miR-21对人胶质瘤细胞株SHG-44放射敏感性影响及其影响机制研究
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摘要
目的:观察miR-21在人脑胶质瘤细胞SHG-44及其辐射抗性模型中的表达差异,探讨敲低miR-21表达联合辐射对SHG-44辐射敏感性的影响,为以miR-21为靶点的分子靶向放疗增敏提供体外研究的理论及实验依据。
方法:使用胶质瘤细胞株SHG-44,建立辐射抗性胶质瘤模型SHG-44抗,分别给予6 MV X射线单次照射0、1、2、4、6、8 Gy,多靶单击模型拟合细胞存活曲线,评估所构建模型的辐射抗性效果。使用Taqman探针实时荧光定量PCR法检测SHG-44及SHG-44抗细胞株中miR-21表达,Western Blot法检测信号转导子和转录激活子3蛋白表达(stat3)。使用脂质体介导采用瞬间转染法转染反义miR-21寡核苷酸(AS-miR-21)及阴性对照寡核苷酸于胶质瘤SHG-44细胞中。设空白对照组、阴性对照转染组及AS-miR-21转染组,成克隆实验计算放射增敏比(SER),绘制细胞存活曲线。流式细胞仪检测上述3组及联合单次6 Gy照射后细胞凋亡率、细胞周期变化。吖啶橙/溴乙啶染色法,在激光共聚焦显微镜下观察辐射联合组SHG-44细胞凋亡的形态学特征。
结果:成功建立了SHG-44抗辐射抗性细胞株,集落形成实验显示SHG-44细胞D0=2.35、SF2=0.62 ,SHG-44抗细胞D0=3.22,SF2=0.74,两组SF2比较差异有统计学意义(t = 4.13,P < 0.05)。qRT-PCR及Western blot法检测SHG-44抗细胞的miR-21表达及stat3蛋白表达均较SHG-44升高。SHG-44细胞转染AS-miR-21组的D0、Dq及SF2值较空白对照组及阴性转染组降低,放射增敏比SERD0、SERDq分别为1.32、2.10。细胞周期分析示转染组较空白对照及阴性对照组的G0+G1期比例增高,S期比例降低且差异均具有统计学意义(P<0.05)。凋亡分析示照射组、miR-21转染组及联合组的早期凋亡率均高于对照组(P<0.05)。AO/EB染色可见联合组凋亡细胞核固缩、核碎裂,凋亡小体形成。
结论:SHG-44为一高表达miR-21细胞株,且SHG-44照射后代细胞miR-21表达增高, stat3蛋白可能参与了miR-21表达的调节。抑制miR-21表达可增加SHG-44细胞放射敏感性,其机制可能与促进细胞凋亡及周期再分布有关。
Objective:To observation miR-21 differential expression in the model of radioresistant glioma SHG-44 cells and SHG-44 cells,and investigate the radiosensitizing effect of knock-down the expression of miR-21 by antisense oligonuleotides of miR-21(AS-miR-21) on human SHG-44 glioma cells.
Methods:Radioresistant cell model(SHG-44R) were established from SHG-44 glioma cells line Then the radiosensitivity of SHG-44 and SHG-44R were studied by clonogenic assay.Multi-target single-hit model were used to plot the survival curve. Meanwhile,expression levels of miR-21 in SHG-44R and SHG-44 were determined by quantitative real time PCR(qRT-PCR). Stat3 protain were detected by western blot.As-miR-21,mediated by LipofectamineTM2000,were transfected to SHG-44 cells.Three groups were studied:blank control group(mock group),negative control and Antisense transfected group(AS-miR-21 gorup). Cells of each group were irradiated with 6 MV X-ray at the dose of 0,1,2,4,6 and 8 Gy.Dose-Suvivial curve of each group was established by colony-forming assay.The influence of AS-miR-21 on cell cycle and cell apoptosis was analyzed by flow cytometry assay after 6 Gy irradiation.Morphology feature of apoptosis was observed by laser confocal micorscope in SHG-44 cells stained with AO/EB.
Results: miR-21 was up-regulation 1.49 fold in SHG-44R cells relative to the SHG-44 cells. The up-regulation of miR-21 expression was shown to be associated with a increase in the level of stat3 protein。The value of D0、Dq and SF2 of AS-miR-21 group declined obviously compared with the mock group and negative control group.Flow cytometric analysis showed that cell cycle distribution changed(G0+G1 phase arrest,S phase decreased) after transfected with AS-miR-21(P<0.05).Apoptosis assay showed the early apoptosis rate was significantely increased in AS-miR-21、irradition alone and combined group than mock or negative control group(P<0.05).
Conclusions:miR-21 may represent a new molecular target and may provide a basis for the use of the AS-miR-21 as potential radiosensitizers for treatment of the glioma tumors.
