过氧化物酶体增殖因子活化受体δ（PPARδ）在大肠癌发生中的作用研究
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摘要
目的：分析人直肠癌组织中PPARδ基因的表达变化及其与直肠癌临床病理特征的关系。
方法：选取2004年4-10月四川大学华西医院普外科手术切除的直肠癌标本86例，以正常直肠粘膜为对照，采用real-time RT-PCR对PPARδmRNA作定量检测，并分析其表达与直肠癌分化程度、病理类型及Dukes分期的关系。
结果：在86例直肠癌组织中，PPARδ表达上调占55．8％(48/86)，其中，45．3％(39/86)上调1．5-5倍，5．8％(5/86)上调10-20倍，4．7％(4/86)大于20倍，PPARδ表达下调占44．2％(38/86)，下调1．5-2．0倍。直肠癌组织中PPARδ的总体表达水平比正常粘膜组平均上调1．046倍，但是两组间并无统计学差异(P=0．863)。在不同分化程度、病理类型及Dukes分期的直肠癌组织中，PPARδ的表达无显著性差异(P＞0．05)。
结论：与正常直肠组织相比，直肠癌组织中约55．8％的PPARδ表达上调，其总体表达水平无显著变化，PPARδ的表达与直肠癌分化程度、病理类型及Dukes分期无关。
目的：探讨PPARδ基因对大肠癌细胞增殖活力及凋亡机能的影响。方法：构建4条表达短发夹结构RNA(shott-hairpin RNA,shRNA)的质粒载体，其中3条为靶向PPARδ基因的候选载体(pS-shRNA-1，-2，-3)，1条为不靶向任何编码序列的阴性干扰载体(pS-shRNA-N)。将人大肠癌细胞株HCT-116分为4个组：①．干扰组：分别用ps-shRNA-1，-2，-3转染细胞；②．阴性干扰组：用pS-shRNA-N转染细胞；③．空白质粒组：用空白pSUPER质粒转染细胞：④．对照组：HCT-116细胞和其它组在相同条件下培养，但不转染质粒。用脂质体2000进行转染，48h后，应用real-time RT-PCR分析PPARδ基因表达，筛选出强效表达载体。采用噻唑蓝(MTT)比色实验、流式细胞术及原位缺口末端标记法(TUNEL)观察PPARδ基因沉默对大肠癌细胞增生、细胞周期及凋亡的影响。
结果：pS-shRNA-1质粒能显著抑制HCT-116细胞中PPARδ的表达，使PPARδmRNA水平下调73．5％(P=0．012)。MTT试验显示，转染后24-96h，对照组、pS-shRNA-N及空白质粒组的光吸收值在各时点均无显著性差异(P＞0．05)，而pS-shRNA-1干扰组在各时点的光吸收值均显著高于前三组细胞(P＜0．05)。转染后48h，干扰组的G_1期细胞分布比对照组显著降低(26．8％VS 38．6％，P=0．037)，而对照组、pS-shRNA-N及空白质粒组均无显著性差异(P＞0．05)，各组在S期与G_2/M期的细胞分布比例(S期：G_2/M期)无显著差异(P=0．782)。转染后48h，pS-shRNA-1干扰组、pS-shRNA-N组、空白质粒组及对照组的细胞凋亡指数分别为3．76±1．81％、3．98±2．0％、4．0±1．64％、4．70±1．93％，各组间无显著性差异(P=0．726)。结论：PPARδ基因可增加G_1期的大肠癌细胞分布，并抑制细胞增殖，PPARδ对大肠癌细胞的凋亡无影响。
PURPOSE: To clarify the expression change of Peroxisome proliferator-activated receptorδ(PPARδ) gene in human colorectal cancer tissues, and determine the correlation of PPARδexpression with clinical and pathological parameters of colorectal cancer. METHODS: Applying Real-time RT-PCR, we quantified PPARδmRNA in 86 tissues from excised primary rectal cancers. In each case, accompanying normal mucosa was collected for comparison.
