15-LOX-1基因抑制胃癌细胞AGS增殖诱导凋亡的作用机制研究
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摘要
目的:脂氧合酶对肿瘤的作用已成为肿瘤研究领域的热点之一,本研究旨在研究15-LOX-1基因抑制人胃癌细胞AGS增殖,诱导其凋亡的作用机制。
方法:通过脂质体介导瞬时转染15-LOX-1基因于胃癌细胞AGS中,以转染空质粒PCDNA3.1的AGS细胞及未转染质粒的AGS细胞为对照,RT-PCR法检测15-LOX-1和PPARγmRNA表达;Western blot法检测15-LOX-1、PPARγ、P27/Skp2、Bax/Bcl-2蛋白表达;四甲基偶氮唑盐法(MTT)检测15-LOX-1和GW9662对胃癌细胞AGS增殖水平的影响。
结果:(1)胃癌细胞AGS中未检测到15-LOX-1mRNA和蛋白的表达,转染后的AGS表达有15-LOX-1的mRNA及蛋白。(2)转染15-LOX-1后细胞周期抑制因子P27表达较未转染和转染空载质粒组显著上调,而S相激酶相关蛋白2(Skp2)表达下降(P<0.05)。(3)转染48小时后,AGS/15-LOX-1组细胞存活率为58.5%,显著低于AGS及AGS/PCDNA3.1组(P<0.05)。AGS/15-LOX-1组细胞加入10uM GW9662作用48小时后,细胞存活率为76.2%,较GW9662作用前显著升高(P<0.05)。(4) AGS、AGS/15-LOX-1、AGS/PCDNA3.1组均能检测到PPARγmRNA和蛋白的表达,且AGS/15-LOX-1组PPARγ表达量较其他两组显著增多(P<0.05),10uM GW9662能够下调AGS/15-LOX-1组PPARγ表达。(5) AGS/15-LOX-1组Bax蛋白的表达较AGS和AGS/PCDNA3.1组上调,而Bcl-2蛋白的表达量下降(P<0.05),加入GW9662作用48h后,AGS/15-LOX-1组Bax/Bcl-2蛋白的表达量与AGS和AGS/PCDNA3.1组无显著差别(P>0.05)。
结论:15-LOX-1可能经由PPARγ途径,通过调节细胞周期蛋白Skp2和P27的表达,使细胞周期阻滞于G0/G1期,并通过调节下游凋亡相关基因Bax/Bcl-2的表达,抑制细胞增殖,促进其凋亡。
Objective: The study was to investigate the mechanism of proliferation inhibition and apoptosis induction by 15-lipoxygenase-1(15-LOX-1) gene on gastric cancer cell AGS.
Methods: AGS cells were divided into three groups: AGS/15-LOX-1 group transfected with PCDNA3.1/15-LOX-1,vector control group transfected with PCDNA3.1 and blank control group without transfection.Plasmids of PCDNA3.1/15-LOX-1 encoding 15-LOX-1 gene were transiently transfected into AGS cells.The expression of 15-LOX-1 and PPARγat mRNA level were measured by reverse transcription polymerase chain reaction(RT-PCR).The expression of 15-LOX-1、PPARγ、Skp2/P27、Bax/Bcl-2 at protein level were measured by western blot.The proliferation of four groups cells(AGS/15-LOX-1、AGS、AGS/15-LOX-1 add with GW9662、AGS add with GW9662) were assessed by thiazolyl blue tetrazolium bromide(MTT) assay respectively.
Results: (1) 15-LOX-1 mRNA and protein were expressed in AGS/15-LOX-1 cells compared with control groups detected by RT-PCR and western blot.(2) P27 which was expressed from AGS cells transfected with PCDNA3.1/15-LOX-1 is up-regulated, meanwhile, S-phase Kinase-associated Protein 2 (Skp2) is down-regulated compared with control groups(P<0.05).(3)There was a significant decline in cell proliferation ability of AGS/15-LOX-1 in comparision with control groups revealed by MTT assay(P<0.05).Cell survival rates were 58.5%,48h after transfection.After added with 10uM GW9662, cell proliferation ability of AGS/15-LOX-1 were 76.2%,48h after intervention.(4)PPARγmRNA and protein were expressed in AGS/15-LOX-1 cells、AGS and AGS/pcDNA3.1 cells detected by RT-PCR and western blot.Also,in AGS/15-LOX-1 cells,the expression of PPARγ was significantly higher than that in AGS and AGS/pcDNA3.1 cells(P<0.05).(5)Bax which was expressed from AGS cells transfected with 15-LOX-1 is up-regulated, meanwhile, Bcl-2 is down-regulated compared with control groups(P<0.05).But 48h after intervent with GW9662, western blot confirmed that there was no statistically significant differences in comparision with control groups(p>0.05).
