada S, et al. Keratin variants predispose to acute liver failure and adverse outcome:race and ethnic associations[J]. Gastroenterology:2010,139:828-835.835 el-e3.
[21]Peters B, Kirfel J, Bussow H, et al. Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex[J]. Mol Biol Cell:2001,12:1775-1789.
[22]Lloyd C, Yu QC, Cheng J, et al. The basal keratin network of stratified squamous epithelia:defining K15 function in the absence of K14[J]. J Cell Biol:1995,129:1329-1344.
[23]Kao WW, Liu CY, Converse RL, et al. Keratin 12-deficient mice have fragile corneal epithelia[J]. Invest Ophthalmol Vis Sci:1996,37:2572-2584.
[24]Baribault H, Price J, Miyai K,et al. Mid-gestational lethality in mice lacking keratin 8[J]. Genes Dev:1993,7:1191-1202.
[25]Baribault H, Penner J, Iozzo RV, et al. Colorectal hyperplasia and inflammation in keratin 8-deficient FVB/N mice[J]. Genes Dev:1994,8:2964-2973.
[26]Magin TM, Schroder R, Leitgeb S, et al. Lessons from keratin 18 knockout mice:formation of novel keratin filaments, secondary loss of keratin 7 and accumulation of liver-specific keratin 8-positive aggregates[J]. J Cell Biol:1998,140:1441-1451.
[27]Ku NO, Michie S, Oshima RG, et al. Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant[J]. J Cell Biol:1995,131:1303-1314.
[28]Zatloukal K, Stumptner C, Lehner M, et al. Cytokeratin 8 protects from hepatotoxicity, and its ratio to cytokeratin 18 determines the ability of hepatocytes to form Mallory bodies[J]. Am J Pathol:2000,156:1263-1274.
[29]Ku NO, Omary MB. A disease-and phosphorylation-related nonmechanical function for keratin 8[J]. J Cell Biol:2006,174:115-125.
[30]Oriolo AS, Wald FA, Ramsauer VP, et al. Intermediate filaments:a role in epithelial polarity[J]. Exp Cell Res:2007,313:2255-2264.
[31]Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth[J]. Nature:2006,441:362-365.
[32]Toivola DM, Tao GZ, Habtezion A, et al. Cellular integrity plus: organelle-related and protein-targeting functions of intermediate filaments[J]. Trends Cell Biol:2005,15:608-617.
[33]Yano S, Komine M, Fujimoto M, et al. Mechanical stretching in vitro regulates signal transduction pathways and cellular proliferation in human epidermal keratinocytes[J]. J Invest Dermatol:2004,122:783-790.
[34]Zatloukal K, French SW, Stumptner C, et al. From Mallory to Mallory-Denk bodies:what, how and why[J]? Exp Cell Res:2007,313:2033-2049.
[35]Fickert P, Trauner M, Fuchsbichler A, et al. Mallory body formation in primary biliary cirrhosis is associated with increased amounts and abnormal phosphorylation and ubiquitination of cytokeratins[J]. J Hepatol:2003,38:387-394.
[36]Sivaramakrishnan S, DeGiulio JV, Lorand L, et al. Micromechanical properties of keratin intermediate filament networks[J]. Proc Natl Acad Sci USA:2008,105:889-894.
[37]Na N, Chandel NS, Litvan J, et al. Mitochondrial reactive oxygen species are required for hypoxia-induced degradation of keratin intermediate filaments[J]. FASEB J:2010,24:799-809.
[38]Nelson DA, Tan TT, Rabson AB, et al. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis[J]. Genes Dev:2004,18:2095-2107.
[39]Sivaramakrishnan S, Schneider JL, Sitikov A, et al. Shear stress induced reorganization of the keratin intermediate filament network requires phosphorylation by protein kinase C zeta[J]. Mol Biol Cell:2009,20:2755-2765.