RESULTS: Among the 86 rectal cancer tissues, 55.8% (48/86) cases showed PPARδoverexpression: 45.3% (39/86) tumors gave an expression level 1.5 to 5.0 times, 5.8% (5/86) tumors 10 to 20 times, and 4.7% (4/86) tumors more than 20 times relative to normal mucosa. However, the general level of PPARδmRNA in rectal cancer tissues is not statistically different from normal mucosa. No significant links were found between PPARδexpression and cell differentiations, pathological categories and Dukes stages.
CONCLUSIONS: The expression of PPARδgene in rectal cancers is not statistically different from normal mucosa, and it doesn't correlate with cell differentiation, pathological categories and Dukes stages.
PURPOSE: To investigate the effects of peroxisome proliferator-activated receptorδ(PPARδ) on the proliferation and apoptosis of human colorectal cancer (CRC) cells.
METHODS: For RNA interfering (RNAi), HCT-116 cells were transfected with short hairpin RNA (shRNA)-expressing plasmids against PPARδor negative control vectors. The efficacy of RNAi was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). The proliferation, cell cycle and apoptosis of HCT-116 cells treated by RNAi, compared with those containing control vectors or untreated, were analyzed respectively using MTT (methyl thiazolyl tetrazolium), flow cytometry (FCM) and TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick end-labeling (TUNEL) assay.
RESULTS: RNAi targeting PPARδresulted in substantial suppression of PPARδexpression and significantly promoted the proliferation of HCT-116 cells relative to those with control vectors or untreated, obviously decreasing the frequency of G_1-phase cells, but had no effect on cell apoptosis.
CONCLUSIONS: PPARδmay inhibit the proliferation of CRC cells and increase the number of G_1-phase cells, without any function in cellapoptosis, which suggests an inhibitive role of PPARδgene in colorectalcarcinogenesis.
方法：选取2004年4-10月四川大学华西医院普外科手术切除的直肠癌标本86例，以正常直肠粘膜为对照，采用real-time RT-PCR对PPARδmRNA作定量检测，并分析其表达与直肠癌分化程度、病理类型及Dukes分期的关系。
结果：在86例直肠癌组织中，PPARδ表达上调占55．8％(48/86)，其中，45．3％(39/86)上调1．5-5倍，5．8％(5/86)上调10-20倍，4．7％(4/86)大于20倍，PPARδ表达下调占44．2％(38/86)，下调1．5-2．0倍。直肠癌组织中PPARδ的总体表达水平比正常粘膜组平均上调1．046倍，但是两组间并无统计学差异(P=0．863)。在不同分化程度、病理类型及Dukes分期的直肠癌组织中，PPARδ的表达无显著性差异(P＞0．05)。
结论：与正常直肠组织相比，直肠癌组织中约55．8％的PPARδ表达上调，其总体表达水平无显著变化，PPARδ的表达与直肠癌分化程度、病理类型及Dukes分期无关。
目的：探讨PPARδ基因对大肠癌细胞增殖活力及凋亡机能的影响。方法：构建4条表达短发夹结构RNA(shott-hairpin RNA,shRNA)的质粒载体，其中3条为靶向PPARδ基因的候选载体(pS-shRNA-1，-2，-3)，1条为不靶向任何编码序列的阴性干扰载体(pS-shRNA-N)。将人大肠癌细胞株HCT-116分为4个组：①．干扰组：分别用ps-shRNA-1，-2，-3转染细胞；②．阴性干扰组：用pS-shRNA-N转染细胞；③．空白质粒组：用空白pSUPER质粒转染细胞：④．对照组：HCT-116细胞和其它组在相同条件下培养，但不转染质粒。用脂质体2000进行转染，48h后，应用real-time RT-PCR分析PPARδ基因表达，筛选出强效表达载体。采用噻唑蓝(MTT)比色实验、流式细胞术及原位缺口末端标记法(TUNEL)观察PPARδ基因沉默对大肠癌细胞增生、细胞周期及凋亡的影响。
结果：pS-shRNA-1质粒能显著抑制HCT-116细胞中PPARδ的表达，使PPARδmRNA水平下调73．5％(P=0．012)。MTT试验显示，转染后24-96h，对照组、pS-shRNA-N及空白质粒组的光吸收值在各时点均无显著性差异(P＞0．05)，而pS-shRNA-1干扰组在各时点的光吸收值均显著高于前三组细胞(P＜0．05)。转染后48h，干扰组的G_1期细胞分布比对照组显著降低(26．8％VS 38．6％，P=0．037)，而对照组、pS-shRNA-N及空白质粒组均无显著性差异(P＞0．05)，各组在S期与G_2/M期的细胞分布比例(S期：G_2/M期)无显著差异(P=0．782)。转染后48h，pS-shRNA-1干扰组、pS-shRNA-N组、空白质粒组及对照组的细胞凋亡指数分别为3．76±1．81％、3．98±2．0％、4．0±1．64％、4．70±1．93％，各组间无显著性差异(P=0．726)。结论：PPARδ基因可增加G_1期的大肠癌细胞分布，并抑制细胞增殖，PPARδ对大肠癌细胞的凋亡无影响。
