粘液表皮样癌耐药机制的研究
|
摘要
粘液表皮样癌，是人类涎腺恶性肿瘤当中一个很常见的类型。根据以往的报道，此恶性肿瘤占所有涎腺恶性肿瘤的百分之三十以上，占颌面部所有肿瘤的5%到10%。而临床上对于此种肿瘤的治疗方法还是以外科手术为主。化疗对于此种肿瘤的效果并不是非常理想，主要障碍主要在于用药之后产生的多药耐药（Multidrugresistance，MDR）。解决了多药耐药的问题，可以为治疗这种恶性肿瘤提供一个新的有效的治疗途径。
MDR是指由于使用一种药物而对多种药物产生耐药性，降低了临床抗肿瘤药物的有效性。目前研究最广泛的耐药机制是细胞将药物泵出的膜转运蛋白。p-糖蛋白（p-glycoprotein，P-gp）、多药耐药相关蛋白（Multidrug resistance-associated protein，MRP）是与耐药相关的两个主要蛋白。
细胞的生物学功能大部分是通过信号通路实现，根据对于信号通路的研究，可以反过来揭示细胞的生物学特性。通过阻断这些和疾病相关的信号通路，可以达到研究和治疗的目的。
我们在前期研究中建立了MC3/5-FU的耐药细胞系，可以和MC3细胞系进行对照。设计多条shRNA片段构建表达载体DNA,对体外培养的人粘液表皮样癌耐药细胞MC3/5-FU进行稳定转染，检测转染效率、检测细胞MDRl基因的mRNA的表达，筛选出更加有效的shRNA片段进行后续研究。检测RNA干扰后细胞耐药逆转率。检测MC3/5-FU和MC3之间信号通路活性差异，寻找耐药相关通路。抑制各通路活性后检测耐药逆转率以及生物学特性。通过抑制各通路活性后检测MDR1表达，并且RNAi沉默MDR1后检测各通路活性，从而推导各耐药相关通路与MDR1之间关系。检测RNAi与抑制各通路表达的抑制剂共同干预MC3/5-FU后耐药逆转率。RNAi沉默MRP1后检测MDR1以及信号通路表达，推测MRP1参与粘液表皮样癌耐药机制。
主要研究内容及结果
第一部分RNAi逆转MC3/5-FU耐药性
用MTT法检测MC3/5-FU耐药倍数，对于诱导药物5-FU耐药倍数为16.7达到高度耐药。针对MDR1基因根据siRNA设计原则设计3条shRNA并分别用脂质体转染MC3/5-FU细胞，real time-PCR检测，片段1沉默效果最佳，并筛选出片段1的稳定转染细胞株，RT-PCR检测细胞细胞MDR1基因表达，测定转染后细胞株耐药倍数及耐药逆转率。转染后细胞株MDR1基因表达量下降，MC3/5-FU细胞对5-FU、BLM、VCR和VBL耐药逆转率分别为达到70.6%、40.8%、48.6%和58.8%。
第二部分抑制信号通路逆转MC3/5-FU耐药性
通过western blot方法找出MC3/5-FU细胞和MC3细胞之间差异的耐药相关细胞信号蛋白，MC3/5-FU细胞中NF-κB、Nrf2-ARE、MAPK/ERK活性明显高于MC3细胞。用抑制剂抑制NF-κB、Nrf2-ARE和MAPK/ERK后MC3/5-FU细胞对5-FU的耐药逆转率分别为67.7%、43.4%和54.3%。。用MTT法测定抑制后MC3/5-FU生长曲线，软琼脂克隆实验计算各种干预后细胞克隆数，可见各种干预后Nrf2-ARE组生长最快，NF-κB和MAPK/ERK组最慢。
第三部分耐药相关信号通路在粘液表皮样癌中与MDR1基因之间的关系
用RT-PCR和western blot.检测耐药相关信号通路在粘液表皮样癌中与MDR1基因之间的关系。 NF-κB、Nrf2-ARE和MAPK/ERK通路活性被抑制后MC3/5-FU细胞MDR1mRNA表达降低，NF-κB通路效果最明显。RNAi沉默MC3/5-FU中MDR1的表达后可见各通路活性未发生明显变化。抑制剂与RNAi共同作用后检测耐药逆转率与RNAi组无明显差异。
第四部分MRP1基因引起耐药的机制
用免疫组化实验检测MEC临床手术标本发现MRP1基因在MEC中表达，且与MDR1基因的表达关系密切。用RNAi沉默MRP1基因后RT-PCR检测发现MDR1基因表达被抑制。沉默MRP1基因后western blot方法检测Nrf2-ARE通路的活性被明显抑制。
结论：
1MDR1基因的表达是粘液表皮样癌细胞产生多药耐药的一个重要因素。
2用RNAi的方法沉默MDR1基因可以有效逆转粘液表皮样癌细胞的耐药性。
3NF-κB、Nrf2-ARE、MAPK/ERK参与粘液表皮样癌细胞的耐药过程，通过抑制这些通路可以逆转粘液表皮样癌细胞的耐药性。
4NF-κB通路在粘液表皮样癌细胞中与MDR1基因的表达关系密切。
5推测在粘液表皮样癌细胞中，MRP1可以激活Nrf2-ARE从而促进MDR1基因表达，导致细胞耐药。而不是传统认为的膜蛋白药泵作用。
Mucoepidermoid carcinoma(MEC) is a common malignacy in salivary glands，itaccounts for about30%of malignant tumors in salivary glands and for5%to10%ofmalignant tumors in maxillofacial region in Chinese population. Anyhow,the main way ofits therapy is still surgery because chemotherapy is not very efficient to the tumor. The mainobstacle is the Multidrug resistance (MDR) effect after medication. Solving the problemof MDR may provide a new efficient way to treat MEC.
MDR reduces the effectiveness of chemotherapy. MDR is characterized by crossresistance to antineoplastic drugs, and the members of the ATP-binding cassette (ABC)transporter superfamily, such as ABCB1(MDR1) and ABCC1(MRP1), which play themost importent role in MDR.
Most biological functions of cells work by signal pathway. The bionomics of cellscan be revealed by studying the signal pathway. Interrupting these signal pathways relatedto illness may creat a new way to study and therapy.
In previous study we established multi drug resistant cell line MC3/5-FU from theparental cell line MC3. Therefor, in this study, we designed several pieces of shRNA,constructed MDR1-shRNA expression vector and silenced MDR1in MC3/5-FU cells withstable transfection. Then we detected the reverse rate of MDR by RNAi. Furthermore, wedetected the NF-κB,Nrf2-ARE and MAPK/ERK signal pathways between MC3/5-FU andMC3to find the MDR related ones. We used RNAi and signal pathway depressor todeduce the relationship between MDR1,MRP1, signal pathways and multidrug resistancein mucoepidermoid carcinoma.
The study includs four parts as follows.
1Reversion of MDR in MC3/5-FU by RNAi.
The plasmid expressing shRNA homologous to MDR1mRNA was constructed withshRNA expressing vector pRNAT-U-6.1/Neo based on the principle of siRNA design.Thecombinant plasmid was transfected stably into MC3/5-FU Cells using Lipofectamine2000.The shRNA efficiency was detected by real time-PCR analysis. The result showedMDR1-shRNA could effectively block the expression of MDR1in MC3/5-FU cells.RT-PCR analysis showed the expression of MDR1was silenced after stable transfection.The resistance index of MC3/5-FU was detected by MTT assay. The result showed thatthe multidrug resistance rates of MC3/5-FU cells to5-FU, BLM, VCR and VBL werereversed by70.6%,40.8%,48.6%and58.8%respectively.
2Reversion of MDR in MC3/5-FU by inhibiting signal pathway.
The expression of signal pathways between MC3/5-FU and MC3cells were detectedby western blot analysis. The results show that the activity of NF-κB,Nrf2-ARE andMAPK/ERK in MC3/5-FU was much higher than in MC3. The reversal of MDR wasdetected after the signal pathways was inhibited by the inhibitors. Inhibition of NF-κB，Nrf2-ARE and MAPK/ERK reversed MDR of MC3/5-FU cells to5-FU by67.7%,43.4%and54.3%respectively. MTT assay and soft agar cloning experiments showed thatinhibition of NF-κB resulted in proliferation inhibition of MC3/5-FU cells.
3The relationship between signal pathway and MDR1gene inmucoepidermoid carcinoma.
The relationship between signal pathway and MDR1gene in MC3/5-FU cell wereinvestigated by RT-PCR and western blot. Inhibition of NF-κB， Nrf2-ARE andMAPK/ERK inhibited MDR1mRNA expression in MC3/5-FU cells, inhibition of NF-κBshowed the strongest effects.While silence of MDR1gene by RNAi did not change theexpression of NF-κB，Nrf2-ARE and MAPK/ERK activity in MC3/5-FU cells.
4The function of MRP1in MDR
MRP1protein was found in surgical samples of MEC by immunohistochemistryexperiment. RT-PCR analysis showed the expression of MDR1in MC3/5-FU cells wasinhibited after MRP1was silenced by RNAi. The activity of each signal pathway wasdetected by western blot after MRP1was silenced by RNAi. The resuit showed onlyNrf2-ARE was inhibited.
Conclusion
1MDR1is an important factor of multi-drug resistance in mucoepidermoid carcinoma.
2Silenc of MDR1by RNAi is effective in the reversal of MDR in mucoepidermoidcarcinoma.
3NF-κB,Nrf2-ARE and MAPK/ERK signal pathways take part in the MDR inmucoepidermoid carcinoma.
4NF-κB pathway has close relationship with the expression of MDR1in mucoepidermoidcarcinoma
5MRP1may enhance the expression of MDR1by activating Nrf2-ARE rather than bymembrane protein as drug pump.