[40]Liao J, Ku NO, Omary MB. Stress, apoptosis, and mitosis induce phosphorylation of human keratin 8 at Ser-73 in tissues and cultured cells[J]. J Biol Chem:1997,272:17565-17573.
[41]Toivola DM, Zhou Q, English LS, et al. Type Ⅱ keratins are phosphorylated on a unique motif during stress and mitosis in tissues and cultured cells[J]. Mol Biol Cell:2002,13:1857-1870.
[42]Kongara S, Kravchuk O, Teplova I, et al. Autophagy regulates keratin 8 homeostasis in mammary epithelial cells and in breast tumors[J]. Mol Cancer Res:2010,8:873-884.
[43]Ku NO, Azhar S, Omary MB. Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization:modulation by a keratin 1-like disease causing mutation[J]. J Biol Chem:2002,277:10775-10782.
[44]He T, Stepulak A, Holmstrom TH, et al. The intermediate filament protein keratin 8 is a novel cytoplasmic substrate for c-Jun N-terminal kinase[J]. J Biol Chem:2002,277:10767-10774.
[45]Ridge KM, Linz L, Flitney FW, et al. Keratin 8 phosphorylation by protein kinase C delta regulates shear stress-mediated disassembly of keratin intermediate filaments in alveolar epithelial cells[J]. J Biol Chem:2005,280:30400-30405.
[46]Omary MB, Ku NO, Liao J, et al. Keratin modifications and solubility properties in epithelial cells and in vitro[J]. Subcell Biochem:1998,31:105-140.
[47]Ku NO, Omary MB. Keratins turn over by ubiquitination in a phosphorylation-modulated fashion[J]. J Cell Biol:2000,149:547-552.
[48]Ku NO, Michie S, Resurreccion EZ, et al. Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression[J]. Proc Natl Acad Sci USA:2002,99:4373-4378.
[49]Hernandez BY, Frierson HF, Moskaluk CA, et al. CK20 and CK7 protein expression in colorectal cancer:demonstration of the utility of a population-based tissue microarray[J]. Hum Pathol:2005,36:275-281.
[50]Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms:a survey of 435 cases[J]. Mod Pathol:2000,13:962-972.
[51]Chu PG, Weiss LM. Expression of cytokeratin 5/6 in epithelial neoplasms: an immunohistochemical study of 509 cases[J]. Mod Pathol:2002,15:6-10.
[52]Nikitakis NG, Tosios KI, Papanikolaou VS, et al. Immunohistochemical expression of cytokeratins 7 and 20 in malignant salivary gland tumors[J], Mod Pathol:2004,17:407-415.
[53]Yaziji H, Battifora H, Barry TS, et al. Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma:identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity[J]. Mod Pathol:2006,19:514-523.
[54]Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms[J]. Histopathology:2002,40:403-439.
[55]Lehr HA, Folpe A, Yaziji H, et al. Cytokeratin 8 immunostaining pattern and E-cadherin expression distinguish lobular from ductal breast carcinoma[J]. Am J Clin Pathol:2000,114:190-196.
[56]Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications[J]. Proc Natl Acad Sci USA:2001,98:10869-10874.
[57]Liu L, Qian J, Singh H, et al. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma:an optimal and practical panel for differential diagnosis[J]. Arch Pathol Lab Med:2007,131:1290-1297.
[58]Moll R, Lowe A, Laufer J, et al. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies[J]. Am J Pathol:1992,140:427-447.
[59]Knosel T, Emde V, Schluns K, et al. Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays[J]. Cell Oncol:2006,28:167-175.
[60]Ausch C, Buxhofer-Ausch V, Olszewski U, et al. Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients[J]. Eur J Surg Oncol:2009,35:1164-1168.
[61]Ulukaya E, Yilmaztepe A, Akgoz S, et al. The levels of caspase-cleaved cytokeratin 18 are elevated in serum from patients with lung cancer and helpful to predict the survival[J]. Lung Cancer:2007,56:399-404.