PURPOSE: To clarify the expression change of Peroxisome proliferator-activated receptorδ(PPARδ) gene in human colorectal cancer tissues, and determine the correlation of PPARδexpression with clinical and pathological parameters of colorectal cancer. METHODS: Applying Real-time RT-PCR, we quantified PPARδmRNA in 86 tissues from excised primary rectal cancers. In each case, accompanying normal mucosa was collected for comparison.
RESULTS: Among the 86 rectal cancer tissues, 55.8% (48/86) cases showed PPARδoverexpression: 45.3% (39/86) tumors gave an expression level 1.5 to 5.0 times, 5.8% (5/86) tumors 10 to 20 times, and 4.7% (4/86) tumors more than 20 times relative to normal mucosa. However, the general level of PPARδmRNA in rectal cancer tissues is not statistically different from normal mucosa. No significant links were found between PPARδexpression and cell differentiations, pathological categories and Dukes stages.
CONCLUSIONS: The expression of PPARδgene in rectal cancers is not statistically different from normal mucosa, and it doesn't correlate with cell differentiation, pathological categories and Dukes stages.
PURPOSE: To investigate the effects of peroxisome proliferator-activated receptorδ(PPARδ) on the proliferation and apoptosis of human colorectal cancer (CRC) cells.
METHODS: For RNA interfering (RNAi), HCT-116 cells were transfected with short hairpin RNA (shRNA)-expressing plasmids against PPARδor negative control vectors. The efficacy of RNAi was assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). The proliferation, cell cycle and apoptosis of HCT-116 cells treated by RNAi, compared with those containing control vectors or untreated, were analyzed respectively using MTT (methyl thiazolyl tetrazolium), flow cytometry (FCM) and TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick end-labeling (TUNEL) assay.
RESULTS: RNAi targeting PPARδresulted in substantial suppression of PPARδexpression and significantly promoted the proliferation of HCT-116 cells relative to those with control vectors or untreated, obviously decreasing the frequency of G_1-phase cells, but had no effect on cell apoptosis.
CONCLUSIONS: PPARδmay inhibit the proliferation of CRC cells and increase the number of G_1-phase cells, without any function in cellapoptosis, which suggests an inhibitive role of PPARδgene in colorectalcarcinogenesis.
引文
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22. Ben Ho Park, Bert Vogelstein, Kenneth W. Kinzler. Genetic disruption of PPAR5 decreases the tumorigenicity of human colon cancer cells. PNAS 2001;98 (5): 2598-2603.
23. Yaacov Barak, Debbie Liao, Weimin He, et al. Effects of peroxisome proliferator-activated receptor5 on placentation, adiposity, and colorectal cancer. PNAS 2002; 99(1): 303-308.
24. Patrice J. Morin, Andrew B. Sparks, Vladimir Korinek, et al. Activation of P-Catenin-Tcf Signaling in Colon Cancer by Mutations in P-Catenin or APC. Science 1997; 275: 1787 -1790.
25. Jinyi Shao, Hongmiao Sheng,Raymond N. DuBois. Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells. Cancer Research 2002; 62:3282-3288.
1. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. PNAS. 1994;91:7355-9.
2. T.E. Akiyama, P.T. Meinke, J.P. Berger. PPAR ligands: potential therapies for metabolic syndrome. Curr. Diab. Rep. 2005; 5 (1): 45.
