GRIM-19对结肠癌凋亡及化疗敏感性影响的研究
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摘要
背景和目的
转录信号转导子与激活子3 ( signal transducers and activators of transcription 3, STAT3)及其介导的信号转导通路参与调节细胞的增殖,凋亡与分化,并介导细胞的恶性转化,体内外阻断(或抑制)某些肿瘤细胞中STAT3信号通路,可诱导瘤细胞凋亡,并抑制瘤细胞生长和存活。近期发现的干扰素(Interferon, IFN)/维甲酸(retinoid,RA)联合应用诱导细胞凋亡相关的基因GRIM-19(Genes associated with Retinoid-Interferon induced Mortality 19, GRIM-19),属STAT3特异性抑制蛋白,本研究旨在构建携带GRIM-19基因的腺病毒并探讨Grim-19对结肠癌凋亡及化疗敏感性影响。
方法
以pcxn2-Grim19重组质粒为模板, PCR扩增Grim19,将Grim19 cDNA克隆于穿梭质粒pAdTrack-CMV , PmeI线性化后,与腺病毒骨架质粒pAdEasy-1共转化BJ5183感受态细胞,获得带有Grim19基因的重组腺病毒质粒Ad-Grim19,并酶切鉴定后,经PacI线性化后转染HEK293包装细胞,观察细胞内绿色荧光蛋白表达情况,并进行3轮扩增,收获腺病毒重组病毒子。将重组腺病毒Ad-Grim19转染sw480细胞并通过流式细胞技术检测其凋亡表现。pcxn2-GRIM19与pcxn2-STAT3质粒在脂质体lipofectamine2000的介导下转染结肠癌细胞sw480,通过蛋白Western Blot分析GRIM19在sw480细胞中的表达情况;利用流式细胞术检测GRIM19对细胞凋亡的影响;GRIM19与顺铂联合应用后分析sw480细胞凋亡表现及bcl-xl蛋白的表达情况。
结果
经酶切鉴定重组腺病毒Ad-Grim19构建成功,荧光表现表明Ad-Grim19在HEK293包装细胞中表达;重组腺病毒pAd-Grim19转染sw480细胞后使其凋亡率升高。外源性的GRIM19基因转染sw480细胞后,GRIM19蛋白表达增加,GRIM19过表达促进sw480细胞凋亡,GRIM19与STAT3共转染sw480细胞时GRIM19的促凋亡作用减弱;GRIM19可使抗凋亡蛋白bcl-xl表达降低,增强顺铂诱导凋亡的作用。
结论
成功构建重组腺病毒Ad-Grim19,Grim19在sw480结肠癌细胞系中的过表达可促进其凋亡其增强其对顺铂的化疗敏感性。
BACKGROUND&OBJECTIVE
Signal transducers and activators of transcription 3 (STAT3)and its pathway are involved in modulating cell proliferation, apoptosis, differentiation, and mediating malignant transformation of cells. If STAT3 and its pathway are blocked in vivo or vitro, the tumor cells will be induced to apoptosis and its proliferation will be inhibited. Now we found a gene named GRIM-19(Genes associated with Retinoid-Interferon induced Mortality 19) is a specific protein to inhibit STAT3. This study was to construct recombinant adenovirus carrying Grim19 gene and examine the effect of recombinant plasmid carrying Grim19 on cell apoptosis and the sensitivity to cisplatin in colon cancer cell.
METHODS
Grim19 cDNA was amplified by PCR, with the template pcxn2-Grim19 ,then cloned into the shuttle plasmid pAdTrack-CMV. The plasmid pAdTrackCMV- Grim19 was linearized by PmeI, followed by homologous recombination with bone plasmid pAdEasy-1 in BJ5183,then identified by enzyme digestion. After linearized by PacI and transfection into HEK293 cells, recombinant adenovirus Ad-Grim19 were obtained in HEK293 cells then amplified by 3 circles. The green fluorescence in HEK293 cells was observed. Ad-Grim19 was transfected into sw480 cells. The rate of apoptosis was detected by FCM. pcxn2- Grim19 and pcxn2- stat3 were transfected into colon cancer cell line sw480 with lipofectamine2000. the efficiency of transfection was detected by Western blot and the effects of Grim19 on apoptosis in sw480 cells was examined by flow cytometry respectively. After combined treatment with cisplatin, the apoptotic effect and the bcl-xl expression were elvaluated.