MDR是指由于使用一种药物而对多种药物产生耐药性，降低了临床抗肿瘤药物的有效性。目前研究最广泛的耐药机制是细胞将药物泵出的膜转运蛋白。p-糖蛋白（p-glycoprotein，P-gp）、多药耐药相关蛋白（Multidrug resistance-associated protein，MRP）是与耐药相关的两个主要蛋白。
细胞的生物学功能大部分是通过信号通路实现，根据对于信号通路的研究，可以反过来揭示细胞的生物学特性。通过阻断这些和疾病相关的信号通路，可以达到研究和治疗的目的。
我们在前期研究中建立了MC3/5-FU的耐药细胞系，可以和MC3细胞系进行对照。设计多条shRNA片段构建表达载体DNA,对体外培养的人粘液表皮样癌耐药细胞MC3/5-FU进行稳定转染，检测转染效率、检测细胞MDRl基因的mRNA的表达，筛选出更加有效的shRNA片段进行后续研究。检测RNA干扰后细胞耐药逆转率。检测MC3/5-FU和MC3之间信号通路活性差异，寻找耐药相关通路。抑制各通路活性后检测耐药逆转率以及生物学特性。通过抑制各通路活性后检测MDR1表达，并且RNAi沉默MDR1后检测各通路活性，从而推导各耐药相关通路与MDR1之间关系。检测RNAi与抑制各通路表达的抑制剂共同干预MC3/5-FU后耐药逆转率。RNAi沉默MRP1后检测MDR1以及信号通路表达，推测MRP1参与粘液表皮样癌耐药机制。
主要研究内容及结果
第一部分RNAi逆转MC3/5-FU耐药性
用MTT法检测MC3/5-FU耐药倍数，对于诱导药物5-FU耐药倍数为16.7达到高度耐药。针对MDR1基因根据siRNA设计原则设计3条shRNA并分别用脂质体转染MC3/5-FU细胞，real time-PCR检测，片段1沉默效果最佳，并筛选出片段1的稳定转染细胞株，RT-PCR检测细胞细胞MDR1基因表达，测定转染后细胞株耐药倍数及耐药逆转率。转染后细胞株MDR1基因表达量下降，MC3/5-FU细胞对5-FU、BLM、VCR和VBL耐药逆转率分别为达到70.6%、40.8%、48.6%和58.8%。
第二部分抑制信号通路逆转MC3/5-FU耐药性
通过western blot方法找出MC3/5-FU细胞和MC3细胞之间差异的耐药相关细胞信号蛋白，MC3/5-FU细胞中NF-κB、Nrf2-ARE、MAPK/ERK活性明显高于MC3细胞。用抑制剂抑制NF-κB、Nrf2-ARE和MAPK/ERK后MC3/5-FU细胞对5-FU的耐药逆转率分别为67.7%、43.4%和54.3%。。用MTT法测定抑制后MC3/5-FU生长曲线，软琼脂克隆实验计算各种干预后细胞克隆数，可见各种干预后Nrf2-ARE组生长最快，NF-κB和MAPK/ERK组最慢。
第三部分耐药相关信号通路在粘液表皮样癌中与MDR1基因之间的关系
用RT-PCR和western blot.检测耐药相关信号通路在粘液表皮样癌中与MDR1基因之间的关系。 NF-κB、Nrf2-ARE和MAPK/ERK通路活性被抑制后MC3/5-FU细胞MDR1mRNA表达降低，NF-κB通路效果最明显。RNAi沉默MC3/5-FU中MDR1的表达后可见各通路活性未发生明显变化。抑制剂与RNAi共同作用后检测耐药逆转率与RNAi组无明显差异。
第四部分MRP1基因引起耐药的机制
用免疫组化实验检测MEC临床手术标本发现MRP1基因在MEC中表达，且与MDR1基因的表达关系密切。用RNAi沉默MRP1基因后RT-PCR检测发现MDR1基因表达被抑制。沉默MRP1基因后western blot方法检测Nrf2-ARE通路的活性被明显抑制。
结论：
1MDR1基因的表达是粘液表皮样癌细胞产生多药耐药的一个重要因素。
2用RNAi的方法沉默MDR1基因可以有效逆转粘液表皮样癌细胞的耐药性。
3NF-κB、Nrf2-ARE、MAPK/ERK参与粘液表皮样癌细胞的耐药过程，通过抑制这些通路可以逆转粘液表皮样癌细胞的耐药性。
4NF-κB通路在粘液表皮样癌细胞中与MDR1基因的表达关系密切。
5推测在粘液表皮样癌细胞中，MRP1可以激活Nrf2-ARE从而促进MDR1基因表达，导致细胞耐药。而不是传统认为的膜蛋白药泵作用。
Mucoepidermoid carcinoma(MEC) is a common malignacy in salivary glands，itaccounts for about30%of malignant tumors in salivary glands and for5%to10%ofmalignant tumors in maxillofacial region in Chinese population. Anyhow,the main way ofits therapy is still surgery because chemotherapy is not very efficient to the tumor. The mainobstacle is the Multidrug resistance (MDR) effect after medication. Solving the problemof MDR may provide a new efficient way to treat MEC.
MDR reduces the effectiveness of chemotherapy. MDR is characterized by crossresistance to antineoplastic drugs, and the members of the ATP-binding cassette (ABC)transporter superfamily, such as ABCB1(MDR1) and ABCC1(MRP1), which play themost importent role in MDR.
Most biological functions of cells work by signal pathway. The bionomics of cellscan be revealed by studying the signal pathway. Interrupting these signal pathways relatedto illness may creat a new way to study and therapy.
In previous study we established multi drug resistant cell line MC3/5-FU from theparental cell line MC3. Therefor, in this study, we designed several pieces of shRNA,constructed MDR1-shRNA expression vector and silenced MDR1in MC3/5-FU cells withstable transfection. Then we detected the reverse rate of MDR by RNAi. Furthermore, wedetected the NF-κB,Nrf2-ARE and MAPK/ERK signal pathways between MC3/5-FU andMC3to find the MDR related ones. We used RNAi and signal pathway depressor todeduce the relationship between MDR1,MRP1, signal pathways and multidrug resistancein mucoepidermoid carcinoma.
The study includs four parts as follows.
1Reversion of MDR in MC3/5-FU by RNAi.
The plasmid expressing shRNA homologous to MDR1mRNA was constructed withshRNA expressing vector pRNAT-U-6.1/Neo based on the principle of siRNA design.Thecombinant plasmid was transfected stably into MC3/5-FU Cells using Lipofectamine2000.The shRNA efficiency was detected by real time-PCR analysis. The result showedMDR1-shRNA could effectively block the expression of MDR1in MC3/5-FU cells.RT-PCR analysis showed the expression of MDR1was silenced after stable transfection.The resistance index of MC3/5-FU was detected by MTT assay. The result showed thatthe multidrug resistance rates of MC3/5-FU cells to5-FU, BLM, VCR and VBL werereversed by70.6%,40.8%,48.6%and58.8%respectively.
2Reversion of MDR in MC3/5-FU by inhibiting signal pathway.
The expression of signal pathways between MC3/5-FU and MC3cells were detectedby western blot analysis. The results show that the activity of NF-κB,Nrf2-ARE andMAPK/ERK in MC3/5-FU was much higher than in MC3. The reversal of MDR wasdetected after the signal pathways was inhibited by the inhibitors. Inhibition of NF-κB，Nrf2-ARE and MAPK/ERK reversed MDR of MC3/5-FU cells to5-FU by67.7%,43.4%and54.3%respectively. MTT assay and soft agar cloning experiments showed thatinhibition of NF-κB resulted in proliferation inhibition of MC3/5-FU cells.
3The relationship between signal pathway and MDR1gene inmucoepidermoid carcinoma.
The relationship between signal pathway and MDR1gene in MC3/5-FU cell wereinvestigated by RT-PCR and western blot. Inhibition of NF-κB， Nrf2-ARE andMAPK/ERK inhibited MDR1mRNA expression in MC3/5-FU cells, inhibition of NF-κBshowed the strongest effects.While silence of MDR1gene by RNAi did not change theexpression of NF-κB，Nrf2-ARE and MAPK/ERK activity in MC3/5-FU cells.
4The function of MRP1in MDR
MRP1protein was found in surgical samples of MEC by immunohistochemistryexperiment. RT-PCR analysis showed the expression of MDR1in MC3/5-FU cells wasinhibited after MRP1was silenced by RNAi. The activity of each signal pathway wasdetected by western blot after MRP1was silenced by RNAi. The resuit showed onlyNrf2-ARE was inhibited.
Conclusion
1MDR1is an important factor of multi-drug resistance in mucoepidermoid carcinoma.
2Silenc of MDR1by RNAi is effective in the reversal of MDR in mucoepidermoidcarcinoma.
3NF-κB,Nrf2-ARE and MAPK/ERK signal pathways take part in the MDR inmucoepidermoid carcinoma.
4NF-κB pathway has close relationship with the expression of MDR1in mucoepidermoidcarcinoma
5MRP1may enhance the expression of MDR1by activating Nrf2-ARE rather than bymembrane protein as drug pump.
引文
1.于世凤.《口腔组织病理学》第四版.北京人民卫生出版社. p.250-3.
2. Pires FR, de Almeida OP, de Araujo VC, et al. Prognostic factors in head and neckmucoepidermoid carcinoma. Arch Otolaryngol Head Neck Surg2004;130:174-80.
3. Yin HF, Okada N, Takagi M. Apoptosis and apoptotic-related factors inmucoepidermoid carcinoma of the oral minor salivary glands. Pathol Int2000;50:603-9.
4. Hicks MJ, el-Naggar AK, Flaitz CM, et al. Histocytologic grading of mucoepidermoidcarcinoma of major salivary glands in prognosis and survival: a clinicopathologic andflow cytometric investigation. Head Neck1995;17:89-95.
5. Liang XJ, Aszalos A. Multidrug transporters as drug targets. Curr Drug Targets.2006Aug;7(8):911-21.
6. Ishikawa T, Tsuji A, Inui K, Sai Y, Anzai N, Wada M, Endou H, Sumino Y. Thegenetic polymorphism of drug transporters: functional analysis approaches.Pharmacogenomics.2004Jan;5(1):67-99.
7. Kubo, H., et al., Expression of the multidrug resistance-associated protein (MRP)gene in urothelial carcinomas. Int J Cancer,1996.69(6): p.488-94.
8. Calatozzolo C,Gelati M,Ciusani E, et al.Expression of drug resistance proteins Pgp,MRP1, MRP3， MRP5and GST-pi in human glioma.J Neurooncol,2005;74(2):113-121
9.赵文增,刘荣红,谢荣辉,孟繁杰,曹斌,王凤安. MRP1在大肠癌中表达的研究.河北医科大学学报,2008;29(4):519
10. Daood M, Tsai C, Ahdab-Barmada M, Watchko JF. ABC Transporter (P-gp/ABCB1,MRP1/ABCC1, BCRP/ABCG2) Expression in the Developing Human CNS.Neuropediatrics.2008;39(4):211-8
11. Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F. The functions and structure ofABC transporters: implications for the design of new inhibitors of Pgp and MRP1tocontrol multidrug resistance (MDR). Curr Drug Targets.2006Jul;7(7):893-909.
12. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization,and single nucleotide polymorphisms of human ABCB1(MDR1), ABCC (MRP), andABCG2(BCRP) efflux transporters. Int J Toxicol.2006Jul-Aug;25(4):231-59.
13. Deeley RG, Cole SP. Substrate recognition and transport by multidrug resistanceprotein1(ABCC1). FEBS Lett.2006Feb13;580(4):1103-11. Epub2005Dec21.
14. Huang Y, Sadée W. Membrane transporters and channels in chemoresistance and-sensitivity of tumor cells. Cancer Lett.2006Aug8;239(2):168-82. Epub2005Oct5.
15. Conseil G, Deeley RG, Cole SP. Polymorphisms of MRP1(ABCC1) and relatedATP-dependent drug transporters. Pharmacogenet Genomics.2005Aug;15(8):523-33.
16. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein,MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol.2005May.1;204(3):216-37
17. Boumendjel A, Baubichon-Cortay H, Trompier D, Perrotton T, Di Pietro A.Anticancer multidrug resistance mediated by MRP1: recent advances in the discoveryof reversal agents. Med Res Rev.2005Jul;25(4):453-72.
18. Rappa G,Finch RA,Sartrelli AC,et al.New insights into the biology and pharmacologyof the multidrug resistance protein(MRP) from gene knockout models[J].BiochemPharmacol,1999;58(4):557-562.
19. Calatozzolo C,Gelati M,Ciusani E, et al.Expression of drug resistance proteins Pgp,MRP1, MRP3, MRP5and GST-pi in human glioma.J Neurooncol,2005;74(2):113-121.
20. Sharom FJ. ABC multidrug transporters: structure, function and role inchemoresistance. Pharmacogenomics.2008Jan;9(1):105-27.
21. Munoz M, Henderson M, Haber M, Norris M. Role of the MRP1/ABCC1multidrugtransporter protein in cancer. IUBMB Life.2007Dec;59(12):752-7.
