Keap1对人非小细胞肺癌生长的影响及其机制研究
摘要
在非小细胞肺癌A549、H460细胞株中,由于Keap1基因突变使Nrf2基因过表达,导致A549、H460细胞获得生存优势,并对抗肿瘤药物产生了耐药性,尤其是多药耐药性。我实验室曲丽艳等将野生型mKeap1-pEGFP基因转染非小细胞肺癌A549细胞后,经筛选得到稳定表达Keap1的A549-mKeap1-pEGFP细胞株,体外实验发现其Nrf2及其调控基因HO-1、NQ01等的表达显著降低,使抗肿瘤药物顺铂、奥沙利铂等对此细胞株的抗增殖作用增强。目前有关此细胞株的在体实验尚未见报道。目的：建立Keap1基因过表达的非小细胞肺癌细胞株裸鼠皮下移植瘤模型,观察不同细胞株的成瘤性和生长差异。方法：本文第一部分,探索以非小细胞肺癌不同细胞株建立裸鼠移植瘤模型的可靠方法,包括改变细胞的数量以及采用裸鼠移植瘤瘤块组织接种的方法,并同时验证前面有关Keap1与非小细胞肺癌细胞生长差异的关系的观点。本文第二部分,将野生型Keap1基因过表达的细胞株A549-mKeap1-pEGFP与对照细胞株A549-pEGFP接种于Balb/c无胸腺裸鼠皮下,观察记录二者所形成移植瘤的生长情况和成瘤性差异。结果：[1]野生型Keap1过表达的A549-mKeap1-pEGFP细胞株与A549-pEGFP细胞株相比,细胞增殖程度、在裸鼠体内成瘤性等均降低,二者之间有显著性差异。[2]成功地以裸鼠移植瘤瘤块移植等方法建立A549、H460细胞株裸鼠移植瘤模型,成瘤率较高,成瘤较快且肿瘤均一性较好。结论：Keap1基因过表达对非小细胞肺癌的增殖和在裸鼠体内的生长具有抑制作用。
In the non-small cell lung carcinoma(NSCLC) A549 and H460 cell lines, mutations in Keapl genes resulted in over-expression of the transcription factor Nrf2 in cells, which could provide much survival advantage to the cell lines, and, potent resistance to anti-cancer drugs as well, particularly the Multi- Drug Resistance (MDR), a focus concern of many scientific research nowadays. My colleagues Qu Liyan etc. have set up a Keapl-over-expressed cell line of A549 (A549-mKeap1-pEGFP) and its counterpart cell line A549-pEGFP. The former has a much less expression of Nrf2 and its related genes such as HO-1, etc. Furthermore, it is more sensible to the anti-proliferative effects of Cisplatin and Oxaliplatin. Hitherto, no in vivo reports about the cell lines have been published yet. Purpose:To establish xenograft tumor models in Balb/c Nude mice subcutaneously,with A549-mKeap1-pEGFP cell line and A549-pEGFP cell line (as a control) and to compare the difference of their growth and proliferation. Method:In the 1st part of the paper, we established xenograft models of the two A549 cell lines by injecting the cultured cells subcutaneously in flanks of each Nude mice, and searched suitable protocol to do that,by using different numbers of cells,and also by transplanting pieces of xenograft tumors subcutaneously in Nude mice, after a mouse with a xenograft tumor was sacrificed and the tumor was removed and cut into small pieces. In the 2nd part of the paper, we established xenograft models of the Keapl-overexpressed A549 cell lines in Nude mice, and investigated the role of Keapl genes in the growth of the cell lines.Results:1.The A549-mKeapl-pEGFP cell line is less proliferative and, as a result, is more difficult to form xenograft models in Nude mice compared to its counterpart A549 -pEGFP cell line.The difference was also showed by the characteristics of the tumor sections.2. It is convinient to establish xenograft models aforementioned by transplanting tumor pieces subcutaneously in Nude mice. Conclusions:1. The expression level of Keapl in the A549 cell line go inversely to the proliferation, growth rate and ability to form xenograft models in Nude mice.