RESULTS
The results of enzyme digestion indicated that Ad-Grim19 was successfully constructed. The fluorescences show the expression of Ad-Grim19 in HEK293 cells. The transfection of Ad-Grim19 into sw480 cells increased the rate of apoptosis. The expression of Grim19 protein upregulated afer transfection. Cell apoptosis was induced by overexpressed Grim19 which could be decreased by cotransfection with stat3. Grim19 down-regulated the Bcl-xL protein expression and enhanced the apoptotic effect of cisplatin.
CONCLUSION
Recombinant adenovirus Ad-Grim19 had been successfully constructed. Overexpression of Grim19 in sw480 colon cancer cell lines can promote apoptosis. Grim19 could accentuate cell apoptosis and the sensitivity to cisplatin in colon cancer cell.
转录信号转导子与激活子3 ( signal transducers and activators of transcription 3, STAT3)及其介导的信号转导通路参与调节细胞的增殖,凋亡与分化,并介导细胞的恶性转化,体内外阻断(或抑制)某些肿瘤细胞中STAT3信号通路,可诱导瘤细胞凋亡,并抑制瘤细胞生长和存活。近期发现的干扰素(Interferon, IFN)/维甲酸(retinoid,RA)联合应用诱导细胞凋亡相关的基因GRIM-19(Genes associated with Retinoid-Interferon induced Mortality 19, GRIM-19),属STAT3特异性抑制蛋白,本研究旨在构建携带GRIM-19基因的腺病毒并探讨Grim-19对结肠癌凋亡及化疗敏感性影响。
方法
以pcxn2-Grim19重组质粒为模板, PCR扩增Grim19,将Grim19 cDNA克隆于穿梭质粒pAdTrack-CMV , PmeI线性化后,与腺病毒骨架质粒pAdEasy-1共转化BJ5183感受态细胞,获得带有Grim19基因的重组腺病毒质粒Ad-Grim19,并酶切鉴定后,经PacI线性化后转染HEK293包装细胞,观察细胞内绿色荧光蛋白表达情况,并进行3轮扩增,收获腺病毒重组病毒子。将重组腺病毒Ad-Grim19转染sw480细胞并通过流式细胞技术检测其凋亡表现。pcxn2-GRIM19与pcxn2-STAT3质粒在脂质体lipofectamine2000的介导下转染结肠癌细胞sw480,通过蛋白Western Blot分析GRIM19在sw480细胞中的表达情况;利用流式细胞术检测GRIM19对细胞凋亡的影响;GRIM19与顺铂联合应用后分析sw480细胞凋亡表现及bcl-xl蛋白的表达情况。
结果
经酶切鉴定重组腺病毒Ad-Grim19构建成功,荧光表现表明Ad-Grim19在HEK293包装细胞中表达;重组腺病毒pAd-Grim19转染sw480细胞后使其凋亡率升高。外源性的GRIM19基因转染sw480细胞后,GRIM19蛋白表达增加,GRIM19过表达促进sw480细胞凋亡,GRIM19与STAT3共转染sw480细胞时GRIM19的促凋亡作用减弱;GRIM19可使抗凋亡蛋白bcl-xl表达降低,增强顺铂诱导凋亡的作用。
结论
成功构建重组腺病毒Ad-Grim19,Grim19在sw480结肠癌细胞系中的过表达可促进其凋亡其增强其对顺铂的化疗敏感性。
BACKGROUND&OBJECTIVE
Signal transducers and activators of transcription 3 (STAT3)and its pathway are involved in modulating cell proliferation, apoptosis, differentiation, and mediating malignant transformation of cells. If STAT3 and its pathway are blocked in vivo or vitro, the tumor cells will be induced to apoptosis and its proliferation will be inhibited. Now we found a gene named GRIM-19(Genes associated with Retinoid-Interferon induced Mortality 19) is a specific protein to inhibit STAT3. This study was to construct recombinant adenovirus carrying Grim19 gene and examine the effect of recombinant plasmid carrying Grim19 on cell apoptosis and the sensitivity to cisplatin in colon cancer cell.