22. Bakos E, Homolya L. Portrait of multifaceted transporter, the multidrugresistance-associated protein1(MRP1/ABCC1). Pflugers Arch.2007Feb;453(5):621-41. Epub2006Dec23.
23. Lin Y，Bai L，Chen W，et a1．The NF-κB activation pathways，emerging moleculartargets for cancer preven-tion and therapy[J]．Expert Opin Ther Targets，2010，l4(1)：45-55．
24. Baud V，Karin M．Is NF-kappaB a good target for cancer therapy?Hopes andpitfalls[J]．Nat Rev Drug Discov，2009，8(1)：33-40．
25. Sethi G，Sung B，Aggarwal BB．Nuclear factor-kappaB activation：from bench tobedside[J]．Exp Biol Med，2008，233f11：21-31．
26. Kriete A，Mayo KL．Atypical pathways of NF-kappaB acti-vation and aging[J]．ExpGerontol，2009，44(4)：250-255．
27. Muthusamy V，Piva TJ．The UV response of the skin：a review of the M APK，NFkappaB and TNFalpha signal transduction pathways[J]．Arch Dermatol Res，2010，302(1)：5-l7．
28. Phelps CB，Ghosh G．Discreet mutations from c-Rel to v-Rel alter kappaB DNArecognition， IkappaBalpha binding， and dimerization： implications for V-Reloncogenicity[J]．Oncogene，2004，23(6)：1229-1238．
29. Wei L，Liu J．Porcine circovirus type2replication is im-paired by inhibition of theextracellular signal--regulated ki-nase(ERK)signaling pathway[J]．Virology，2009，386(1)：203-209．
30.卓佳，陈柏坤，薛向阳，等．核因子NF-κB p65和I-cB-d在宫颈癌中的表达及意义『J]．温州医学院学报，2005，35(3)：182-l84．
31. Johmura Suzuki M，Osada S，et a1．FAD24，a regulator of adipogenesis and DNAreplication， inhibits H-RAS-mediated transformation by repressing NF-kappaBactivity[J]．Biochem Biophys Res Commun，2008，369(2)：464-470．
32. Reuter S，Charlet J，Juncker T，et a1．Efect of curcumin on nuclear factor kappaBsignaling pathways in human chronic myelogenous K562leukemia cells[J]．Ann N YAcad Sci，2009．117l(8)：436-447．
33. Yu C，Rahmani M，Conrad D，et a1．The proteasome inhibi-tor bortezomib interactssynergistically with histonedeacetylase inhibitors to induce apoptosis in Bcr／Abl+cellssensitive and resistant to STI571[J]．Blood，2003，102(10)：3765-3774．
34. Rangaswami H，Bulbule A，Kundu GC．Nuclear factor-induc-ing kinase plays acrucial role in osteopontin-induced M APK／IkappaBalpha kinase-dependent nuclearfactor kappaB-me-diated promatrix metalloproteinase-9activation[J]．J Biol Chem，2004，279(37)：3892l一38935．
35. Dahlman JM，Wang J，Bakkar N，et a1．The RelA／p65sub-unit of NF-κBspecifically regulates cyclin D1protein stability： implications for cell cyclewithdrawal and skeletal myogenesis[J]--1Cell Biochem，2009，106(1)：42-51．
36. Bentires-Alj M，Barbu V，Fillet M，et a1．NF-kappaB tran-scription factor inducesdrug resistance through MDR1expression in cancer cells[J]．Oncogene，2003，22(1)：9O一97．
37. Patel NM，Nozaki S，Shortle NH，et a1．Paclitaxel sensitiv-ity of breast cancer cellswith constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressorand parthenolide[J]．Oncogene，2000，19(36)：4159-4169．
38. Uetsuka H，Haisa M，Kimura M，et a1．Inhibition of inducible NF-κB activityreduces chemoresistance to5-fluorouracilin human stomach cancer cell line[J]．ExpCell Res，2003，289(1：27-35．
39. Wang X，Omura S，Szweda LI，et a1．Rapamycin inhibits proteasome activatorexpression and proteasome activity [J]．Eur J lmmunol，1997，27(11)：278l一2786．
40. Aggarwal BB Shishodia S Takada et a1．Curcumin suppresses the paclitaxel-inducednuclear factor-kappaB path-way in breast cancer in nude mice[J]．Clin Cancer Res，2005，l1(20)：7490-7498．
41. Sweeney CJ，Mehrotra S，Sadaria M R，et a1．The sesquiter-pene lactone parthenolidein combination with docetaxel reduces metastasis and improves survival in axenograft model ofbreast cancer[J]．Mol CancerTher，2005，4(6)：1004-1012．
42. Farhana L，Dawson M I，Fontana JA．Apoptosis induction by a ovel retinoid-relatedmolecule requires nuclear factor-kappaB activation[J]．Cancer Res，2005，65(11)：4909-4917．
43.沈利群，徐祥，梁华平，等．NF-κB p50业基同源结构域相互作用多肽的筛选『J1．细胞与分子免疫学杂志，2007，23(9)：804-806．
44.李生茂，梁华平，徐祥，等．NF-κB p50和p65蛋白保守结构域原核表达系统的建立fJ1．第三军医大学学报，2004，26(10)：878-881．
45.徐祥，梁华平，郑江，等．p65结合肽与p65的亲和力检测及其对NF-κB DNA结合活性抑制作用的鉴定.．第三军医大学学报，2006，28(7)：621-625．
46. Morris M J，Kelly W K，Slovin S，et a1．A phase I1trial of bortezomib and prednisonefor castration resistant metastatic prostate cancer[J]．J Urol，2007，178(6)：2378-2383
47.周伟民，金培英，平金良，等．硼替佐米抑制核因子-κB活化对LOVO细胞增殖的影响『J1．温州医学院学报，2010，40(2)：156-159．
48. Lee CH，Jeon YT，Kim SH，et a1．NF-κB as a potential molecular target for cancertherapy[J]．BioFactors，2007，29(1)：19-35．
49. Shibata T．Ohta T．Tong KI,et al. Cancer related mutations in NRF2impair itsrecognition by Keapl-Cul3E3ligaseand promote malignancy，Proc Natl Acad SciUSA，2008，105(36)：l3568一l3573
50. Dinkova-Kostova AT．Holtzclaw WD，Cole RN，et a1．Direct evidence that sulfhydrylgroups of Keap1are the sensors regu-lating induction of phase2enzymes that protectagainst car-cinogens and oxidants，Proc Natl Acad Sci USA，2002，99(18)：l1908-11913
51. Singh A，M isra V，Thimm ulappa RK，et a1．Dysfunctional KEAP1一NRF2interaction in non．small-cell lung cancer．PloS Med，2006，3(10):e420
52. M inerva RG，Kwak MK，Dolan PM，el af．Sensitivity to carcinogenesis is increasedand chemoprotective efficacy of enzyme inducers is lost in nrf2transcriptionfactor-deficient mice，Proc Nat Acad Sci USA，200l，98(6)：3410．3415
53. Morimitsu Y，Nakagawa Y，Hayashi K，et a1．A sulforaphane analogue that potentlyactivates the Nrf2-dependent detoxifi-cation pathway，J Biol Chem，2002，277(5)：3456-3463
54. Lee JM， Calkins MJ， Chan K， et a1． Identmcation of the NF-E2-relatedfactor-2-dependent genes conferring protection againstoxidative stress in primarycortical astrocytes using oligonucle-otide microaray analysis，J Biol Chem，2003，278(14)：12029-12038
55. Thimmulappa RK，Mai KH，Srisuma S，et a1．Identification of Nrf2一regulated genesinduced by the chemopreventive agent sulfo raphane by o1igonucleOtide microarray，Cancer Res，2002，62(181：5196-5203
56. Lee JS，Surh YJ．Nrf2as a novel molecular target for chemoprevention，Cancer Lett，2005，224(2)：171-184
57. Nguyen T，Sherratt PJ，Pickett CB．Regulatory mechanisms controlling geneexpression mediated by the antioxidant response element，Annu Rev PharmacolToxicol，2003，43：233-26O
58. Wakabayashi N，Dinkova-Kostova AT，Holtzclaw W D，et a1．Protection againstelectrophile and oxidant stress by induction of the phase2response：fate of cysteinesof the Keap1sensor modified by inducers，Proc Natl Acad Sci USA，2004，101(7)：2040-2045
59. Zipper LM．M ulcahy RT．The Keapl BTB／POZ dimerization function is requiredto sequester Nrf2in cytoplasm，J Biol Chem，2002，277(39)：36544-36552
60. Padm anabhan B，Tong KI，Ohta T，et a1．Structural basis for defects of Keapl activityprovoked by its point mutations in lung cancer，Mol Cell，2006，21(5)：689-700
61. Frohlich DA，M ccabe M T，Am old RS，et a1．The role of Nrf2in increased reactiveoxygen species and DNA damage in prostate tumorigenesis，Oncogene，2008，27(31)：4353-4362
62. Itoh K，W akabayashi N，Katoh Y，et a1．Keapl represses nuclear activation ofantioxidant responsive elements by Nrf2through binding to the amino-terminal Neh2domain，Genes Dev，1999，13(1)：76-86
63. Stacy DR，Ely K，M assion PP，el a1．Increased expression of nuclear factor E2p45一related factor2fNRF2)in head and neck squamous cell carcinomas，Head Neck，2006，28(9)：813-818
64. Kim JH，Bogner PN，Ranmath N，el a1．Elevated peroxiredoxin1．but notNF-E2-related factor2．is an independent prognostic factor for disease recurrence andreduced survival in stage I non-small cell lung cancer，Clin Cancer Res，2007，13(13)：3875-3882
65. Cho JM，Manandhar S，Lee HR，et a1．Role of the Nrf2-antioxidant system incytotoxicity mediated by anticancer cisplatin：im plication to cancer cell resistance，Cancer Lett，2008．260(1-21：96-1O8
66. Tarumoto T，Nagai T，Ohmine K，et a1．Ascorbic acid restores sensitivity to imatinibvia suppression of Nrf2一dependent gene expression in the im atinib-resistant cellline，Exp Hematol，2004，32(4)：375-381
67. Girard L，Zochbauer-Muller S，Virmani AK，et a1．Genome-wide allelotyping of lungcancer identifies new regions of allelic loss，differences between small eell lungcancer and non-small eell lung cancer，and loci clustering，Cancer Res，2000，60(17)：4894．4906
68. Soini Y，Nap~nkangas U，J~irvinen K，el a1．Expression of t-glutamyl cysteinesynthetase in nonsmall cell lung carcinoma，Cancer，2001，92(11)：2911-2919
69. Sahoo SK，Sawa T，Fang J，et a1．Pegylated zinc protoporphyrin：a water-solubleheine oxygenase inhibitor with tum or-targeting capacity，Bioconjug Chem，2002，13(5)：1031-1038
70. Tanaka S，Akaike T，Fang J，et a1．Antiapoptotic effect of haem oxygenase-1inducedby nitric oxide in experimental solid tumour，Br J Cancer，2003，88(6)：902-909
71. Fang J，Sawa T，Akaike T，et a1．In vivo antitumor activity of pegylated zincprOtOpOrphyrin：targeted inhibition of heme oxygenase in solid tumor，Cancer Res，2003，63(13)：3567-3574
72. Kim HR，Kim S，Kim EJ，et a1Suppression of Nrf2-driven heme oxygenase-1enhances the chemosensitivity of lung cancer A549cells toward cisplatin，LungCancer，2008，60(1)：47-56