Conclusion:The expression of 15-LOX-1 could effectively regulate the expression of Skp2 and P27 to resort gastric carcinoma cell in period G0/G1 and inhibit carcinoma cell proliferation.The expression of 15-LOX-1 could up-regulated expression of bax and low-regulated expression of Bcl-2 through PPARγ,which may be the mechanism of 15-LOX-1 gene induce the apoptosis of human gastric cancer AGS cells.
方法:通过脂质体介导瞬时转染15-LOX-1基因于胃癌细胞AGS中,以转染空质粒PCDNA3.1的AGS细胞及未转染质粒的AGS细胞为对照,RT-PCR法检测15-LOX-1和PPARγmRNA表达;Western blot法检测15-LOX-1、PPARγ、P27/Skp2、Bax/Bcl-2蛋白表达;四甲基偶氮唑盐法(MTT)检测15-LOX-1和GW9662对胃癌细胞AGS增殖水平的影响。
结果:(1)胃癌细胞AGS中未检测到15-LOX-1mRNA和蛋白的表达,转染后的AGS表达有15-LOX-1的mRNA及蛋白。(2)转染15-LOX-1后细胞周期抑制因子P27表达较未转染和转染空载质粒组显著上调,而S相激酶相关蛋白2(Skp2)表达下降(P<0.05)。(3)转染48小时后,AGS/15-LOX-1组细胞存活率为58.5%,显著低于AGS及AGS/PCDNA3.1组(P<0.05)。AGS/15-LOX-1组细胞加入10uM GW9662作用48小时后,细胞存活率为76.2%,较GW9662作用前显著升高(P<0.05)。(4) AGS、AGS/15-LOX-1、AGS/PCDNA3.1组均能检测到PPARγmRNA和蛋白的表达,且AGS/15-LOX-1组PPARγ表达量较其他两组显著增多(P<0.05),10uM GW9662能够下调AGS/15-LOX-1组PPARγ表达。(5) AGS/15-LOX-1组Bax蛋白的表达较AGS和AGS/PCDNA3.1组上调,而Bcl-2蛋白的表达量下降(P<0.05),加入GW9662作用48h后,AGS/15-LOX-1组Bax/Bcl-2蛋白的表达量与AGS和AGS/PCDNA3.1组无显著差别(P>0.05)。
结论:15-LOX-1可能经由PPARγ途径,通过调节细胞周期蛋白Skp2和P27的表达,使细胞周期阻滞于G0/G1期,并通过调节下游凋亡相关基因Bax/Bcl-2的表达,抑制细胞增殖,促进其凋亡。
Objective: The study was to investigate the mechanism of proliferation inhibition and apoptosis induction by 15-lipoxygenase-1(15-LOX-1) gene on gastric cancer cell AGS.
Methods: AGS cells were divided into three groups: AGS/15-LOX-1 group transfected with PCDNA3.1/15-LOX-1,vector control group transfected with PCDNA3.1 and blank control group without transfection.Plasmids of PCDNA3.1/15-LOX-1 encoding 15-LOX-1 gene were transiently transfected into AGS cells.The expression of 15-LOX-1 and PPARγat mRNA level were measured by reverse transcription polymerase chain reaction(RT-PCR).The expression of 15-LOX-1、PPARγ、Skp2/P27、Bax/Bcl-2 at protein level were measured by western blot.The proliferation of four groups cells(AGS/15-LOX-1、AGS、AGS/15-LOX-1 add with GW9662、AGS add with GW9662) were assessed by thiazolyl blue tetrazolium bromide(MTT) assay respectively.