方法:使用胶质瘤细胞株SHG-44,建立辐射抗性胶质瘤模型SHG-44抗,分别给予6 MV X射线单次照射0、1、2、4、6、8 Gy,多靶单击模型拟合细胞存活曲线,评估所构建模型的辐射抗性效果。使用Taqman探针实时荧光定量PCR法检测SHG-44及SHG-44抗细胞株中miR-21表达,Western Blot法检测信号转导子和转录激活子3蛋白表达(stat3)。使用脂质体介导采用瞬间转染法转染反义miR-21寡核苷酸(AS-miR-21)及阴性对照寡核苷酸于胶质瘤SHG-44细胞中。设空白对照组、阴性对照转染组及AS-miR-21转染组,成克隆实验计算放射增敏比(SER),绘制细胞存活曲线。流式细胞仪检测上述3组及联合单次6 Gy照射后细胞凋亡率、细胞周期变化。吖啶橙/溴乙啶染色法,在激光共聚焦显微镜下观察辐射联合组SHG-44细胞凋亡的形态学特征。
结果:成功建立了SHG-44抗辐射抗性细胞株,集落形成实验显示SHG-44细胞D0=2.35、SF2=0.62 ,SHG-44抗细胞D0=3.22,SF2=0.74,两组SF2比较差异有统计学意义(t = 4.13,P < 0.05)。qRT-PCR及Western blot法检测SHG-44抗细胞的miR-21表达及stat3蛋白表达均较SHG-44升高。SHG-44细胞转染AS-miR-21组的D0、Dq及SF2值较空白对照组及阴性转染组降低,放射增敏比SERD0、SERDq分别为1.32、2.10。细胞周期分析示转染组较空白对照及阴性对照组的G0+G1期比例增高,S期比例降低且差异均具有统计学意义(P<0.05)。凋亡分析示照射组、miR-21转染组及联合组的早期凋亡率均高于对照组(P<0.05)。AO/EB染色可见联合组凋亡细胞核固缩、核碎裂,凋亡小体形成。
结论:SHG-44为一高表达miR-21细胞株,且SHG-44照射后代细胞miR-21表达增高, stat3蛋白可能参与了miR-21表达的调节。抑制miR-21表达可增加SHG-44细胞放射敏感性,其机制可能与促进细胞凋亡及周期再分布有关。
Objective:To observation miR-21 differential expression in the model of radioresistant glioma SHG-44 cells and SHG-44 cells,and investigate the radiosensitizing effect of knock-down the expression of miR-21 by antisense oligonuleotides of miR-21(AS-miR-21) on human SHG-44 glioma cells.
Methods:Radioresistant cell model(SHG-44R) were established from SHG-44 glioma cells line Then the radiosensitivity of SHG-44 and SHG-44R were studied by clonogenic assay.Multi-target single-hit model were used to plot the survival curve. Meanwhile,expression levels of miR-21 in SHG-44R and SHG-44 were determined by quantitative real time PCR(qRT-PCR). Stat3 protain were detected by western blot.As-miR-21,mediated by LipofectamineTM2000,were transfected to SHG-44 cells.Three groups were studied:blank control group(mock group),negative control and Antisense transfected group(AS-miR-21 gorup). Cells of each group were irradiated with 6 MV X-ray at the dose of 0,1,2,4,6 and 8 Gy.Dose-Suvivial curve of each group was established by colony-forming assay.The influence of AS-miR-21 on cell cycle and cell apoptosis was analyzed by flow cytometry assay after 6 Gy irradiation.Morphology feature of apoptosis was observed by laser confocal micorscope in SHG-44 cells stained with AO/EB.
Results: miR-21 was up-regulation 1.49 fold in SHG-44R cells relative to the SHG-44 cells. The up-regulation of miR-21 expression was shown to be associated with a increase in the level of stat3 protein。The value of D0、Dq and SF2 of AS-miR-21 group declined obviously compared with the mock group and negative control group.Flow cytometric analysis showed that cell cycle distribution changed(G0+G1 phase arrest,S phase decreased) after transfected with AS-miR-21(P<0.05).Apoptosis assay showed the early apoptosis rate was significantely increased in AS-miR-21、irradition alone and combined group than mock or negative control group(P<0.05).
Conclusions:miR-21 may represent a new molecular target and may provide a basis for the use of the AS-miR-21 as potential radiosensitizers for treatment of the glioma tumors.
引文
[1] CiafrèSA, Galardi S, Mangiola A.Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun.2005,334:1351-1358.
[2] Nam EJ, Yoon H, Kim SW. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res,2008,14:2690-2695.
[3] Zhang Z, Li Z, Gao C.miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest,2008,88:1358-1366.
[4]周菊英,李莉,周乐源,等.胶质瘤SHG-44细胞株受照后代辐射抗性的研究.中华放射肿瘤学杂志,2008,17:238-240.