3. B. Desvergne, W. Wahli. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 1999; 20 (5): 649- 688.
4. C.H. Lee, P. Olson, R.M. Evans. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003;144 (6): 2201.
5. L. Michalik, B. Desvergne, W. Wahli. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat. Rev. Cancer. 2004;4 (1): 61.
6. William Jr RO, Jennifer LS, Mike RS, et al. A selective peroxisome proliferator-activated receptor d agonist promotes reverse cholesterol transport. PNAS. 2001 ;98: 5306-11.
7. Yaacov B, Debbie L, Weimin H, et al. Effects of peroxisome proliferator-activated receptor d on placentation, adiposity, and colorectal cancer. PNAS. 2002; 99(1):303-8.
8. N.S. Tan, L. Michalik, B. Desvergne, W. Wahli. Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs. Expert Opin. Ther.Targets. 2004;8 (1): 39.
9. Guoliang Ding, Lihong Cheng, Qianhong Qin, Sonya Frontin, Qinglin Yang. PPAR5 modulates lipopolysaccharide-induced TNFa inflammation signaling in cultured cardiomyocytes. Journal of Molecular and Cellular Cardiology. 2006; 40: 821-828.
10. Tong-Chuan He, Timotly AC, Bert V, et al. PPARd is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999; 99: 335-45.
11. JOg H, Jiirgen B. The Wnt signalling pathway. J Cell Sci. 2000; 113: 3545.
12. Rajinish A. Gupta, JianTan, WadeF.Krause, etal. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor8 in colorectal cancer. PNAS 2000; 97(24): 13275-13280.
13. Ben Ho Park, Bert Vogelstein, and Kenneth W. Kinzler. Genetic disruption of PPAR5decreases the tumorigenicity of human colon cancer cells. PNAS. 2001; 98(5): 2598-2603.
14. L Yang, ZG Zhou, HZ Luo, B Zhou, QJ Xia, and C Tian . Quantitative analysis of PPARdelta mRNA by real-time RT-PCR in 86 rectal cancer tissues. Eur J Surg. 2006; 32(2): 181-5.
15. L.C. Chen, C.Y. Hao, Y.S. Chiu, P. Wong, J.S. Melnick, M. Brotman, J. Moretto, F. Mendes, A.P. Smith, J.L. Bennington, D. Moore, N.M. Lee. Alteration of gene expression in normal-appearing colon mucosa of APC(min) mice and human cancer patients. Cancer Res. 2004; 64 (10): 3694-700.
16. F.S. Harman, C.J. Nicol, H.E. Marin, J.M. Ward, F.J. Gonzalez, J.M. Peters. Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat. Med. 2004; 10 (5): 481-3.
17. Barak, Y., Liao, D., He, W., Ong, E.S., Nelson, M.C., Olefsky, J.M., Boland, R., and Evans, R.M. Effects of peroxisome proliferator-activated receptorδ on placentation, adiposity, and colorectal cancer. Proc. Natl. Acad. Sci. USA 2002; 99, 303-308.
18. Simone Mocellin, Rodolfo Costa, Donato Nitti. RNA interference: ready to silence cancer? J Mol Med. 2006; 84: 4-15.
19. Lisa Scherer, John J. Rossi. Recent applications of RNA interference (RNAi) in mammalian systems. Letters in Peptide Science 2003; 10: 255-267.
20. Shankar P, Manjunath N, Lieberman J. The prospect of silencing disease using RNA interference. JAMA. 2005;293:1367-1373.
21. Check E. News feature: a crucial test. Nat Med. 2005; 11: 243-244.
22. Michael WP, Graham WH, Leo D. Relative expression software tool (REST(?)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002; 30(9):e36.
23. Qiu S, Adema CM, Lane T. A computational study of off-target effects of RNA interference. Nucleic Acids Res. 2005; 33: 1834-1847.
24.N.S. Tan, L. Michalik, N. Noy, R. Yasmin, C. Pacot, M. Heim, B.Fluhrnann, B. Desvergne, W. Wahli. Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev. 2001; 15 (24): 3263-77.