73. Loboda A，Was H，Jozkowicz A，et a1．Janus face of Nrf2一Ho一1axis in cancer--f iend in chemoprevention．foe in anticancer therapy，Lung Cancer，2008，60(1)：1-3
74. Logsdon CD，Simeone DM，Binkley C，et a1．Molecular profiling of pancreaticadenocarcinoma and chronic pancreatitis identifies multiple genes differentiallyregulated in pancreatic cancer，Cancer Res，2003，63(10)：2649-2657
75. Brar SS，Kennedy TP，Whorton AR，et a1．Reactive oxygen species from NAD(P)H：quinone oxidoreductase constitutively activate NF-κB in malignant melanomacells．Am J Physiol CeII Physiol，2001，280(3)：C659一C676
76. Deng HB，Parekh HK，Chow KC，et a1．Increased expression of dihydrodioldehydrogenase induces resistance to cisplatin in human ovarian carcinoma cells，JBio，Chem，2002，277(17)：15035-15043
77. Ohara H，Miyabe Y，Deyashiki Y，et a1．Reduction of drug ketones by dihydrodioldehydrogenases，carbonyl reductase and aldehyde reductase of human liver，BiochemPharmacol，1995，5O(2)：221-227
78. Ax W，Soldan M，Koch L，et a1．Development of daunorubicin resistance in tumourcells by induction of carbonyl reduction，Biochem Pharmacol，2000，59(3)：293-300
79. Hsu NY，Ho HC，Chow KC，et a1．Overexpression ofdihydrodiol dehydrogenase asa prognostic marker of non-small cell lung cancer，Cancer Res，2001，61(6)：2727-2731
80. Ciaccio PJ，Jaiswal AK，Tew KD．Regulation of human dihydrodiol dehydrogenaseby Michael acceptor xenobiotics，J Biol Chem，1994，269(22)：15558-15562
81. Palackal NT，Lee SH，Harvey RG，et a1．Activation of polycyclic aromatichydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-ketoreductase(AKR1C)enzymes andtheir functional overexpression in human lungcarcinoma(A549)cells，J BioZ Chem，2002，277(27)：24799-24808
82. Courehesne WE，Kunisawa R，Thomer J．A putative protein kinase over_comespheromome-induced arrest of cell cycling in S．cerevisiae[J]．Cell，1989；58：1107-1119．
83. Boulton TG，Nye SH，Robbins DJ。et a1．ERKs：a family of protein-serineVthreoninekinases that are activated and tyrosine phosphorylated in response in insulin andNGF[J]．Cell，1991；65：663-675．
84. Ahn NG。Krebs EG．Evidence for all epidermal growth fact0r～stimu1ated proteinkinase cascade in Swiss333cells．Activation of serine peptide kinase activity bymyelin basic pmteln kiuases in vitro[J]．J Biol Chem，1990；265：11495-11501．
85. Rossomando AJ，Payne DM，weber MJ，et．Evidence that vo42，a major tyrosinekinase target protein，is a mitogen-activated sefine／threonine protein kinase[J]．ProcNatl Acad Sci USA，1989；86：6940-6943．
86. Widmann C，Gisbon S，Jarpe B，et a1．Mitogen-activated protein kinase：conservationof a three-kinase module from yeast to human[J]．Phys Rev，1999；79：143-180．
87. Momon DK．The Raf一1kinaseas atrallsduaer ofIIlito c8i目[J]．Cancer Ceas，1990；2：377．
88. Wittingho for A Nass N．How Ras-related proteinstalktotheir efec-tor[J]．TIBS，1996；21(2)：488．
89. Bokemer D，Sorokin A，Dunn MJ．Multiple intercellular MAP kinase signalingcascades[J]．K／dney／nt，1996；49：1187．
90. Ferrcll JE.Bhatt RR． Mechanistic studies of the dual phosphorylation ofmitogen-activated protein kinase[J]．J Biol Chem。1997；272：19008-19016．
91.丁桂霞，张爱华，陈荣华．Ras／Raf／ERK信号传导通路在肾脏疾病中作用的研究进展[J]．国外医学儿科学分册。2000；27(5)：231-235．
92.卢建，余应年，许仁宝．受体信号转导系统与疾病[M]．济南：山东科学技术出版社。2001：pp253．
93. Mihenger ill，Conner J。Famham PJ．An inhibitory Raf一1mutant suppressesexpression of a subset of v-raf-activated genes[J]．J Biol Chem。1993；268：15674-15680．
94. Pages G。Lenorrnand P。LAllemain G，et a1．Mitegen-activated protein kinases042mapk and044mapk are required for fibroblast proliferation [J]．Proc Ned Acid SciUSA。1993；90：8319-8323．
95. Wang LM，Keegan AD，Paul WE，et a1．IL-4activates a distinct Rjgnal tmnsducfioncascade from IL一3in factor-dependent myeloid cells [J] EMBO J，1992；11：4899-4908．
96. CasiLlas AM，Amaral K，Chegini-Farahani S，et a1．Okadaic acid acti．rates042mitogen-activated protein kinases(MAP kinase；ERK一2) in B-lymphocytes butinhibits rather than augments eelular proliferatlon：contrast with phorbol12一myrlstate13一acetate[J]．Biochem J，1993；290：545-550．
97. Qui MS。Green SH．PC12cell neuronal diferentiation is associated with prolongedp21ras activity and consequent prolonged ERK activity l J J．Neuron，1992；9：705-717．
98. Traverse S，Gomez N，Paterson H，et a1．Sustained activation ofthe mitogen-activatedprotein(MAP)kinase caseilde may be required for diferentiation of PC12cells：comparison of the efects of nerve growth factor and epidermal growthfactor[J]．Bioehem J，1992；288；351-355．
99. Dikie I，Sehlessinger J，Lax Irit．PC12cells overexpressing the insulin receptorundergo insulin-dependent neuronal diferentiation[J] Curr Biol19944：702-708．
100.Verlhac MH。de Pennart H，Maro B，et a1．MAP kinase bec0me88tablv activated atmetaphase and is associated with micmmbule-organifing centers during meioticmaturation of mouse oocytes[J]．Dev Biol，1993；158：330-340．
101.WangItG，Miyashima T,Takayama S，et a1．Apoptosis regulation byin-teraction of Bcl一2protein and Rat"一1kinase[J]．Orwogen，1994；9：2751．
102.Blogoskonny MV，Sehulte T，Nguyen P，et al。Taxol-induced apoptosis andphophorylation of Bcl一2protein involves c-Raf一1and repre．sents a novel e-Raf-Isignal transduction pethway[J]．Cancer Res，1996；56：1851．
103.Wmabe M，Masuda YS，Nakajo Y．vt a1．The cooperative interaction of twodiferential signaling pathway in response to bufalin induced apoptosis in humanleukaemia U937cells[J]．J Biol Chem，1996；271(24)：14067．
104.Guo X，Ma N，Wang J，Song J，Bu X，ChengY，et a1．Increased p38-MAPK isresponsible for chemotherapy resistan ce in human gastric cancer cells[J]．BMCCancer，2008，8(1)：375~84．
1. JZ Wu, ZQ Situ, ZB Liu et al. Selection and characterization of a highly metastaticcell clone from mucoepidertmoid carcinoma cell line derived from human salivarygland. Chin J Dental Res1998;1:71
2.缪叶，秦楠，李焰，刘峰，吴军正*。高转移人涎腺黏液表皮样癌耐药细胞系的建立及其生物学特性。实用口腔医学杂志,2009；25(3)：340-343。
3. Snow K,Judd W. Characterisation of adriamycin and amsacrine2resistant humanleukaemic T cell lines[J]. Br J Cancer,1991,63(1):17228.
4. Derek Kofi o，Boahene，Kerry D，et a1．M ucoepidermoid Carci-noma of theParotid Gland：The Mayo Clinic ExperienceEJ]．Arch Otolaryngol Head Neck Surg，2004，130：849-856
5.王益华．涎腺粘液表皮样癌78例临床分析rj]．局解手术学杂志，2010：477-478
6. Cherry S，Silverman N．Host-pathogen interactions in drosophila：new tricks from allold friend[J]．Nat lmm,mol，2OO6，7(9)：911-917．
7. Obbard DJ，Jiqqins FM，Halliqan DL，et a1．Natural Selection drives extremely rapidevolutionin antiviralRNAi genes[J]．CurtBiol，2006，16(6)：580-585．
8. CarusoR，PaUoneF，FirmD，ct a1．Pmtease-activated receptor-2activation in gastricaaIlcer cells promotes epidermal growth factor receptor transactivation andproliferation[J]．Am J Pathol，2006，169(1)：268-278．
9. Li GH，Wei H，Chen ZT，et a1．STAT3silencing with lentivirus inhibits growth andinduces apoptosis and diferentiation of U251cells[J]．J Neurooncol，2009，91(2)：165-174．
10. Chen XL，Cao LQ，She MR，et a1．Gli一1siRNA induced apoptosis in Huh7cens[J]．World J Gastroenterol，2008，14(4)：582-589．
11. Liu JN，Gao YD，Wang JH， ct aJ． Construction and expression of diabody[CD3P-gp without Etag．Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi，2007，23：946-949．
12. Li L' Ma LL， Gao P， et a1． Reve~al ofmuhidrug resistance of MCF一7／ADRin nude mice by grape seed polypheno1． ZhonghHa Waike Zazhi，2004，42：795-798．
13. Dignam JD， Lebovitz RM， Roeder RG． Accurate transcription initiation by RNApolymerase II in a soluble extract from isolated mammalian nuclei．Nucleic AcidsRes，1983，11：1475-1489．
14. Norgaard JM，Olesen LH，Hokland P．Changing pigture of cellular drug resistance inhuman leukemia． Crit Rev Oncol Hematol，2004，50：39-49．
15. Nooter K， Sonneveld P． Clinical relevance of p-glycoprotein expression inhaematolog／cal malignancies．Leukemla Research．I994．18：233．
16. Farhana L，Dawson M I，Fontana JA．Apoptosis induction by a ovel retinoid-relatedmolecule requires nuclear factor-kappaB activation[J]．Cancer Res，2005，65(11)：4909-4917．
17. Morimitsu Y，Nakagawa Y，Hayashi K，et a1．A sulforaphane analogue that potentlyactivates the Nrf2-dependent detoxifi-cation pathway，J Biol Chem，2002，277(5)：3456-3463
18. Lee JM， Calkins MJ， Chan K， et a1． Identmcation of the NF-E2-relatedfactor-2-dependent genes conferring protection againstoxidative stress in primarycortical astrocytes using oligonucle-otide microaray analysis，J Biol Chem，2003，278(14)：12029-12038
19. Wang XJ，Sun Z。Villeneuve NF，et a1．Nrf2enhances resistance of cancer cells tochemotherapeutic drugs，the dark side of Nrf2[J]．Carcinogenesis，2008，29(6)：1235—1243．
20. Kim HR，Kim s，Kim EJ，et a1．Suppression of Nrf2-driven heineoxygenase-1enhances the chemosensitivity of lung cancer A549cellstowardcisplatin[J]．LungCancer，2008，60(1)：47—56．
21. Kim SK。Yang JW，Kim MR，et a1．Increased expression of Nrf2／ARE-dependentanti—-oxidant proteins in tamoxifen-。resistant breast cancereeHs[J]．Free Radic BiolMed，2008，45(4)：537—546．
22. Kobayashi A，Ohta T，Yamamoto M．Unique function of the Nrf2-keapl pathway inthe inducible expression of antioxidant and detoxifyingenzynmes[J]． MethodsEnzymol，2004，378：273—286．