[5] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)).Method,2001,25(4):402-408.
[6]王洗,刘强.脑胶质瘤辐射敏感性相关基因的研究进展.国际放射医学核医学杂志,2008,32:311-313.
[7]周冲王利利周菊英.微RNA在分子放射生物学中的研究进展.国际放射医学核医学杂志,2009,33(2) 109-112.
[8] Chan JA, Krichevsky AM, Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res,2005,65(14):6029-6033.
[9] Krichevsky AM, Gabriely G.miR-21: a small multi-faceted RNA. J Cell Mol Med,2009,13:39-53.
[10] Rossi L, Bonmassar E, Faraoni I.Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro.Pharmacol Res,2007, 56:248-253.
[11] Blower PE, Chung JH, Verducci JS, et al. MicroRNAs modulate the chemosensitivity of tumor cells.Mol Cancer Ther,2008,7:1-9
[12] Roversi G, Pfundt R, Moroni RF,et al.Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.Oncogene,2006,25:1571-1583.
[13] Fulci V, Chiaretti S, Goldoni M,et al.Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia.Blood,2007,109:4944-4951.
[14] L?ffler D, Brocke-Heidrich K, Pfeifer G,et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer.Blood,2007,110:1330-1333.
[15]祝宝让.反义STAT3设计及其对肺腺癌A549细胞辐射敏感性影响的研究.中国优秀硕士学位论文全文数据库,2007,(03).
[1] Chan JA, Krichevsky AM, Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res,2005,65(14):6029-6033.
[2] Zhu S, Wu H, Wu F, et al.MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.Cell Res,2008,18(3):350-359.
[3] Krichevsky AM, Gabriely G.miR-21: a small multi-faceted RNA.J Cell Mol Med,2009,13(1):39-53.
[4]王芳,孟颖,刘民,等. MicroRNA-21反义寡核苷酸可以抑制U373MG细胞对替尼泊苷VM-26的耐受性.中国生物化学与分子生物学报, 2008,24(7):674-678.
[5] Corsten MF, Miranda R, Kasmieh R et al. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cell Res, 2007,67(19):8994-9000.
[6] Weidhaas JB, Babar I, Nallur SM,et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res, 2007,67(23):11111-11116.
[7] Josson S, Sung SY, Lao K,et al.Radiation modulation of microRNA in prostate cancer cell lines. Prostate,2008,68(15):1599-1606.
[8]周菊英,涂彧,徐晓婷,等.对乙酰氨基酚对不同脑胶质瘤细胞的放射增敏作用及其机制研究.中华放射医学与防护杂志,2008,28(5):502-505.
[9] Papagiannakopoulos T, Shapiro A, Kosik KS.MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells.Cancer Res,2008,68(19):8164-8172.
[10]殷蔚伯,余子豪,徐国镇,等.肿瘤放射治疗学(第四版).中国协和医科大学出版社,2008:299..
[1] Lee RC,Feinbaum RL,Ambros V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J].Cell,1993,75(5):843-854.
[2] BJ,Slack FJ,Basson M,et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J].Nature,2000,403(6772):901-906.
[3] Sassen S, Miska EA, Caldas C.MicroRNA: implications for cancer[J].Virchows Arch,2008,452(1):1-10.
[4] Venturini L,Battmer K,Castoldi M,et al.Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells[J].Blood,2007,109(10):4399-4405.
[5] Welch C,Chen Y,Stallings RL.MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells[J].Oncogene,2007, 26(34): 5017-5022.
[6] Ishii H,Saito T.Radiation-induced response of micro RNA expression in murine embryonic stem cells[J].Med Chem,2006,2(6):555-563.
[7] Marsit CJ,Eddy K,Kelsey KT.MicroRNA responses to cellular stress[J].Cancer Res,2006,66(22):10843-10848.
[8] Maes OC,An J,Sarojini H,et al.Changes in MicroRNA expression patterns in human fibroblasts after low-LET radiation[J].J Cell Biochem,2008,105(3):824-834.
[9] Jaklevic B,Uyetake L,Wichmann A,et al.Modulation of ionizing radiation-induced apoptosis by bantam microRNA in Drosophila[J].Dev Biol,2008,320(1):122-130.
[10] Ohnishi T,Takahashi A,Mori E,et al.p53 Targeting can enhance cancer therapy via radiation, heat and anti-cancer agents[J].Anticancer Agents Med Chem,2008,8(5): 564-570.
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[2] Nam EJ, Yoon H, Kim SW. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res,2008,14:2690-2695.
[3] Zhang Z, Li Z, Gao C.miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest,2008,88:1358-1366.
[4]周菊英,李莉,周乐源,等.胶质瘤SHG-44细胞株受照后代辐射抗性的研究.中华放射肿瘤学杂志,2008,17:238-240.