Results: (1) 15-LOX-1 mRNA and protein were expressed in AGS/15-LOX-1 cells compared with control groups detected by RT-PCR and western blot.(2) P27 which was expressed from AGS cells transfected with PCDNA3.1/15-LOX-1 is up-regulated, meanwhile, S-phase Kinase-associated Protein 2 (Skp2) is down-regulated compared with control groups(P<0.05).(3)There was a significant decline in cell proliferation ability of AGS/15-LOX-1 in comparision with control groups revealed by MTT assay(P<0.05).Cell survival rates were 58.5%,48h after transfection.After added with 10uM GW9662, cell proliferation ability of AGS/15-LOX-1 were 76.2%,48h after intervention.(4)PPARγmRNA and protein were expressed in AGS/15-LOX-1 cells、AGS and AGS/pcDNA3.1 cells detected by RT-PCR and western blot.Also,in AGS/15-LOX-1 cells,the expression of PPARγ was significantly higher than that in AGS and AGS/pcDNA3.1 cells(P<0.05).(5)Bax which was expressed from AGS cells transfected with 15-LOX-1 is up-regulated, meanwhile, Bcl-2 is down-regulated compared with control groups(P<0.05).But 48h after intervent with GW9662, western blot confirmed that there was no statistically significant differences in comparision with control groups(p>0.05).
Conclusion:The expression of 15-LOX-1 could effectively regulate the expression of Skp2 and P27 to resort gastric carcinoma cell in period G0/G1 and inhibit carcinoma cell proliferation.The expression of 15-LOX-1 could up-regulated expression of bax and low-regulated expression of Bcl-2 through PPARγ,which may be the mechanism of 15-LOX-1 gene induce the apoptosis of human gastric cancer AGS cells.
引文
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[1] Fujii D, Yoshida K, Tanabe K, et al. The ligands of peroxisome proliferator-activated receptor (PPAR) gamma inhibit growth of human esophageal carcinoma cells through induction of apoptosis and cell cycle arrest. Anticancer Res, 2004, 24(3a):1409-1416.
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[6] Shureiqi I, Wu Y, Chen D, et al. The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Cancer Res. 2005, 65(24):11486-11492.
[7] Hsi LC, Xi X, Lotan R, et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Cancer Res, 2004, 64(23):8778-8781.
[8] Zuo X, Wu Y, Morris JS, et al. Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene, 2006, 25(8):1225-1241.
[9] Hennig R, Kehl T, Noor S, et al. 15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. Neoplasia, 2007, 9(11):917-926.
[10] Jiang WG, Watkins G, Douglas-Jones A, et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[11] Dong YW, Wang XP, Wu K,et al. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor gamma involves angiogenesis inhibition. World J Gastroenterol, 2009, 15(4):441-448.
[12] Eibl G. The Role of PPAR-gamma and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Res, 2008,326915.
[13] Jiang WG, Watkins G, Douglas-Jones A,et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[14] Liu C, Xu D, Sj?berg J, et al. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res, 2004, 297(1):61-67.colorectal cancer. Ann Surg, 2005, 241(6):941-946.
[6] Shureiqi I, Wu Y, Chen D, et al. The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Cancer Res. 2005, 65(24):11486-11492.
[7] Hsi LC, Xi X, Lotan R, et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Cancer Res, 2004, 64(23):8778-8781.
[8] Zuo X, Wu Y, Morris JS, et al. Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene, 2006, 25(8):1225-1241.
[9] Hennig R, Kehl T, Noor S, et al. 15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. Neoplasia, 2007, 9(11):917-926.
[10] Jiang WG, Watkins G, Douglas-Jones A, et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[11] Dong YW, Wang XP, Wu K,et al. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor gamma involves angiogenesis inhibition. World J Gastroenterol, 2009, 15(4):441-448.
[12] Eibl G. The Role of PPAR-gamma and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Res, 2008,326915.
[13] Jiang WG, Watkins G, Douglas-Jones A,et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[14] Liu C, Xu D, Sj?berg J, et al. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res, 2004, 297(1):61-67.
2. Romano M, Claria J. Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J. 2003 Nov;17(14):1986-95.
3. Claria J, Romano M.Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer. Curr Pharm Des. 2005;11(26):3431-47.
4. Shureiqi I,Wojno KJ,Poore JA,et al. Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers.Carcinogenesis,1999,20(10):1985–1995
5. Shureiqi I,Xu X,Chen D,et al.Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression.Cancer Res,2001,61(12):4879–4884
6. Hennig R,Rao SM,Büchler MW,et al.Decreased 15-Lipoxygenase-1(15-LOX-1) Expression in Human Pancreatic Adenocarcinoma.Pancreatolo-gy,2003,3:209–269.