23. Zhang DD．Mechanistic studies of the Nrf2-Keap1signaling pathway[J]．Drug MetabRev，2006，38(4)：769-789．
24. Sun Z，Zhang S，Chan JY，et a1．Keap1controls postinduction repression of the Nrf2一mediated antioxidant response by escorting nuclear export ofNrf2[J]．MolCellBiol，2007，27(18)：6334-6349．2331-2337．
25. Thimmulappa RK，Mai KH，Srisuma S，et a1．Identification of Nrf2一regulated genesinduced by the chemopreventive agent sulfo raphane by o1igonucleOtide microarray，Cancer Res，2002，62(181：5196-5203
26. Lee JS，Surh YJ．Nrf2as a novel molecular target for chemoprevention，Cancer Lett，2005，224(2)：171-184
27. Nguyen T，Sherratt PJ，Pickett CB．Regulatory mechanisms controlling geneexpression mediated by the antioxidant response element，Annu Rev PharmacolToxicol，2003，43：233-26O
28. Wakabayashi N，Dinkova-Kostova AT，Holtzclaw W D，et a1．Protection againstelectrophile and oxidant stress by induction of the phase2response：fate of cysteinesof the Keap1sensor modified by inducers，Proc Natl Acad Sci USA，2004，101(7)：2040-2045
29. Bokemer D，Sorokin A，Dunn MJ．Multiple intercellular MAP kinase signalingcascades[J]．K／dney／nt，1996；49：1187．
30. Ferrcll JE.Bhatt RR． Mechanistic studies of the dual phosphorylation ofmitogen-activated protein kinase[J]．J Biol Chem。1997；272：19008-19016．
31.丁桂霞，张爱华，陈荣华．Ras／Raf／ERK信号传导通路在肾脏疾病中作用的研究进展[J]．国外医学儿科学分册。2000；27(5)：231-235．
32. Mihenger ill，Conner J。Famham PJ．An inhibitory Raf一1mutant suppressesexpression of a subset of v-raf-activated genes[J]．J Biol Chem。1993；268：15674-15680．
33. Pages G。Lenorrnand P。LAllemain G，et a1．Mitegen-activated protein kinases042mapk and044mapk are required for fibroblast proliferation [J]．Proc Ned Acid SciUSA。1993；90：8319-8323．
34. Wang LM，Keegan AD，Paul WE，et a1．IL-4activates a distinct Rjgnal tmnsducfioncascade from IL一3in factor-dependent myeloid cells [J] EMBO J，1992；11：4899-4908．
35. CasiLlas AM，Amaral K，Chegini-Farahani S，et a1．Okadaic acid acti．rates042mitogen-activated protein kinases(MAP kinase；ERK-2) in B-lymphocytes but inhibitsrather than augments eelular proliferatlon： contrast with phorbol12-myrlstate13-acetate[J]．Biochem J，1993；290：545-550．
36. Cole SPC，BhadmaiG，Gedash Jn，et a1．Overexpresaiott of a transporter gene in8muhidrug resistant human lung tiniest cellline[j]．Science，1992，258：1650．
37. J Barrad MA，Broxtterrnan I-IJ，Wri t KA，et a1． Imnmnodetection of a190KdProtein non-P-glyeoprotein–conning MDR celia derived from small cell and non—small—cell lung tumors[J]．Br J Cancer.1992。65：21．
38. Jedlitschky G，Leier I，Buehhck U，et a1．ATP—dependent transport of glutathioneS-conjugaes by the multidrug resistance-associated protein [J]．Cancer R，1994，54：4833．
39. Lin HL，I WY，uu TY，et a1．Rever．l of Taxd resistance in hepatoma by cy-closporinA： involvement of the PI-3knase—AKT1pathway[J]．Br J Cancer，2003，88(6)：973—980．
40. Gallego, M.A., et al., Apoptosis-inducing factor determines the chemoresistance ofnon-small-cell lung carcinomas. Oncogene,2004.23(37):6282-91.
41. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA. AIF-mediated programmednecrosis: a highly regulated way to die. Cell Cycle.2007Nov1;6(21):2612-9.
42. Fok JY, Mehta K. Tissue transglutaminase induces the release of apoptosis inducingfactor and results in apoptotic death of pancreatic cancer cells. Apoptosis.2007Aug;12(8):1455-63
43. Millan A, Huerta S Apoptosis-inducing factor and colon cancer. J Surg Res.2009Jan;151(1):163-70.
44. Joza N, Pospisilik JA, Hangen E, Hanada T, Modjtahedi N, Penninger JM, Kroemer G.AIF: not just an apoptosis-inducing factor. Ann N Y Acad Sci.2009Aug;1171:2-11.
45. Lorenzo HK, Susin SA. Therapeutic potential of AIF-mediated caspase-independentprogrammed cell death. Drug Resist Updat.2007Dec;10(6):235-55.
46. Yang X, Fraser M, Abedini MR, Bai T, Tsang BK. Regulation of apoptosis-inducingfactor-mediated, cisplatin-induced apoptosis by Akt. Br J Cancer.2008Feb26;98(4):803-8.
47. Gallego MA, Ballot C, Kluza J, Hajji N, Martoriati A, Castéra L, Cuevas C,Formstecher P, Joseph B, Kroemer G, Bailly C, Marchetti P. Overcomingchemoresistance of non-small cell lung carcinoma through restoration of an AIF-dependent apoptotic pathway. Oncogene.2008Mar27;27(14):1981-92. E
48.陶虹等, p53基因对人肺癌细胞系耐药性的影响.中国肺癌杂志,2008.11(2):157-164.
49. Lee, Y.S., et al., Influence of p53expression on sensitivity of cancer cells tobleomycin. J Biochem Mol Toxicol,2010.
50. Gómez-Raposo C, Mendiola M, Barriuso J, Hardisson D, Redondo A. Molecularcharacterization of ovarian cancer by gene-expression profiling. Gynecol Oncol.2010May1.[Epub ahead of print]
51. Simon R. Challenges of microarray data and the evaluation of gene expression profilesignatures. Cancer Invest.2008May;26(4):327-32.
52. Surowiak P. Prediction of the response to chemotherapy in ovarian cancers..FoliaMorphol (Warsz).2006Nov;65(4):285-94.
53. Voduc D, Kenney C, Nielsen TO. Tissue microarrays in clinical oncology. SeminRadiat Oncol.2008Apr;18(2):89-97.
54. Wu Junzheng,Situ Zhengqiang,Chen Jianyuan et al. Chemosensitivity of salivarygland and oral cancer. cell lines. Chin Med J,1992;105:1026
55. Tilesi F, Fradiani P, Socci V, Willems D, Ascenzioni F Design and validation ofsiRNAs and shRNAs. Curr Opin Mol Ther.2009Apr;11(2):156-64.
56.徐叔云主编.临床药物学.人民卫生出版社.第3版.2004年7月.北京.448-455页
57. Snow K,Judd W.Characterisation of adriamycin and amsacrine-resistant humanleukaemic T cell lines[J].Br J Cancer,1991;63(1):17-28.
58. Tsujimoto S, Fujimoto K, Okajima E, Ozono S, Okajima E, Hirao Y5-Fluorouracilincorporated into the tissue RNA of human and rat bladder carcinoma afteradministration of1-(2-tetrahydrofuryl)-5-fluorouracil combined with uracil. Int J ClinOncol.2008Apr;13(2):138-43.
59. Bhattacharya S, Mariani TJ. Array of hope: expression profiling identifies diseasebiomarkers and mechanism. Biochem Soc Trans.2009Aug;37(Pt4):855-62.
60. Zhang JT. Use of arrays to investigate the contribution of ATP-binding cassettetransporters to drug resistance in cancer chemotherapy and prediction ofchemosensitivity. Cell Res.2007Apr;17(4):311-23.
61. Ness SA. Microarray analysis: basic strategies for successful experiments. MolBiotechnol.2007Jul;36(3):205-19.
62. Wang TH, Chao A. Microarray analysis of gene expression of cancer to guide the useof chemotherapeutics. Taiwan J Obstet Gynecol.2007Sep;46(3):222-9.
63. Ivanov, S., et al., Expression of hypoxia-inducible cell-surface transmembranecarbonic anhydrases in human cancer. Am J Pathol,2001.158(3): p.905-19.
64. Pastorekova, S., et al., Carbonic anhydrases: current state of the art, therapeuticapplications and future prospects. J Enzyme Inhib Med Chem,2004.19(3): p.199-229.
65. Loncaster, J.A., et al., Carbonic anhydrase (CA IX) expression, a potential newintrinsic marker of hypoxia: correlations with tumor oxygen measurements andprognosis in locally advanced carcinoma of the cervix. Cancer Res,2001.61(17):p.6394-9.
66. Kim, J.Y., et al., Tumor-associated carbonic anhydrases are linked to metastases inprimary cervical cancer. J Cancer Res Clin Oncol,2006.132(5): p.302-8.
67. Lee, S., et al., Tumor carbonic anhydrase9expression is associated with the presenceof lymph node metastases in uterine cervical cancer. Cancer Sci,2007.98(3): p.329-33.
2. Pires FR, de Almeida OP, de Araujo VC, et al. Prognostic factors in head and neckmucoepidermoid carcinoma. Arch Otolaryngol Head Neck Surg2004;130:174-80.
3. Yin HF, Okada N, Takagi M. Apoptosis and apoptotic-related factors inmucoepidermoid carcinoma of the oral minor salivary glands. Pathol Int2000;50:603-9.
4. Hicks MJ, el-Naggar AK, Flaitz CM, et al. Histocytologic grading of mucoepidermoidcarcinoma of major salivary glands in prognosis and survival: a clinicopathologic andflow cytometric investigation. Head Neck1995;17:89-95.
5. Liang XJ, Aszalos A. Multidrug transporters as drug targets. Curr Drug Targets.2006Aug;7(8):911-21.
6. Ishikawa T, Tsuji A, Inui K, Sai Y, Anzai N, Wada M, Endou H, Sumino Y. Thegenetic polymorphism of drug transporters: functional analysis approaches.Pharmacogenomics.2004Jan;5(1):67-99.
7. Kubo, H., et al., Expression of the multidrug resistance-associated protein (MRP)gene in urothelial carcinomas. Int J Cancer,1996.69(6): p.488-94.
8. Calatozzolo C,Gelati M,Ciusani E, et al.Expression of drug resistance proteins Pgp,MRP1, MRP3， MRP5and GST-pi in human glioma.J Neurooncol,2005;74(2):113-121
9.赵文增,刘荣红,谢荣辉,孟繁杰,曹斌,王凤安. MRP1在大肠癌中表达的研究.河北医科大学学报,2008;29(4):519
10. Daood M, Tsai C, Ahdab-Barmada M, Watchko JF. ABC Transporter (P-gp/ABCB1,MRP1/ABCC1, BCRP/ABCG2) Expression in the Developing Human CNS.Neuropediatrics.2008;39(4):211-8
11. Teodori E, Dei S, Martelli C, Scapecchi S, Gualtieri F. The functions and structure ofABC transporters: implications for the design of new inhibitors of Pgp and MRP1tocontrol multidrug resistance (MDR). Curr Drug Targets.2006Jul;7(7):893-909.
12. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization,and single nucleotide polymorphisms of human ABCB1(MDR1), ABCC (MRP), andABCG2(BCRP) efflux transporters. Int J Toxicol.2006Jul-Aug;25(4):231-59.
13. Deeley RG, Cole SP. Substrate recognition and transport by multidrug resistanceprotein1(ABCC1). FEBS Lett.2006Feb13;580(4):1103-11. Epub2005Dec21.
14. Huang Y, Sadée W. Membrane transporters and channels in chemoresistance and-sensitivity of tumor cells. Cancer Lett.2006Aug8;239(2):168-82. Epub2005Oct5.
15. Conseil G, Deeley RG, Cole SP. Polymorphisms of MRP1(ABCC1) and relatedATP-dependent drug transporters. Pharmacogenet Genomics.2005Aug;15(8):523-33.
16. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein,MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol.2005May.1;204(3):216-37
17. Boumendjel A, Baubichon-Cortay H, Trompier D, Perrotton T, Di Pietro A.Anticancer multidrug resistance mediated by MRP1: recent advances in the discoveryof reversal agents. Med Res Rev.2005Jul;25(4):453-72.
18. Rappa G,Finch RA,Sartrelli AC,et al.New insights into the biology and pharmacologyof the multidrug resistance protein(MRP) from gene knockout models[J].BiochemPharmacol,1999;58(4):557-562.
19. Calatozzolo C,Gelati M,Ciusani E, et al.Expression of drug resistance proteins Pgp,MRP1, MRP3, MRP5and GST-pi in human glioma.J Neurooncol,2005;74(2):113-121.
20. Sharom FJ. ABC multidrug transporters: structure, function and role inchemoresistance. Pharmacogenomics.2008Jan;9(1):105-27.
21. Munoz M, Henderson M, Haber M, Norris M. Role of the MRP1/ABCC1multidrugtransporter protein in cancer. IUBMB Life.2007Dec;59(12):752-7.
22. Bakos E, Homolya L. Portrait of multifaceted transporter, the multidrugresistance-associated protein1(MRP1/ABCC1). Pflugers Arch.2007Feb;453(5):621-41. Epub2006Dec23.
23. Lin Y，Bai L，Chen W，et a1．The NF-κB activation pathways，emerging moleculartargets for cancer preven-tion and therapy[J]．Expert Opin Ther Targets，2010，l4(1)：45-55．
24. Baud V，Karin M．Is NF-kappaB a good target for cancer therapy?Hopes andpitfalls[J]．Nat Rev Drug Discov，2009，8(1)：33-40．
25. Sethi G，Sung B，Aggarwal BB．Nuclear factor-kappaB activation：from bench tobedside[J]．Exp Biol Med，2008，233f11：21-31．
26. Kriete A，Mayo KL．Atypical pathways of NF-kappaB acti-vation and aging[J]．ExpGerontol，2009，44(4)：250-255．
27. Muthusamy V，Piva TJ．The UV response of the skin：a review of the M APK，NFkappaB and TNFalpha signal transduction pathways[J]．Arch Dermatol Res，2010，302(1)：5-l7．
28. Phelps CB，Ghosh G．Discreet mutations from c-Rel to v-Rel alter kappaB DNArecognition， IkappaBalpha binding， and dimerization： implications for V-Reloncogenicity[J]．Oncogene，2004，23(6)：1229-1238．
29. Wei L，Liu J．Porcine circovirus type2replication is im-paired by inhibition of theextracellular signal--regulated ki-nase(ERK)signaling pathway[J]．Virology，2009，386(1)：203-209．
30.卓佳，陈柏坤，薛向阳，等．核因子NF-κB p65和I-cB-d在宫颈癌中的表达及意义『J]．温州医学院学报，2005，35(3)：182-l84．
31. Johmura Suzuki M，Osada S，et a1．FAD24，a regulator of adipogenesis and DNAreplication， inhibits H-RAS-mediated transformation by repressing NF-kappaBactivity[J]．Biochem Biophys Res Commun，2008，369(2)：464-470．
32. Reuter S，Charlet J，Juncker T，et a1．Efect of curcumin on nuclear factor kappaBsignaling pathways in human chronic myelogenous K562leukemia cells[J]．Ann N YAcad Sci，2009．117l(8)：436-447．
33. Yu C，Rahmani M，Conrad D，et a1．The proteasome inhibi-tor bortezomib interactssynergistically with histonedeacetylase inhibitors to induce apoptosis in Bcr／Abl+cellssensitive and resistant to STI571[J]．Blood，2003，102(10)：3765-3774．
34. Rangaswami H，Bulbule A，Kundu GC．Nuclear factor-induc-ing kinase plays acrucial role in osteopontin-induced M APK／IkappaBalpha kinase-dependent nuclearfactor kappaB-me-diated promatrix metalloproteinase-9activation[J]．J Biol Chem，2004，279(37)：3892l一38935．
35. Dahlman JM，Wang J，Bakkar N，et a1．The RelA／p65sub-unit of NF-κBspecifically regulates cyclin D1protein stability： implications for cell cyclewithdrawal and skeletal myogenesis[J]--1Cell Biochem，2009，106(1)：42-51．
36. Bentires-Alj M，Barbu V，Fillet M，et a1．NF-kappaB tran-scription factor inducesdrug resistance through MDR1expression in cancer cells[J]．Oncogene，2003，22(1)：9O一97．
37. Patel NM，Nozaki S，Shortle NH，et a1．Paclitaxel sensitiv-ity of breast cancer cellswith constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressorand parthenolide[J]．Oncogene，2000，19(36)：4159-4169．
38. Uetsuka H，Haisa M，Kimura M，et a1．Inhibition of inducible NF-κB activityreduces chemoresistance to5-fluorouracilin human stomach cancer cell line[J]．ExpCell Res，2003，289(1：27-35．
39. Wang X，Omura S，Szweda LI，et a1．Rapamycin inhibits proteasome activatorexpression and proteasome activity [J]．Eur J lmmunol，1997，27(11)：278l一2786．
40. Aggarwal BB Shishodia S Takada et a1．Curcumin suppresses the paclitaxel-inducednuclear factor-kappaB path-way in breast cancer in nude mice[J]．Clin Cancer Res，2005，l1(20)：7490-7498．
41. Sweeney CJ，Mehrotra S，Sadaria M R，et a1．The sesquiter-pene lactone parthenolidein combination with docetaxel reduces metastasis and improves survival in axenograft model ofbreast cancer[J]．Mol CancerTher，2005，4(6)：1004-1012．
42. Farhana L，Dawson M I，Fontana JA．Apoptosis induction by a ovel retinoid-relatedmolecule requires nuclear factor-kappaB activation[J]．Cancer Res，2005，65(11)：4909-4917．
43.沈利群，徐祥，梁华平，等．NF-κB p50业基同源结构域相互作用多肽的筛选『J1．细胞与分子免疫学杂志，2007，23(9)：804-806．
44.李生茂，梁华平，徐祥，等．NF-κB p50和p65蛋白保守结构域原核表达系统的建立fJ1．第三军医大学学报，2004，26(10)：878-881．
45.徐祥，梁华平，郑江，等．p65结合肽与p65的亲和力检测及其对NF-κB DNA结合活性抑制作用的鉴定.．第三军医大学学报，2006，28(7)：621-625．
46. Morris M J，Kelly W K，Slovin S，et a1．A phase I1trial of bortezomib and prednisonefor castration resistant metastatic prostate cancer[J]．J Urol，2007，178(6)：2378-2383
47.周伟民，金培英，平金良，等．硼替佐米抑制核因子-κB活化对LOVO细胞增殖的影响『J1．温州医学院学报，2010，40(2)：156-159．
48. Lee CH，Jeon YT，Kim SH，et a1．NF-κB as a potential molecular target for cancertherapy[J]．BioFactors，2007，29(1)：19-35．
49. Shibata T．Ohta T．Tong KI,et al. Cancer related mutations in NRF2impair itsrecognition by Keapl-Cul3E3ligaseand promote malignancy，Proc Natl Acad SciUSA，2008，105(36)：l3568一l3573
50. Dinkova-Kostova AT．Holtzclaw WD，Cole RN，et a1．Direct evidence that sulfhydrylgroups of Keap1are the sensors regu-lating induction of phase2enzymes that protectagainst car-cinogens and oxidants，Proc Natl Acad Sci USA，2002，99(18)：l1908-11913
51. Singh A，M isra V，Thimm ulappa RK，et a1．Dysfunctional KEAP1一NRF2interaction in non．small-cell lung cancer．PloS Med，2006，3(10):e420
52. M inerva RG，Kwak MK，Dolan PM，el af．Sensitivity to carcinogenesis is increasedand chemoprotective efficacy of enzyme inducers is lost in nrf2transcriptionfactor-deficient mice，Proc Nat Acad Sci USA，200l，98(6)：3410．3415
53. Morimitsu Y，Nakagawa Y，Hayashi K，et a1．A sulforaphane analogue that potentlyactivates the Nrf2-dependent detoxifi-cation pathway，J Biol Chem，2002，277(5)：3456-3463
54. Lee JM， Calkins MJ， Chan K， et a1． Identmcation of the NF-E2-relatedfactor-2-dependent genes conferring protection againstoxidative stress in primarycortical astrocytes using oligonucle-otide microaray analysis，J Biol Chem，2003，278(14)：12029-12038
55. Thimmulappa RK，Mai KH，Srisuma S，et a1．Identification of Nrf2一regulated genesinduced by the chemopreventive agent sulfo raphane by o1igonucleOtide microarray，Cancer Res，2002，62(181：5196-5203
56. Lee JS，Surh YJ．Nrf2as a novel molecular target for chemoprevention，Cancer Lett，2005，224(2)：171-184
57. Nguyen T，Sherratt PJ，Pickett CB．Regulatory mechanisms controlling geneexpression mediated by the antioxidant response element，Annu Rev PharmacolToxicol，2003，43：233-26O
58. Wakabayashi N，Dinkova-Kostova AT，Holtzclaw W D，et a1．Protection againstelectrophile and oxidant stress by induction of the phase2response：fate of cysteinesof the Keap1sensor modified by inducers，Proc Natl Acad Sci USA，2004，101(7)：2040-2045
59. Zipper LM．M ulcahy RT．The Keapl BTB／POZ dimerization function is requiredto sequester Nrf2in cytoplasm，J Biol Chem，2002，277(39)：36544-36552
60. Padm anabhan B，Tong KI，Ohta T，et a1．Structural basis for defects of Keapl activityprovoked by its point mutations in lung cancer，Mol Cell，2006，21(5)：689-700