25. Jinyi Shao, Hongmiao Sheng, Raymond N. DuBois. Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells. Cancer Research. 2002; 62: 3282-3288.
26. Kinzler W. K., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996; 87: 159-170.
27. Gary D. Wu. A Nuclear Receptor to Prevent Colon Cancer, the New England Journal of Medicine. 2000; 342: 651-653.
2. Powell SM, Zilz N, Beazer Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235-7.
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8．钟芸诗，姚礼庆．结直肠癌研究的新位点—PPAR的研究进展．中国现代医学杂志．2002；12(13)：37-39．
9. Rajnish A.Gupta, Jian Tan, Wade F.Krause,et al. Prostacyclin—mediated activation of peroxisome proliferator-activated receptorδin colorectal cancer[J].PNAS,2000,97(24): 13275.
10. William Jr RO, Jennifer LS, Mike RS, et al. A selective peroxisome proliferator-activated receptor d agonist promotes reverse cholesterol transport. PNAS. 2001;98: 5306-11.
11. Yaacov B, Debbie L, Weimin H, et al. Effects of peroxisome proliferator-activated receptor d on placentation, adiposity, and colorectal cancer. PNAS. 2002; 99(1):303-8.
12. N.S. Tan, L. Michalik, B. Desvergne, W. Wahli. Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs. Expert Opin. Ther.Targets. 2004;8 (1): 39.
13. Tong-Chuan He,TimothyA.chan, Bert Vogelstein,etal. PPARδ is an APC——regulated Target of Nonsteroidal Anti-inflammatory Drugs. Cell,1999, 99: 335-345.
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16. L.C. Chen, C.Y. Hao, Y.S. Chiu, P. Wong, J.S. Melnick, M. Brotman, J. Moretto, F. Mendes, A.P. Smith, J.L. Bennington, D. Moore, N.M. Lee. Alteration of gene expression in normal-appearing colon mucosa of APC(min) mice and human cancer patients. Cancer Res. 2004; 64 (10): 3694-700.
17. Barak, Y., Liao, D., He, W., Ong, E.S., Nelson, M.C., Olefsky, J.M., Boland, R., and Evans, R.M. Effects of peroxisome proliferator-activated receptorS on placentation, adiposity, and colorectal cancer. Proc. Natl. Acad. Sci. USA 2002; 99, 303-308.
18. F.S. Harman, C.J. Nicol, H.E. Marin, J.M. Ward, F.J. Gonzalez, J.M. Peters. Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat. Med. 2004; 10 (5): 481-3.
19. Michael W.Pfaffle, Graham W. Horgan, Leo Dempfle. Relative expression software tool (REST?) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Research, 2002, 30(9): e36.
20. Mygind,T., Birkelund,S., Birkebaek,N., Oestergaard,L., Jensen,J., Christiansen,G. Determination of PCR efficiency in chelex-100 purified clinical samples and comparison of Real-time quantitative PCR and conventional PCR for detection of Chlamydia pneumoniae. BMC Microbiol, 2002, 2(1): 17.
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23. Jinyi Shao, Hongmiao Sheng, Raymond N. DuBois. Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells. Cancer Research. 2002; 62: 3282-3288.
24. Simone Mocellin, Rodolfo Costa, Donato Nitti. RNA interference: ready to silence cancer? J Mol Med. 2006; 84: 4-15.
25. Jiang M, Milner J. Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene. 2002,21:6041-6048.
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27. Qiu S, Adema CM, Lane T. A computational study of off-target effects of RNA interference. Nucleic Acids Res. 2005; 33: 1834-1847.
28. N.S. Tan, L. Michalik, N. Noy, R. Yasmin, C. Pacot, M. Heim, B.Fluhmann, B. Desvergne, W. Wahli. Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev. 2001; 15 (24): 3263-77.
29. Ben Ho Park, Bert Vogelstein, and Kenneth W. Kinzler. Genetic disruption of PPARSdecreases the tumorigenicity of human colon cancer cells. PNAS. 2001; 98(5): 2598-2603.