[62]Linder S, Olofsson MH, Herrmann R, et al. Utilization of cytokeratin-based biomarkers for pharmacodynamic studies[J]. Expert Rev Mol Diagn:2010,10:353-359.
[63]Uenishi T, Yamazaki O, Tanaka H, et al. Serum cytokeratin 19 fragment (CYFRA21-1) as a prognostic factor in intrahepatic cholangiocarcinoma[J]. Ann Surg Oncol:2008,15:583-589.
[64]Matros E, Bailey G, Clancy T, et al. Cytokeratin 20 expression identifies a subtype of pancreatic adenocarcinoma with decreased overall survival[J]. Cancer.2006,106:693-702.
[65]Katsuragi K, Yashiro M, Sawada T, et al. Prognostic impact of PCR-based identification of isolated tumour cells in the peritoneal lavage fluid of gastric cancer patients who underwent a curative R0 resection[J]. Br J Cancer:2007,97:550-556.
[66]Yang XR, Xu Y, Shi GM, et al. Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection[J]. Clin Cancer Res:2008,14:3850-3859.
[67]Stefansson IM, Salvesen HB, Akslen LA. Loss of p63 and cytokeratin 5/6 expression is associated with more aggressive tumors in endometrial carcinoma patients[J]. Int J Cancer:2006,118:1227-1233.
[68]Mertz KD, Demichelis F, Sboner A, et al. Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer[J]. Int J Cancer:2008,123:569-576.
[69]Bluemke K, Bilkenroth U, Meye A, et al. Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis[J]. Cancer Epidemiol Biomarkers Prev:2009,18:2190-2194.
[70]Weckermann D, Polzer B, Ragg T, et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer[J]. J Clin Oncol:2009,27:1549-1556.
[71]Chen N, Gong J, Chen X, et al. Cytokeratin expression in malignant melanoma:potential application of in-situ hybridization analysis of Mrna[J]. Melanoma Res:2009,19:87-93.
[72]Cheang MC, Voduc D, Bajdik C, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype[J]. Clin Cancer Res:2008,14:1368-1376.
[73]Van de Rijn M, Perou CM, Tibshirani R, et al. Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome[J]. Am J Pathol:2002,161:1991-1996.
[74]Ignatiadis M, Xenidis N, Perraki M, et al. Different prognostic value of cytokeratin-19 mRNA positive circulating tumor cells according to estrogen receptor and HER2 status in early-stage breast cancer[J]. J Clin Oncol:2007,25:5194-5202.
[75]Xenidis N, Ignatiadis M, Apostolaki S, et al. Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer[J]. J Clin Oncol:2009,27:2177-2184.
[76]Zajchowski DA, Bartholdi MF, Gong Y, et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells[J]. Cancer Res:2001,61:5168-5178.
[77]Woelfle U, Sauter G, Santjer S, et al. Down-regulated expression of cytokeratin 18 promotes progression of human breast cancer[J]. Clin Cancer Res:2004,10:2670-2674.
[78]Iwaya K, Ogawa H, Mukai Y, et al. Ubiquitin-immunoreactive degradation products of cytokeratin 8/18 correlate with aggressive breast cancer [J]. Cancer Sci:2003,94:864-870.
[79]Casanova ML, Bravo A, Ramirez A, et al. Exocrine pancreatic disorders in transsgenic mice expressing human keratin 8[J]. J Clin Invest:1999,103:1587-1595.
[80]Casanova ML, Bravo A, Martinez-Palacio J, et al. Epidermal abnormalities and increased malignancy of skin tumors in human epidermal keratin 8-expressing transgenic mice[J]. FASEB J:2004,18:1556-1558.
[81]Chu YW, Runyan RB, Oshima RG, et al. Expression of complete keratin filaments in mouse L cells augments cell migration and invasion[J]. Proc Natl Acad Sci USA:1993,90:4261-4265.