61. Frohlich DA，M ccabe M T，Am old RS，et a1．The role of Nrf2in increased reactiveoxygen species and DNA damage in prostate tumorigenesis，Oncogene，2008，27(31)：4353-4362
62. Itoh K，W akabayashi N，Katoh Y，et a1．Keapl represses nuclear activation ofantioxidant responsive elements by Nrf2through binding to the amino-terminal Neh2domain，Genes Dev，1999，13(1)：76-86
63. Stacy DR，Ely K，M assion PP，el a1．Increased expression of nuclear factor E2p45一related factor2fNRF2)in head and neck squamous cell carcinomas，Head Neck，2006，28(9)：813-818
64. Kim JH，Bogner PN，Ranmath N，el a1．Elevated peroxiredoxin1．but notNF-E2-related factor2．is an independent prognostic factor for disease recurrence andreduced survival in stage I non-small cell lung cancer，Clin Cancer Res，2007，13(13)：3875-3882
65. Cho JM，Manandhar S，Lee HR，et a1．Role of the Nrf2-antioxidant system incytotoxicity mediated by anticancer cisplatin：im plication to cancer cell resistance，Cancer Lett，2008．260(1-21：96-1O8
66. Tarumoto T，Nagai T，Ohmine K，et a1．Ascorbic acid restores sensitivity to imatinibvia suppression of Nrf2一dependent gene expression in the im atinib-resistant cellline，Exp Hematol，2004，32(4)：375-381
67. Girard L，Zochbauer-Muller S，Virmani AK，et a1．Genome-wide allelotyping of lungcancer identifies new regions of allelic loss，differences between small eell lungcancer and non-small eell lung cancer，and loci clustering，Cancer Res，2000，60(17)：4894．4906
68. Soini Y，Nap~nkangas U，J~irvinen K，el a1．Expression of t-glutamyl cysteinesynthetase in nonsmall cell lung carcinoma，Cancer，2001，92(11)：2911-2919
69. Sahoo SK，Sawa T，Fang J，et a1．Pegylated zinc protoporphyrin：a water-solubleheine oxygenase inhibitor with tum or-targeting capacity，Bioconjug Chem，2002，13(5)：1031-1038
70. Tanaka S，Akaike T，Fang J，et a1．Antiapoptotic effect of haem oxygenase-1inducedby nitric oxide in experimental solid tumour，Br J Cancer，2003，88(6)：902-909
71. Fang J，Sawa T，Akaike T，et a1．In vivo antitumor activity of pegylated zincprOtOpOrphyrin：targeted inhibition of heme oxygenase in solid tumor，Cancer Res，2003，63(13)：3567-3574
72. Kim HR，Kim S，Kim EJ，et a1Suppression of Nrf2-driven heme oxygenase-1enhances the chemosensitivity of lung cancer A549cells toward cisplatin，LungCancer，2008，60(1)：47-56
73. Loboda A，Was H，Jozkowicz A，et a1．Janus face of Nrf2一Ho一1axis in cancer--f iend in chemoprevention．foe in anticancer therapy，Lung Cancer，2008，60(1)：1-3
74. Logsdon CD，Simeone DM，Binkley C，et a1．Molecular profiling of pancreaticadenocarcinoma and chronic pancreatitis identifies multiple genes differentiallyregulated in pancreatic cancer，Cancer Res，2003，63(10)：2649-2657
75. Brar SS，Kennedy TP，Whorton AR，et a1．Reactive oxygen species from NAD(P)H：quinone oxidoreductase constitutively activate NF-κB in malignant melanomacells．Am J Physiol CeII Physiol，2001，280(3)：C659一C676
76. Deng HB，Parekh HK，Chow KC，et a1．Increased expression of dihydrodioldehydrogenase induces resistance to cisplatin in human ovarian carcinoma cells，JBio，Chem，2002，277(17)：15035-15043
77. Ohara H，Miyabe Y，Deyashiki Y，et a1．Reduction of drug ketones by dihydrodioldehydrogenases，carbonyl reductase and aldehyde reductase of human liver，BiochemPharmacol，1995，5O(2)：221-227
78. Ax W，Soldan M，Koch L，et a1．Development of daunorubicin resistance in tumourcells by induction of carbonyl reduction，Biochem Pharmacol，2000，59(3)：293-300
79. Hsu NY，Ho HC，Chow KC，et a1．Overexpression ofdihydrodiol dehydrogenase asa prognostic marker of non-small cell lung cancer，Cancer Res，2001，61(6)：2727-2731
80. Ciaccio PJ，Jaiswal AK，Tew KD．Regulation of human dihydrodiol dehydrogenaseby Michael acceptor xenobiotics，J Biol Chem，1994，269(22)：15558-15562
81. Palackal NT，Lee SH，Harvey RG，et a1．Activation of polycyclic aromatichydrocarbon trans-dihydrodiol proximate carcinogens by human aldo-ketoreductase(AKR1C)enzymes andtheir functional overexpression in human lungcarcinoma(A549)cells，J BioZ Chem，2002，277(27)：24799-24808
82. Courehesne WE，Kunisawa R，Thomer J．A putative protein kinase over_comespheromome-induced arrest of cell cycling in S．cerevisiae[J]．Cell，1989；58：1107-1119．
83. Boulton TG，Nye SH，Robbins DJ。et a1．ERKs：a family of protein-serineVthreoninekinases that are activated and tyrosine phosphorylated in response in insulin andNGF[J]．Cell，1991；65：663-675．
84. Ahn NG。Krebs EG．Evidence for all epidermal growth fact0r～stimu1ated proteinkinase cascade in Swiss333cells．Activation of serine peptide kinase activity bymyelin basic pmteln kiuases in vitro[J]．J Biol Chem，1990；265：11495-11501．
85. Rossomando AJ，Payne DM，weber MJ，et．Evidence that vo42，a major tyrosinekinase target protein，is a mitogen-activated sefine／threonine protein kinase[J]．ProcNatl Acad Sci USA，1989；86：6940-6943．
86. Widmann C，Gisbon S，Jarpe B，et a1．Mitogen-activated protein kinase：conservationof a three-kinase module from yeast to human[J]．Phys Rev，1999；79：143-180．
87. Momon DK．The Raf一1kinaseas atrallsduaer ofIIlito c8i目[J]．Cancer Ceas，1990；2：377．
88. Wittingho for A Nass N．How Ras-related proteinstalktotheir efec-tor[J]．TIBS，1996；21(2)：488．
89. Bokemer D，Sorokin A，Dunn MJ．Multiple intercellular MAP kinase signalingcascades[J]．K／dney／nt，1996；49：1187．
90. Ferrcll JE.Bhatt RR． Mechanistic studies of the dual phosphorylation ofmitogen-activated protein kinase[J]．J Biol Chem。1997；272：19008-19016．
91.丁桂霞，张爱华，陈荣华．Ras／Raf／ERK信号传导通路在肾脏疾病中作用的研究进展[J]．国外医学儿科学分册。2000；27(5)：231-235．
92.卢建，余应年，许仁宝．受体信号转导系统与疾病[M]．济南：山东科学技术出版社。2001：pp253．
93. Mihenger ill，Conner J。Famham PJ．An inhibitory Raf一1mutant suppressesexpression of a subset of v-raf-activated genes[J]．J Biol Chem。1993；268：15674-15680．
94. Pages G。Lenorrnand P。LAllemain G，et a1．Mitegen-activated protein kinases042mapk and044mapk are required for fibroblast proliferation [J]．Proc Ned Acid SciUSA。1993；90：8319-8323．
95. Wang LM，Keegan AD，Paul WE，et a1．IL-4activates a distinct Rjgnal tmnsducfioncascade from IL一3in factor-dependent myeloid cells [J] EMBO J，1992；11：4899-4908．
96. CasiLlas AM，Amaral K，Chegini-Farahani S，et a1．Okadaic acid acti．rates042mitogen-activated protein kinases(MAP kinase；ERK一2) in B-lymphocytes butinhibits rather than augments eelular proliferatlon：contrast with phorbol12一myrlstate13一acetate[J]．Biochem J，1993；290：545-550．
97. Qui MS。Green SH．PC12cell neuronal diferentiation is associated with prolongedp21ras activity and consequent prolonged ERK activity l J J．Neuron，1992；9：705-717．
98. Traverse S，Gomez N，Paterson H，et a1．Sustained activation ofthe mitogen-activatedprotein(MAP)kinase caseilde may be required for diferentiation of PC12cells：comparison of the efects of nerve growth factor and epidermal growthfactor[J]．Bioehem J，1992；288；351-355．
99. Dikie I，Sehlessinger J，Lax Irit．PC12cells overexpressing the insulin receptorundergo insulin-dependent neuronal diferentiation[J] Curr Biol19944：702-708．
100.Verlhac MH。de Pennart H，Maro B，et a1．MAP kinase bec0me88tablv activated atmetaphase and is associated with micmmbule-organifing centers during meioticmaturation of mouse oocytes[J]．Dev Biol，1993；158：330-340．
101.WangItG，Miyashima T,Takayama S，et a1．Apoptosis regulation byin-teraction of Bcl一2protein and Rat"一1kinase[J]．Orwogen，1994；9：2751．
102.Blogoskonny MV，Sehulte T，Nguyen P，et al。Taxol-induced apoptosis andphophorylation of Bcl一2protein involves c-Raf一1and repre．sents a novel e-Raf-Isignal transduction pethway[J]．Cancer Res，1996；56：1851．
103.Wmabe M，Masuda YS，Nakajo Y．vt a1．The cooperative interaction of twodiferential signaling pathway in response to bufalin induced apoptosis in humanleukaemia U937cells[J]．J Biol Chem，1996；271(24)：14067．
104.Guo X，Ma N，Wang J，Song J，Bu X，ChengY，et a1．Increased p38-MAPK isresponsible for chemotherapy resistan ce in human gastric cancer cells[J]．BMCCancer，2008，8(1)：375~84．
1. JZ Wu, ZQ Situ, ZB Liu et al. Selection and characterization of a highly metastaticcell clone from mucoepidertmoid carcinoma cell line derived from human salivarygland. Chin J Dental Res1998;1:71
2.缪叶，秦楠，李焰，刘峰，吴军正*。高转移人涎腺黏液表皮样癌耐药细胞系的建立及其生物学特性。实用口腔医学杂志,2009；25(3)：340-343。
3. Snow K,Judd W. Characterisation of adriamycin and amsacrine2resistant humanleukaemic T cell lines[J]. Br J Cancer,1991,63(1):17228.