30. Gary D. Wu. A Nuclear Receptor to Prevent Colon Cancer, the New England Journal of Medicine. 2000; 342: 651-653.
31. Gary D. Wu. A Nuclear Receptor to Prevent Colon Cancer, the New England Journal of Medicine. 2000; 342: 651-653.
1. IssemanI, Green S. Activation of a member of the steroid hormone receptor superfamily by Peroxisome proliferator.Nature, 1990:645-650.
2. Yoshikawa,T., Brkanac,Z., Dupont,B.R.,etal. Assignment of the human nuclear hormone receptor, NUC 1 (PPARD),to chromosome 6p21. 1-p21.2. Genomics 1996,35 (3):637-638.
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4．刘美莲，宋惠萍．过氧化物酶增值激活受体研究的新进展．国外医学．生理病理科学与临床分册．2001，21(5)：413-416．
5．钟芸诗，姚礼庆．结直肠癌研究的新位点—PPAR的研究进展．中国现代医学杂志．2002，12(13)：37-39．
6. Rajnish A.Gupta, Jian Tan, Wade F.Krause,etal.Prostacyclin—mediated activation of peroxisome proliferator-activated receptorδin colorectal cancer. PNAS,2000,97(24): 13275-13280.
7．张延龄．结直肠癌的发病机制．国外医学外科学分册，2003，30(2)：96-98．
8．张维，刘爽，徐宁志．Wnt信号传导通路及其在肿瘤发生中的作用．世界华人消化杂志，2002，10(10)：1201-1205．
9．孔民，白阳，王敬泽．wnt信号传导途径及其与结直肠癌的关联．细胞生物学杂志，2003，25(6)：343-347．
10．来茂德．结直肠癌发生的分子机制研究进展．中华病理学杂志．2000，29(6)：450-455．
11．钟芸诗，姚礼庆．过氧化物酶体增值因子活化受体δ(PPARδ)在结直肠癌中的表达及其意义—附80例临床分析．中国现代医学杂志 2003，13(22)：93-96．
12. Tong-Chuan He,Timothy A.chan, Bert Vogelstein,etal. PPARδ is an APC——regulated Target of Nonsteroidal Anti-inflammatory Drags. Cell,1999, 99: 335-345.
13. Gillian Hawcroft,Mark D Amico,Charis Albonese,etal. Indomethacin induces differential expression of β-Catenin, and T cell factor target gene in human colorectal ancer cells. Carcinomogenesis, 2002, 23(1): 107-114.
14. Imad shureiqi,Wei Jiang,Xiangsheng Zuo,etal.The 15-1ipoxygenase-1 product 13-S-Hydroxyoctadecadienoic acid down regulates PPARδ to induce apoptosis in colorectal cancer cells. PNAS, 2003, 100(17): 9968-9973.
15．张乾勇．120PPAR的结构与功能及其生物学作用．国外医学卫生学分册，2000，27(5)：284-288．
16. Brian Con, Laine J.Murphey, William E.Zarkert, etal. Human colorectal cancer cells efficiently conjulate the cyclopentenone prostaglandin, prostaglandin J2, to glutathione. BBA, 2002,1584(1): 37-45.
1. Kliewer, S. A., Forman, B. M., Blumberg, B., et al. Differential Expression and Activation of a Family of Murine Peroxisome Proliferator-Activated Receptors. PNAS 1994;91: 7355-7359.
2. Willson, T. M., Brown, P. J, Sternbach, D. D., Henke, B. R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem 2000;43: 527-550.
3. Kliewer, S. A., Lehmann, J. M., Milburn, M. V., Willson, T. M. The PPARs and RXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog. Horm. Res 1999; 54: 345-367.
4. Peters, J. M, Cattley, R. C.,Gonzalez, F. J. Role of PPARAalpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643.Carcinogenesis 1997;18:2029-2033.
5. Tontonoz, P., Singer, S., Forman, B. M., et al. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor y and the retinoid X receptor. PNAS 1997;94: 237 - 241
6. Mueller, E., Sarraf, P., Tontonoz, P., et al. Terminal differentiation of human breast cancer through PPARAgamma. Mol. Cell 1998;1:465-470.