In the non-small cell lung carcinoma(NSCLC) A549 and H460 cell lines, mutations in Keapl genes resulted in over-expression of the transcription factor Nrf2 in cells, which could provide much survival advantage to the cell lines, and, potent resistance to anti-cancer drugs as well, particularly the Multi- Drug Resistance (MDR), a focus concern of many scientific research nowadays. My colleagues Qu Liyan etc. have set up a Keapl-over-expressed cell line of A549 (A549-mKeap1-pEGFP) and its counterpart cell line A549-pEGFP. The former has a much less expression of Nrf2 and its related genes such as HO-1, etc. Furthermore, it is more sensible to the anti-proliferative effects of Cisplatin and Oxaliplatin. Hitherto, no in vivo reports about the cell lines have been published yet. Purpose:To establish xenograft tumor models in Balb/c Nude mice subcutaneously,with A549-mKeap1-pEGFP cell line and A549-pEGFP cell line (as a control) and to compare the difference of their growth and proliferation. Method:In the 1st part of the paper, we established xenograft models of the two A549 cell lines by injecting the cultured cells subcutaneously in flanks of each Nude mice, and searched suitable protocol to do that,by using different numbers of cells,and also by transplanting pieces of xenograft tumors subcutaneously in Nude mice, after a mouse with a xenograft tumor was sacrificed and the tumor was removed and cut into small pieces. In the 2nd part of the paper, we established xenograft models of the Keapl-overexpressed A549 cell lines in Nude mice, and investigated the role of Keapl genes in the growth of the cell lines.Results:1.The A549-mKeapl-pEGFP cell line is less proliferative and, as a result, is more difficult to form xenograft models in Nude mice compared to its counterpart A549 -pEGFP cell line.The difference was also showed by the characteristics of the tumor sections.2. It is convinient to establish xenograft models aforementioned by transplanting tumor pieces subcutaneously in Nude mice. Conclusions:1. The expression level of Keapl in the A549 cell line go inversely to the proliferation, growth rate and ability to form xenograft models in Nude mice.
引文
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[5]J.D. Hayes, M. McMahon.Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention[J], Cancer Lett,2001,174,103-113.
[6]Kobayashi A, Ohta T, Yamamoto M.Unique function of the Nrf2-keapl pathway in the inducible expression of antioxidant and detoxifying enzynmes[J]. Methods Enzymol,2004,378,273-286.
[7]Y.-J. Surh.Cancer chemoprevention with dietary phytochemicals[J], Nature Rev Cancer,2003, 3(10):768-80.
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[13]Wen Qing-lian,Wu Jing-bo,Fan Juan,et al(文庆莲,吴敬波,范娟等)Comparing of the Methods for Estabilishment on Human Nasopharyngeal Carcinoma Xenografts under the Skin of Mude Mice [J]. CANCER RESEARCH ON PREVENTION AND TREATMENT(肿瘤防治研究),2007,34(3):229-230 (in Chinese).
[14]Rygaard J, Povlsen C. O. Heterotransplantation of a human malignant tumor to nude mice[J]. Act Path Microbiol Scand,1969(77):758-760.
[15]Singh A, Boldin-Adamsky S, Thimmulappa RK,et al.RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy [J]. Cancer Res,2008,68,7975-7984.
[16]C.J. Harvey.Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress[J]. Free Radic Biol Med,2009,46(4):443-453.
[17]Liao Mei-yan,Zhou Yun-feng,Feng mao-hui,et al(廖美焱,周云峰,冯茂辉等).Establishment of a high-implanted human lung cancer model in nude mice. [J]. CHINESE JOURNAL OF EXPERIMENTAL SURGERY(中华实验外科杂志),2009,26(9)：1216-1217(in Chinese).
[18]Xu C, Huang MT, Shen G, et al. Inhibition of 7,12-Dimethylbenz[a] anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor2[J]. Cancer Res 2006,66,8293-6.
[19]Zheng Sun, Donna D. Zhang. Keapl Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2[J]. MOL. CELL. BIOL,2007,27 (18):6334-6349.
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[2]J.T. Wilkinson, M.L. Clapper.Detoxication enzymes and chemoprevention[J], Proc. Soc. Exp. Biol. Med,1997,216,192-200.
[3]John D. Hayes, Michael McMahon, Sudhir Chowdhry, et al. Dinkova-Kostova Cancer Chemoprevention Mechanisms Mediated Through the Keap1-Nrf2 Pathway[J]. ANTIOXIDANTS & REDOX SIGNALING,2010,13,1713-48.