[82]Chu YW, Seftor EA, Romer LH, et al. Experimental coexpression of vimentin and keratin intermediate filaments in human melanoma cells augments motility[J]. Am J Pathol:1996,148:63-69.
[83]Hendrix MJ, Seftor EA, Seftor RE, et al. Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior[J]. Am J Pathol:1997,150:483-495.
[84]Beil M, Micoulet A, von Wichert G, et al. Sphingosylphosphorylcholine regulates keratin network architecture and visco-elastic properties of human cancer cells[J]. Nat Cell Biol:2003,5:803-811.
[85]Rolli CG, Seufferlein T, Kemkemer R, et al. Impact of tumor cell cytoskeleton organization on invasiveness and migration:a microchannel-based approach[J]. PLoS One:2010,5:e8726.
[86]Mizuuchi E, Semba S, Kodama Y, et al. Down-modulation of keratin 8 phosphorylation levels by PRL-3 contributes to colorectal carcinoma progression[J]. Int J Cancer:2009,124:1802-1810.
[87]Meng Y, Wu Z, Yin X, et al. Keratin 18 attenuates estrogen receptor alpha-mediated signaling by sequestering LRP16 in cytoplasm[J]. BMC Cell Biol:2009,10:96.
[88]Harada M, Strnad P, Toivola DM, et al. Autophagy modulates keratin-containing inclusion formation and apoptosis in cell culture in a context-dependent fashion[J]. Exp Cell Res:2008,314:1753-1764.
[89]Vijayaraj P, Kroger C, Reuter U, et al. Keratins regulate protein biosynthesis through localization of GLUT1 and-3 upstream of AMP kinase and Raptor[J]. J Cell Biol:2009,187:175-184.
[90]Fortier AM, Van Themsche C, Asselin E, et al. Akt isoforms regulate intermediate filament protein levels in epithelial carcinoma cells[J]. FEBS Lett:2010,584:984-988.
[91]Fields AP, Regala RP. Protein kinase C iota:human oncogene, prognostic marker and therapeutic target[J]. Pharmacol Res:2007,55:487-497.
[92]Mashukova A, Oriolo AS, Wald FA, et al. Rescue of atypical protein kinase C in epithelia by the cytoskeleton and Hsp70 family chaperones[J]. J Cell Sci:2009,122:2491-2503.
[93]Van den IP, Norman DG, Quinlan RA. Molecular chaperones:small heat shock proteins in the limelight[J]. Curr Biol:1999,9:R103-R105.
[94]Gilbert S, Loranger A, Daigle N, et al. Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation[J]. J Cell Biol:2001,154:763-773.
[95]Ku NO, Soetikno RM, Omary MB. Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury[J]. Hepatology:2003,37:1006-1014.
[96]Ashkenazi A. Directing cancer cells to self-destruct with proapoptotic receptor agonists[J]. Nat Rev Drug Discov:2008,7:1001-1012.
[97]Bauman PA, Dalton WS, Anderson JM, et al. Expression of cytokeratin confers multiple drug resistance[J]. Proc Natl Acad Sci USA:1994,91:5311-5314.
[98]Anderson JM, Heindl LM, Bauman PA, et al. Cytokeratin expression results in a drug-resistant phenotype to six different chemotherapeutic agents [J]. Clin Cancer Res:1996,2:97-105.
[99]Liu F, Fan D, Qi J, et al. Co-expression of cytokeratin 8 and breast cancer resistant protein indicates a multifactorial drug-resistant phenotype in human breast cancer cell line[J]. Life Sci:2008,83:496-501.
[100]Liu F, Chen Z, Wang J, et al. Overexpression of cell surface cytokeratin 8 in multidrug-resistant MCF-7/MX cells enhances cell adhesion to the extracellular matrix[J]. Neoplasia:2008,10:1275-1284.