METHODS
Grim19 cDNA was amplified by PCR, with the template pcxn2-Grim19 ,then cloned into the shuttle plasmid pAdTrack-CMV. The plasmid pAdTrackCMV- Grim19 was linearized by PmeI, followed by homologous recombination with bone plasmid pAdEasy-1 in BJ5183,then identified by enzyme digestion. After linearized by PacI and transfection into HEK293 cells, recombinant adenovirus Ad-Grim19 were obtained in HEK293 cells then amplified by 3 circles. The green fluorescence in HEK293 cells was observed. Ad-Grim19 was transfected into sw480 cells. The rate of apoptosis was detected by FCM. pcxn2- Grim19 and pcxn2- stat3 were transfected into colon cancer cell line sw480 with lipofectamine2000. the efficiency of transfection was detected by Western blot and the effects of Grim19 on apoptosis in sw480 cells was examined by flow cytometry respectively. After combined treatment with cisplatin, the apoptotic effect and the bcl-xl expression were elvaluated.
RESULTS
The results of enzyme digestion indicated that Ad-Grim19 was successfully constructed. The fluorescences show the expression of Ad-Grim19 in HEK293 cells. The transfection of Ad-Grim19 into sw480 cells increased the rate of apoptosis. The expression of Grim19 protein upregulated afer transfection. Cell apoptosis was induced by overexpressed Grim19 which could be decreased by cotransfection with stat3. Grim19 down-regulated the Bcl-xL protein expression and enhanced the apoptotic effect of cisplatin.
CONCLUSION
Recombinant adenovirus Ad-Grim19 had been successfully constructed. Overexpression of Grim19 in sw480 colon cancer cell lines can promote apoptosis. Grim19 could accentuate cell apoptosis and the sensitivity to cisplatin in colon cancer cell.
引文
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7. Zhang J, Yang J, Roy S K et al. The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 [J]. Proc Natl Acad Sci USA, 2003, 100(16):9342-9347.
8. Lufei C, Ma J, Huang G et al. GRIM-19, a death-regulatory gene product, suppresses STAT3 activity via functional interaction [J]. EMBO J, 2003 , 22(6): 1325-1335.
9.马向涛、王杉等,癌基因STAT3与结直肠癌临床病理特征的关系.中华普通外科杂志2002,17(7):401-403.
10. Q Lin, R Lai, LR Chirieac, et al. Constitutive Activation of JAK3/STAT3 in Colon Carcinoma Tumors and Cell Lines. American Journal of Pathology. 2005;167:969-980.
11. I Alchanati, SC Nallar, P Sun, et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas. Oncogene. 2006, 25:7138–7147
12. X Zhang, Q Huang, Z Yang, et al. GW112, A Novel Antiapoptotic Protein That Promotes Tumor Growth. Cancer Research. 2004;64:2474-2481.
13. Ma X, Kalakonda S, Srinivasula SM, et al. GRIM-19 associates with the serine protease HtrA2 for promoting cell death. Oncogene. 2007;26:4842-4849.
14.龚龙波,罗学来,刘双又;等,GRIM-19及其靶基因产物STAT3与结直肠癌恶性程度的关系.癌症, 2007,(7):683-687
15. Song J I , Grandis J R . STAT signaling in head and neck cancer [J ] . Oncogene, 2000 , 19 (21) : 2489 - 2495.
16. Weber-Nordt R M, Egen C , Wehinger J, et al . Constitutive activation of STAT proteins in primary lymphoid and myeloid leu2 kemia cells and in Epstein-Barr virus ( EBV)-related lymphoma cell lines [J]. Blood , 1996 , 88 (3) : 809 - 816.