7. Hennig R,Rao SM,Büchler MW,et al.Decreased 15-Lipoxygenase-1(15-LOX-1) Expression in Human Pancreatic Adenocarcinoma.Pancreatolo-gy,2003,3:209–269.
8. Jong SK,Seung JB,Frank G,et al.Overexpression of 15- lipoxygenase-1 induces growth arrest through phosphorylation of p53 in humancolorectal cancer cells.Mol Cancer Res,2005,3(9):511-517.
9. Shappell,S.B.Gupta,R.A.Manning,S.Whitehead,R.Boeglin,W.E.Schneider,C.Case,T.Price,J.15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells.Cancer Res.2001;61:497-503
10.李勇,李建英,陈丰霖,等.15-脂氧合酶-1在胃癌中的表达及其临床意义[J].胃肠病学和肝病学杂志,2006(06) :576-580
11.林芬,李建英,陈丰霖,等.15-脂氧合酶-1在胃癌细胞AGS中的表达[J].福建医科大学学报,2009,34(1):23-27.
12. Jing Wu,Harry Hua Xiang Xia, Shui Ping Tu, Dai Ming Fan,Marie Chia Mi Lin, Hsiang Fu Kung, Shiu Kum Lam and Benjamin Chun Yu Wong,15-Lipoxygenase-1 mediates cyclooxygenase-2 inhibitor-induced apoptosis in gastric cancer.Carcinogenesis.2003;24:243-247
13. Brash AR.Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate.J Biol Chem 1999; 274(34):23679–23682
14. Fu YG,Sung JJ,Wu KC,etal.Inhibiton of gastric cancer-associated angiogenensis by antisense COX-2 transfectants.Cancer Lett.2005,224:243-52
15. Han S,Kim HY,Park K, et al. Expression of p27Kip1 and cyclin D1 proteins is inversely correlated and is associated with poor clinical outcome in human gastric cancer.J Surg Oncol. 1999,71(3):147-154.
16. Ohtani M,Isozaki H,Fujii K,et al. Impact of the expression of cyclin-dependent kinase inhibitor p27Kip1 and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma. Cancer, 1999,85(8):1711-1718. .
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18.马秀梅,刘江惠,郭建文,等.胃癌组织Skp2表达的意义及其与P27、PTEN表达的关系[J].癌症2006,25(1):56-61.
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[8] Zuo X, Wu Y, Morris JS, et al. Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene, 2006, 25(8):1225-1241.
[9] Hennig R, Kehl T, Noor S, et al. 15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. Neoplasia, 2007, 9(11):917-926.
[10] Jiang WG, Watkins G, Douglas-Jones A, et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[11] Dong YW, Wang XP, Wu K,et al. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor gamma involves angiogenesis inhibition. World J Gastroenterol, 2009, 15(4):441-448.
[12] Eibl G. The Role of PPAR-gamma and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Res, 2008,326915.
[13] Jiang WG, Watkins G, Douglas-Jones A,et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[14] Liu C, Xu D, Sj?berg J, et al. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res, 2004, 297(1):61-67.colorectal cancer. Ann Surg, 2005, 241(6):941-946.
[6] Shureiqi I, Wu Y, Chen D, et al. The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. Cancer Res. 2005, 65(24):11486-11492.
[7] Hsi LC, Xi X, Lotan R, et al. The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells. Cancer Res, 2004, 64(23):8778-8781.
[8] Zuo X, Wu Y, Morris JS, et al. Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. Oncogene, 2006, 25(8):1225-1241.
[9] Hennig R, Kehl T, Noor S, et al. 15-lipoxygenase-1 production is lost in pancreatic cancer and overexpression of the gene inhibits tumor cell growth. Neoplasia, 2007, 9(11):917-926.
[10] Jiang WG, Watkins G, Douglas-Jones A, et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[11] Dong YW, Wang XP, Wu K,et al. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor gamma involves angiogenesis inhibition. World J Gastroenterol, 2009, 15(4):441-448.
[12] Eibl G. The Role of PPAR-gamma and Its Interaction with COX-2 in Pancreatic Cancer. PPAR Res, 2008,326915.
[13] Jiang WG, Watkins G, Douglas-Jones A,et al. Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.. Prostaglandins Leukot Essent Fatty Acids, 2006, 74(4):235-245.
[14] Liu C, Xu D, Sj?berg J, et al. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res, 2004, 297(1):61-67.