[5] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)).Method,2001,25(4):402-408.
[6]王洗,刘强.脑胶质瘤辐射敏感性相关基因的研究进展.国际放射医学核医学杂志,2008,32:311-313.
[7]周冲王利利周菊英.微RNA在分子放射生物学中的研究进展.国际放射医学核医学杂志,2009,33(2) 109-112.
[8] Chan JA, Krichevsky AM, Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res,2005,65(14):6029-6033.
[9] Krichevsky AM, Gabriely G.miR-21: a small multi-faceted RNA. J Cell Mol Med,2009,13:39-53.
[10] Rossi L, Bonmassar E, Faraoni I.Modification of miR gene expression pattern in human colon cancer cells following exposure to 5-fluorouracil in vitro.Pharmacol Res,2007, 56:248-253.
[11] Blower PE, Chung JH, Verducci JS, et al. MicroRNAs modulate the chemosensitivity of tumor cells.Mol Cancer Ther,2008,7:1-9
[12] Roversi G, Pfundt R, Moroni RF,et al.Identification of novel genomic markers related to progression to glioblastoma through genomic profiling of 25 primary glioma cell lines.Oncogene,2006,25:1571-1583.
[13] Fulci V, Chiaretti S, Goldoni M,et al.Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia.Blood,2007,109:4944-4951.
[14] L?ffler D, Brocke-Heidrich K, Pfeifer G,et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer.Blood,2007,110:1330-1333.
[15]祝宝让.反义STAT3设计及其对肺腺癌A549细胞辐射敏感性影响的研究.中国优秀硕士学位论文全文数据库,2007,(03).
[1] Chan JA, Krichevsky AM, Kosik KS.MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.Cancer Res,2005,65(14):6029-6033.
[2] Zhu S, Wu H, Wu F, et al.MicroRNA-21 targets tumor suppressor genes in invasion and metastasis.Cell Res,2008,18(3):350-359.
[3] Krichevsky AM, Gabriely G.miR-21: a small multi-faceted RNA.J Cell Mol Med,2009,13(1):39-53.
[4]王芳,孟颖,刘民,等. MicroRNA-21反义寡核苷酸可以抑制U373MG细胞对替尼泊苷VM-26的耐受性.中国生物化学与分子生物学报, 2008,24(7):674-678.
[5] Corsten MF, Miranda R, Kasmieh R et al. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas.Cell Res, 2007,67(19):8994-9000.
[6] Weidhaas JB, Babar I, Nallur SM,et al. MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy. Cancer Res, 2007,67(23):11111-11116.
[7] Josson S, Sung SY, Lao K,et al.Radiation modulation of microRNA in prostate cancer cell lines. Prostate,2008,68(15):1599-1606.
[8]周菊英,涂彧,徐晓婷,等.对乙酰氨基酚对不同脑胶质瘤细胞的放射增敏作用及其机制研究.中华放射医学与防护杂志,2008,28(5):502-505.
[9] Papagiannakopoulos T, Shapiro A, Kosik KS.MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells.Cancer Res,2008,68(19):8164-8172.
[10]殷蔚伯,余子豪,徐国镇,等.肿瘤放射治疗学(第四版).中国协和医科大学出版社,2008:299..
[1] Lee RC,Feinbaum RL,Ambros V.The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J].Cell,1993,75(5):843-854.
[2] BJ,Slack FJ,Basson M,et al.The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans[J].Nature,2000,403(6772):901-906.
[3] Sassen S, Miska EA, Caldas C.MicroRNA: implications for cancer[J].Virchows Arch,2008,452(1):1-10.
[4] Venturini L,Battmer K,Castoldi M,et al.Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells[J].Blood,2007,109(10):4399-4405.
[5] Welch C,Chen Y,Stallings RL.MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells[J].Oncogene,2007, 26(34): 5017-5022.
[6] Ishii H,Saito T.Radiation-induced response of micro RNA expression in murine embryonic stem cells[J].Med Chem,2006,2(6):555-563.
[7] Marsit CJ,Eddy K,Kelsey KT.MicroRNA responses to cellular stress[J].Cancer Res,2006,66(22):10843-10848.
[8] Maes OC,An J,Sarojini H,et al.Changes in MicroRNA expression patterns in human fibroblasts after low-LET radiation[J].J Cell Biochem,2008,105(3):824-834.
[9] Jaklevic B,Uyetake L,Wichmann A,et al.Modulation of ionizing radiation-induced apoptosis by bantam microRNA in Drosophila[J].Dev Biol,2008,320(1):122-130.
[10] Ohnishi T,Takahashi A,Mori E,et al.p53 Targeting can enhance cancer therapy via radiation, heat and anti-cancer agents[J].Anticancer Agents Med Chem,2008,8(5): 564-570.
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