17. Zushi S, Shinomura Y, Kiyohara T , et al . STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells[J ] . Int J Cancer , 1998 , 78 (3) : 326 - 330.
18.马向涛,王杉,叶颖江,等,Stat3及其靶基因产物与结直肠癌恶性程度关系的研究[J ].癌症, 2003,22(11):1135-1139
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21. Benihoud K, Yeh P , Perricaudet M. Adenovirus vectors for gene delivery . Curr Opin Biotechnol , 1999 , 10 (5) : 440 -447.
22. He TC , Zhou S , da Costa L T , et al . A simplified system for generating recombinant adenoviruses . Proc Natl Acad Sci USA , 1998 , 95 (5): 2509 - 2514.
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2. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene. 2000 May 15;19(21):2474-88.
3. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002 Apr;8(4):945-54.
4. Turkon J, and Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene. 2000 19,6613-6626.
5. Iwamoto T,Senga T, Naito Y,Matsuda S, Miyake Y,Yoshimura A,Hamaguchi M. The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK-STAT activation. Oncogene 2000 19(41),4795-4801
6. Levy DE, Danell JE Jr., Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol.2002 3(9),651-662
7. Zhang J, Yang J, Roy S K et al. The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3 [J]. Proc Natl Acad Sci USA, 2003, 100(16):9342-9347.
8. Lufei C, Ma J, Huang G et al. GRIM-19, a death-regulatory gene product, suppresses STAT3 activity via functional interaction [J]. EMBO J, 2003 , 22(6): 1325-1335.
9.马向涛、王杉等,癌基因STAT3与结直肠癌临床病理特征的关系.中华普通外科杂志2002,17(7):401-403.
10. Q Lin, R Lai, LR Chirieac, et al. Constitutive Activation of JAK3/STAT3 in Colon Carcinoma Tumors and Cell Lines. American Journal of Pathology. 2005;167:969-980.
11. I Alchanati, SC Nallar, P Sun, et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas. Oncogene. 2006, 25:7138–7147
12. X Zhang, Q Huang, Z Yang, et al. GW112, A Novel Antiapoptotic Protein That Promotes Tumor Growth. Cancer Research. 2004;64:2474-2481.
13. Ma X, Kalakonda S, Srinivasula SM, et al. GRIM-19 associates with the serine protease HtrA2 for promoting cell death. Oncogene. 2007;26:4842-4849.
14.龚龙波,罗学来,刘双又;等,GRIM-19及其靶基因产物STAT3与结直肠癌恶性程度的关系.癌症, 2007,(7):683-687
15. Song J I , Grandis J R . STAT signaling in head and neck cancer [J ] . Oncogene, 2000 , 19 (21) : 2489 - 2495.
16. Weber-Nordt R M, Egen C , Wehinger J, et al . Constitutive activation of STAT proteins in primary lymphoid and myeloid leu2 kemia cells and in Epstein-Barr virus ( EBV)-related lymphoma cell lines [J]. Blood , 1996 , 88 (3) : 809 - 816.
17. Zushi S, Shinomura Y, Kiyohara T , et al . STAT3 mediates the survival signal in oncogenic ras-transfected intestinal epithelial cells[J ] . Int J Cancer , 1998 , 78 (3) : 326 - 330.
18.马向涛,王杉,叶颖江,等,Stat3及其靶基因产物与结直肠癌恶性程度关系的研究[J ].癌症, 2003,22(11):1135-1139
19. Real PJ, Sierra A, De Juan A, et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 2002;21:7611-7618.
20. Song H, Sondak VK, Barber DL, et al. Modulation of Janus kinase 2 by cisplatin in cancer cells. Int J Oncol. 2004;24:1017-1026.
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