[4]Qu Li-yan,Gao Peng,Wang Hong-yan,et al(曲丽艳,高鹏,王洪燕等).Nrf2 down-regulated cell line H460-N5 with Keapl over-expression increased sensitivity to anti-cancer drugs [J].Journal of Zhejiang University(Medical Sciences)(浙江大学学报医学版),2010,39(1)：6-10(in Chinese).
[5]J.D. Hayes, M. McMahon.Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention[J], Cancer Lett,2001,174,103-113.
[6]Kobayashi A, Ohta T, Yamamoto M.Unique function of the Nrf2-keapl pathway in the inducible expression of antioxidant and detoxifying enzynmes[J]. Methods Enzymol,2004,378,273-286.
[7]Y.-J. Surh.Cancer chemoprevention with dietary phytochemicals[J], Nature Rev Cancer,2003, 3(10):768-80.
[8]Mi-Kyoung Kwak, Nobunao Wakabayashi, Thomas W. Kensler. Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers[J]. Mutation Research,2004,555, 133-148.
[9]Spiro SG, Silvestri GA.The treatment of advanced non-small cell lung cancer[J]. Curr Opin Pulm Med,2005,11,287-291.
[10]Chiu. F.L, Lin, J.K. Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts[J]. Prostate,2008,68,61-71.
[11]Shi RX, Ong CN, Shen HM.Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells[J]. Oncogene,2004,23,7712-7721.
[12]Ranxin Shi. Luteolin sensitizes the anticancer effect of cisplatinVia c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization[J]. Mol. Cancer Ther 2007,6,1338-1347.
[13]Wen Qing-lian,Wu Jing-bo,Fan Juan,et al(文庆莲,吴敬波,范娟等)Comparing of the Methods for Estabilishment on Human Nasopharyngeal Carcinoma Xenografts under the Skin of Mude Mice [J]. CANCER RESEARCH ON PREVENTION AND TREATMENT(肿瘤防治研究),2007,34(3):229-230 (in Chinese).
[14]Rygaard J, Povlsen C. O. Heterotransplantation of a human malignant tumor to nude mice[J]. Act Path Microbiol Scand,1969(77):758-760.
[15]Singh A, Boldin-Adamsky S, Thimmulappa RK,et al.RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy [J]. Cancer Res,2008,68,7975-7984.
[16]C.J. Harvey.Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress[J]. Free Radic Biol Med,2009,46(4):443-453.
[17]Liao Mei-yan,Zhou Yun-feng,Feng mao-hui,et al(廖美焱,周云峰,冯茂辉等).Establishment of a high-implanted human lung cancer model in nude mice. [J]. CHINESE JOURNAL OF EXPERIMENTAL SURGERY(中华实验外科杂志),2009,26(9)：1216-1217(in Chinese).
[18]Xu C, Huang MT, Shen G, et al. Inhibition of 7,12-Dimethylbenz[a] anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor2[J]. Cancer Res 2006,66,8293-6.
[19]Zheng Sun, Donna D. Zhang. Keapl Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2[J]. MOL. CELL. BIOL,2007,27 (18):6334-6349.
[1]M.M. Manson, A. Gescher, E.A. Hudson, et al. Blocking and suppressing mechanisms of chemoprevention by dietary constituents[J], Toxicol. Lett,2000, 112/113,499-505.
[2]Lynne M. Howells, Robert G. Britton, Marco Mazzoletti,et al. Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3',4',5'- Trimethoxyflavonol, a Quercetin Analogue[J]. Cancer Prev Res,2010,3(8): 929-39.
[3]Hayes JD, McMahon M, Chowdhry S,et al. Cancer Chemoprevention Mechanisms Mediated Through the Keapl-Nrf2 Pathway[J]. ANTIOXIDANTS & REDOX SIGNALING,2010,13(11):1713-1748.
[4]Robbins MG, Hauder J, Somoza V,et al. Induction of Detoxification Enzymes by Feeding Unblanched Brussels Sprouts Containing Active Myrosinase to Mice for 2 Wk[J]. JOURNAL OF FOOD SCIENCE,75(6):190-H199.
[5]Yanaka A, Fahey JW, Fukumoto A, et al. Dietary sulforaphane-rich broccoli sprouts reduce colonization and attenuate gastritis in Helicobacter pylori infected mice and humans[J]. Cancer Prev Res (Phila Pa),2009,2,353-60.
[6]Hong WK, Sporn MB. Recent advances in chemoprevention of cancer[J]. Science, 1997,278,1073-7.
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