7. Sarraf, P., Mueller, E., Jones, D., et al. Differentiation and reversal of malignant changes in colon cancer through PPARAgamma. Nat. Med.l998;4:1046-1052
8. William R. Oliver, Jr., Jennifer L. Shenk, Mike R. Snaith, et al. A selective peroxisome proliferator-activated receptor (?)agonist promotes reverse cholesterol transport. PNAS 2001;98: 5306 - 5311.
9. Yaacov Barak, Debbie Liao, Weimin He, etal. Effects of peroxisome proliferator-activated receptor5 on placentation, adiposity, and colorectal cancer. PNAS 2002; 99 (1): 303-308.
10. Tong-Chuan He, Timotly A.Chan, Bert Vogelstein, et al. PPAR5is an APC-regulated Target of nonsteroidal anti-inflammatory drugs. Cell 1999;99:335-345.
11. Powell, S. M., Zilz, N., Beazer-Barclay, Y., Bryan, T. M., et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235-237.
12. Jorg Hiilsken, Jiirgen Behrens. The Wnt signalling pathway. Journal of Cell Science 2000;113: 3545.
13. Rajinish A.Gupta, Jian Tan, WadeF.Krause, etal. Prostacyclin-mediated activation of peroxisome proliferator-activated receptorδ in colorectal cancer. PNAS 2000;97(24): 13275-13280.
14. Roy, H. K., Karolski, W. J., Ratashak, A. Distal bowel selectivity in the chemoprevention of experimental colon carcinogenesis by the non-steroidal anti-inflammatory drug nabumetone. Int. J. Cancer 2001;92:609 -615.
15.Bieche I, Onody P, Laurendeau I, et al. Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem 1999;45:1148-56.
16. David G. Ginzinger. Gene quantification using real-time quantitative PCR: An emerging technology hits the mainstream. Experimental Hematology 2002;30:503-512.
17. Michael W.Pfaffl. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 2001;29(9):2002-2007.
18. Mygind,T., Birkelund,S., Birkebaek,N., Oestergaard,L., Jensen,J., Christiansen,G Determination of PCR efficiency in chelex-100 purified clinical samples and comparison of Real-time quantitative PCR and conventional PCR for detection of Chlamydia pneumoniae. BMC Microbiol. 2002;2(1):17.
19. Michael W.Pfaffle, Graham W. Horgan, Leo Dempfle. Relative expression software tool(REST(?)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Research 2002; 30(9): e36.
20. Manly,B. (1997) Randomization, Bootstrap and Monte Carlo Methods in Biology. Chapman & Hall.
21.Horgan,G.W. and Rouault,J. (2000) Introduction to Randomisation Tests. Biomathematics and Statistics Scotland.
22. Ben Ho Park, Bert Vogelstein, Kenneth W. Kinzler. Genetic disruption of PPAR5 decreases the tumorigenicity of human colon cancer cells. PNAS 2001;98 (5): 2598-2603.
23. Yaacov Barak, Debbie Liao, Weimin He, et al. Effects of peroxisome proliferator-activated receptor5 on placentation, adiposity, and colorectal cancer. PNAS 2002; 99(1): 303-308.
24. Patrice J. Morin, Andrew B. Sparks, Vladimir Korinek, et al. Activation of P-Catenin-Tcf Signaling in Colon Cancer by Mutations in P-Catenin or APC. Science 1997; 275: 1787 -1790.
25. Jinyi Shao, Hongmiao Sheng,Raymond N. DuBois. Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells. Cancer Research 2002; 62:3282-3288.
1. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. PNAS. 1994;91:7355-9.
2. T.E. Akiyama, P.T. Meinke, J.P. Berger. PPAR ligands: potential therapies for metabolic syndrome. Curr. Diab. Rep. 2005; 5 (1): 45.
3. B. Desvergne, W. Wahli. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 1999; 20 (5): 649- 688.
4. C.H. Lee, P. Olson, R.M. Evans. Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology 2003;144 (6): 2201.
5. L. Michalik, B. Desvergne, W. Wahli. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat. Rev. Cancer. 2004;4 (1): 61.
6. William Jr RO, Jennifer LS, Mike RS, et al. A selective peroxisome proliferator-activated receptor d agonist promotes reverse cholesterol transport. PNAS. 2001 ;98: 5306-11.