4. Derek Kofi o，Boahene，Kerry D，et a1．M ucoepidermoid Carci-noma of theParotid Gland：The Mayo Clinic ExperienceEJ]．Arch Otolaryngol Head Neck Surg，2004，130：849-856
5.王益华．涎腺粘液表皮样癌78例临床分析rj]．局解手术学杂志，2010：477-478
6. Cherry S，Silverman N．Host-pathogen interactions in drosophila：new tricks from allold friend[J]．Nat lmm,mol，2OO6，7(9)：911-917．
7. Obbard DJ，Jiqqins FM，Halliqan DL，et a1．Natural Selection drives extremely rapidevolutionin antiviralRNAi genes[J]．CurtBiol，2006，16(6)：580-585．
8. CarusoR，PaUoneF，FirmD，ct a1．Pmtease-activated receptor-2activation in gastricaaIlcer cells promotes epidermal growth factor receptor transactivation andproliferation[J]．Am J Pathol，2006，169(1)：268-278．
9. Li GH，Wei H，Chen ZT，et a1．STAT3silencing with lentivirus inhibits growth andinduces apoptosis and diferentiation of U251cells[J]．J Neurooncol，2009，91(2)：165-174．
10. Chen XL，Cao LQ，She MR，et a1．Gli一1siRNA induced apoptosis in Huh7cens[J]．World J Gastroenterol，2008，14(4)：582-589．
11. Liu JN，Gao YD，Wang JH， ct aJ． Construction and expression of diabody[CD3P-gp without Etag．Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi，2007，23：946-949．
12. Li L' Ma LL， Gao P， et a1． Reve~al ofmuhidrug resistance of MCF一7／ADRin nude mice by grape seed polypheno1． ZhonghHa Waike Zazhi，2004，42：795-798．
13. Dignam JD， Lebovitz RM， Roeder RG． Accurate transcription initiation by RNApolymerase II in a soluble extract from isolated mammalian nuclei．Nucleic AcidsRes，1983，11：1475-1489．
14. Norgaard JM，Olesen LH，Hokland P．Changing pigture of cellular drug resistance inhuman leukemia． Crit Rev Oncol Hematol，2004，50：39-49．
15. Nooter K， Sonneveld P． Clinical relevance of p-glycoprotein expression inhaematolog／cal malignancies．Leukemla Research．I994．18：233．
16. Farhana L，Dawson M I，Fontana JA．Apoptosis induction by a ovel retinoid-relatedmolecule requires nuclear factor-kappaB activation[J]．Cancer Res，2005，65(11)：4909-4917．
17. Morimitsu Y，Nakagawa Y，Hayashi K，et a1．A sulforaphane analogue that potentlyactivates the Nrf2-dependent detoxifi-cation pathway，J Biol Chem，2002，277(5)：3456-3463
18. Lee JM， Calkins MJ， Chan K， et a1． Identmcation of the NF-E2-relatedfactor-2-dependent genes conferring protection againstoxidative stress in primarycortical astrocytes using oligonucle-otide microaray analysis，J Biol Chem，2003，278(14)：12029-12038
19. Wang XJ，Sun Z。Villeneuve NF，et a1．Nrf2enhances resistance of cancer cells tochemotherapeutic drugs，the dark side of Nrf2[J]．Carcinogenesis，2008，29(6)：1235—1243．
20. Kim HR，Kim s，Kim EJ，et a1．Suppression of Nrf2-driven heineoxygenase-1enhances the chemosensitivity of lung cancer A549cellstowardcisplatin[J]．LungCancer，2008，60(1)：47—56．
21. Kim SK。Yang JW，Kim MR，et a1．Increased expression of Nrf2／ARE-dependentanti—-oxidant proteins in tamoxifen-。resistant breast cancereeHs[J]．Free Radic BiolMed，2008，45(4)：537—546．
22. Kobayashi A，Ohta T，Yamamoto M．Unique function of the Nrf2-keapl pathway inthe inducible expression of antioxidant and detoxifyingenzynmes[J]． MethodsEnzymol，2004，378：273—286．
23. Zhang DD．Mechanistic studies of the Nrf2-Keap1signaling pathway[J]．Drug MetabRev，2006，38(4)：769-789．
24. Sun Z，Zhang S，Chan JY，et a1．Keap1controls postinduction repression of the Nrf2一mediated antioxidant response by escorting nuclear export ofNrf2[J]．MolCellBiol，2007，27(18)：6334-6349．2331-2337．
25. Thimmulappa RK，Mai KH，Srisuma S，et a1．Identification of Nrf2一regulated genesinduced by the chemopreventive agent sulfo raphane by o1igonucleOtide microarray，Cancer Res，2002，62(181：5196-5203
26. Lee JS，Surh YJ．Nrf2as a novel molecular target for chemoprevention，Cancer Lett，2005，224(2)：171-184
27. Nguyen T，Sherratt PJ，Pickett CB．Regulatory mechanisms controlling geneexpression mediated by the antioxidant response element，Annu Rev PharmacolToxicol，2003，43：233-26O
28. Wakabayashi N，Dinkova-Kostova AT，Holtzclaw W D，et a1．Protection againstelectrophile and oxidant stress by induction of the phase2response：fate of cysteinesof the Keap1sensor modified by inducers，Proc Natl Acad Sci USA，2004，101(7)：2040-2045
29. Bokemer D，Sorokin A，Dunn MJ．Multiple intercellular MAP kinase signalingcascades[J]．K／dney／nt，1996；49：1187．
30. Ferrcll JE.Bhatt RR． Mechanistic studies of the dual phosphorylation ofmitogen-activated protein kinase[J]．J Biol Chem。1997；272：19008-19016．
31.丁桂霞，张爱华，陈荣华．Ras／Raf／ERK信号传导通路在肾脏疾病中作用的研究进展[J]．国外医学儿科学分册。2000；27(5)：231-235．
32. Mihenger ill，Conner J。Famham PJ．An inhibitory Raf一1mutant suppressesexpression of a subset of v-raf-activated genes[J]．J Biol Chem。1993；268：15674-15680．
33. Pages G。Lenorrnand P。LAllemain G，et a1．Mitegen-activated protein kinases042mapk and044mapk are required for fibroblast proliferation [J]．Proc Ned Acid SciUSA。1993；90：8319-8323．
34. Wang LM，Keegan AD，Paul WE，et a1．IL-4activates a distinct Rjgnal tmnsducfioncascade from IL一3in factor-dependent myeloid cells [J] EMBO J，1992；11：4899-4908．
35. CasiLlas AM，Amaral K，Chegini-Farahani S，et a1．Okadaic acid acti．rates042mitogen-activated protein kinases(MAP kinase；ERK-2) in B-lymphocytes but inhibitsrather than augments eelular proliferatlon： contrast with phorbol12-myrlstate13-acetate[J]．Biochem J，1993；290：545-550．
36. Cole SPC，BhadmaiG，Gedash Jn，et a1．Overexpresaiott of a transporter gene in8muhidrug resistant human lung tiniest cellline[j]．Science，1992，258：1650．
37. J Barrad MA，Broxtterrnan I-IJ，Wri t KA，et a1． Imnmnodetection of a190KdProtein non-P-glyeoprotein–conning MDR celia derived from small cell and non—small—cell lung tumors[J]．Br J Cancer.1992。65：21．
38. Jedlitschky G，Leier I，Buehhck U，et a1．ATP—dependent transport of glutathioneS-conjugaes by the multidrug resistance-associated protein [J]．Cancer R，1994，54：4833．
39. Lin HL，I WY，uu TY，et a1．Rever．l of Taxd resistance in hepatoma by cy-closporinA： involvement of the PI-3knase—AKT1pathway[J]．Br J Cancer，2003，88(6)：973—980．
40. Gallego, M.A., et al., Apoptosis-inducing factor determines the chemoresistance ofnon-small-cell lung carcinomas. Oncogene,2004.23(37):6282-91.
41. Boujrad H, Gubkina O, Robert N, Krantic S, Susin SA. AIF-mediated programmednecrosis: a highly regulated way to die. Cell Cycle.2007Nov1;6(21):2612-9.
42. Fok JY, Mehta K. Tissue transglutaminase induces the release of apoptosis inducingfactor and results in apoptotic death of pancreatic cancer cells. Apoptosis.2007Aug;12(8):1455-63
43. Millan A, Huerta S Apoptosis-inducing factor and colon cancer. J Surg Res.2009Jan;151(1):163-70.
44. Joza N, Pospisilik JA, Hangen E, Hanada T, Modjtahedi N, Penninger JM, Kroemer G.AIF: not just an apoptosis-inducing factor. Ann N Y Acad Sci.2009Aug;1171:2-11.
45. Lorenzo HK, Susin SA. Therapeutic potential of AIF-mediated caspase-independentprogrammed cell death. Drug Resist Updat.2007Dec;10(6):235-55.
46. Yang X, Fraser M, Abedini MR, Bai T, Tsang BK. Regulation of apoptosis-inducingfactor-mediated, cisplatin-induced apoptosis by Akt. Br J Cancer.2008Feb26;98(4):803-8.
47. Gallego MA, Ballot C, Kluza J, Hajji N, Martoriati A, Castéra L, Cuevas C,Formstecher P, Joseph B, Kroemer G, Bailly C, Marchetti P. Overcomingchemoresistance of non-small cell lung carcinoma through restoration of an AIF-dependent apoptotic pathway. Oncogene.2008Mar27;27(14):1981-92. E
48.陶虹等, p53基因对人肺癌细胞系耐药性的影响.中国肺癌杂志,2008.11(2):157-164.
49. Lee, Y.S., et al., Influence of p53expression on sensitivity of cancer cells tobleomycin. J Biochem Mol Toxicol,2010.
50. Gómez-Raposo C, Mendiola M, Barriuso J, Hardisson D, Redondo A. Molecularcharacterization of ovarian cancer by gene-expression profiling. Gynecol Oncol.2010May1.[Epub ahead of print]
51. Simon R. Challenges of microarray data and the evaluation of gene expression profilesignatures. Cancer Invest.2008May;26(4):327-32.
52. Surowiak P. Prediction of the response to chemotherapy in ovarian cancers..FoliaMorphol (Warsz).2006Nov;65(4):285-94.
53. Voduc D, Kenney C, Nielsen TO. Tissue microarrays in clinical oncology. SeminRadiat Oncol.2008Apr;18(2):89-97.
54. Wu Junzheng,Situ Zhengqiang,Chen Jianyuan et al. Chemosensitivity of salivarygland and oral cancer. cell lines. Chin Med J,1992;105:1026
55. Tilesi F, Fradiani P, Socci V, Willems D, Ascenzioni F Design and validation ofsiRNAs and shRNAs. Curr Opin Mol Ther.2009Apr;11(2):156-64.
56.徐叔云主编.临床药物学.人民卫生出版社.第3版.2004年7月.北京.448-455页
57. Snow K,Judd W.Characterisation of adriamycin and amsacrine-resistant humanleukaemic T cell lines[J].Br J Cancer,1991;63(1):17-28.
58. Tsujimoto S, Fujimoto K, Okajima E, Ozono S, Okajima E, Hirao Y5-Fluorouracilincorporated into the tissue RNA of human and rat bladder carcinoma afteradministration of1-(2-tetrahydrofuryl)-5-fluorouracil combined with uracil. Int J ClinOncol.2008Apr;13(2):138-43.
59. Bhattacharya S, Mariani TJ. Array of hope: expression profiling identifies diseasebiomarkers and mechanism. Biochem Soc Trans.2009Aug;37(Pt4):855-62.
60. Zhang JT. Use of arrays to investigate the contribution of ATP-binding cassettetransporters to drug resistance in cancer chemotherapy and prediction ofchemosensitivity. Cell Res.2007Apr;17(4):311-23.
61. Ness SA. Microarray analysis: basic strategies for successful experiments. MolBiotechnol.2007Jul;36(3):205-19.
62. Wang TH, Chao A. Microarray analysis of gene expression of cancer to guide the useof chemotherapeutics. Taiwan J Obstet Gynecol.2007Sep;46(3):222-9.
63. Ivanov, S., et al., Expression of hypoxia-inducible cell-surface transmembranecarbonic anhydrases in human cancer. Am J Pathol,2001.158(3): p.905-19.
64. Pastorekova, S., et al., Carbonic anhydrases: current state of the art, therapeuticapplications and future prospects. J Enzyme Inhib Med Chem,2004.19(3): p.199-229.
65. Loncaster, J.A., et al., Carbonic anhydrase (CA IX) expression, a potential newintrinsic marker of hypoxia: correlations with tumor oxygen measurements andprognosis in locally advanced carcinoma of the cervix. Cancer Res,2001.61(17):p.6394-9.
66. Kim, J.Y., et al., Tumor-associated carbonic anhydrases are linked to metastases inprimary cervical cancer. J Cancer Res Clin Oncol,2006.132(5): p.302-8.
67. Lee, S., et al., Tumor carbonic anhydrase9expression is associated with the presenceof lymph node metastases in uterine cervical cancer. Cancer Sci,2007.98(3): p.329-33.