7. Yaacov B, Debbie L, Weimin H, et al. Effects of peroxisome proliferator-activated receptor d on placentation, adiposity, and colorectal cancer. PNAS. 2002; 99(1):303-8.
8. N.S. Tan, L. Michalik, B. Desvergne, W. Wahli. Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs. Expert Opin. Ther.Targets. 2004;8 (1): 39.
9. Guoliang Ding, Lihong Cheng, Qianhong Qin, Sonya Frontin, Qinglin Yang. PPAR5 modulates lipopolysaccharide-induced TNFa inflammation signaling in cultured cardiomyocytes. Journal of Molecular and Cellular Cardiology. 2006; 40: 821-828.
10. Tong-Chuan He, Timotly AC, Bert V, et al. PPARd is an APC regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999; 99: 335-45.
11. JOg H, Jiirgen B. The Wnt signalling pathway. J Cell Sci. 2000; 113: 3545.
12. Rajinish A. Gupta, JianTan, WadeF.Krause, etal. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor8 in colorectal cancer. PNAS 2000; 97(24): 13275-13280.
13. Ben Ho Park, Bert Vogelstein, and Kenneth W. Kinzler. Genetic disruption of PPAR5decreases the tumorigenicity of human colon cancer cells. PNAS. 2001; 98(5): 2598-2603.
14. L Yang, ZG Zhou, HZ Luo, B Zhou, QJ Xia, and C Tian . Quantitative analysis of PPARdelta mRNA by real-time RT-PCR in 86 rectal cancer tissues. Eur J Surg. 2006; 32(2): 181-5.
15. L.C. Chen, C.Y. Hao, Y.S. Chiu, P. Wong, J.S. Melnick, M. Brotman, J. Moretto, F. Mendes, A.P. Smith, J.L. Bennington, D. Moore, N.M. Lee. Alteration of gene expression in normal-appearing colon mucosa of APC(min) mice and human cancer patients. Cancer Res. 2004; 64 (10): 3694-700.
16. F.S. Harman, C.J. Nicol, H.E. Marin, J.M. Ward, F.J. Gonzalez, J.M. Peters. Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat. Med. 2004; 10 (5): 481-3.
17. Barak, Y., Liao, D., He, W., Ong, E.S., Nelson, M.C., Olefsky, J.M., Boland, R., and Evans, R.M. Effects of peroxisome proliferator-activated receptorδ on placentation, adiposity, and colorectal cancer. Proc. Natl. Acad. Sci. USA 2002; 99, 303-308.
18. Simone Mocellin, Rodolfo Costa, Donato Nitti. RNA interference: ready to silence cancer? J Mol Med. 2006; 84: 4-15.
19. Lisa Scherer, John J. Rossi. Recent applications of RNA interference (RNAi) in mammalian systems. Letters in Peptide Science 2003; 10: 255-267.
20. Shankar P, Manjunath N, Lieberman J. The prospect of silencing disease using RNA interference. JAMA. 2005;293:1367-1373.
21. Check E. News feature: a crucial test. Nat Med. 2005; 11: 243-244.
22. Michael WP, Graham WH, Leo D. Relative expression software tool (REST(?)) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res. 2002; 30(9):e36.
23. Qiu S, Adema CM, Lane T. A computational study of off-target effects of RNA interference. Nucleic Acids Res. 2005; 33: 1834-1847.
24.N.S. Tan, L. Michalik, N. Noy, R. Yasmin, C. Pacot, M. Heim, B.Fluhrnann, B. Desvergne, W. Wahli. Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev. 2001; 15 (24): 3263-77.
25. Jinyi Shao, Hongmiao Sheng, Raymond N. DuBois. Peroxisome Proliferator-activated Receptors Modulate K-Ras-mediated Transformation of Intestinal Epithelial Cells. Cancer Research. 2002; 62: 3282-3288.
26. Kinzler W. K., Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996; 87: 159-170.
27. Gary D. Wu. A Nuclear Receptor to Prevent Colon Cancer, the New England Journal of Medicine. 2000; 342: 651-653.