notch-1基因在胶质瘤中的作用及对Akt-mTOR通路的调控
摘要
Notch信号转导系统在肿瘤发生发展中起重要作用,本实验室前期的研究发现notch-1基因在胶质瘤中表达明显增高,与胶质瘤的发生密切相关,但是Notch-1影响胶质瘤哪些生物学行为及其调控机制仍不清楚。本研究构建了表达Notch-1胞内段NICD(Notch-1的活化形式)的慢病毒,并利用本实验室前期构建好的Notch-1 RNA干扰慢病毒,感染人神经胶质瘤U251细胞,研究Notch-1表达下调和活化对U251胶质瘤细胞增殖、细胞周期、细胞凋亡、侵袭和血管发生的影响及可能的机制。
本研究共分为四部分:
第一部分:notch-1基因胞内段NICD的克隆和慢病毒包装
采用长片段克隆的方法,从胶质瘤U251细胞中提取RNA,经逆转录获得人Notch-1胞内段NICD的cDNA,PCR扩增后将其连接入TA克隆载体pCR-XL-TOPO质粒,测序正确后,经酶切、连接,构建pNL-NICD-IRES2-EGFP慢病毒表达质粒,再和辅助包装质粒Helper和VSVG共转染293T细胞,超滤离心浓缩后,获得滴度为2.0E+8 TU/ml的慢病毒。该病毒感染U251胶质瘤细胞后,荧光显微镜观察感染效率,RT-PCR和Western-blot检测NICD的表达,结果表明NICD的mRNA和蛋白表达量较对照组分别增加约1.6和1.4倍(P < 0.05),说明notch-1基因胞内段NICD克隆成功,并能在细胞内稳定高效表达。
第二部分:Notch-1对胶质瘤细胞增殖、细胞周期和凋亡的影响及机制研究
用notch-1基因RNA干扰或高表达NICD的慢病毒分别感染U251胶质瘤细胞后,用MTT检测细胞增殖、流式细胞术检测细胞周期、Annexin-V法和AO-EB染色检测细胞凋亡、Western-blot法检测周期相关蛋白cyclin D1、CDK-4、P27和凋亡相关蛋白Bcl-2、MCL-1、PARP-1、caspase-3、caspase-9的变化。结果表明:阻断Notch-1能抑制U251细胞的生长,细胞阻滞于G1期(P < 0.05),S期细胞减少(P < 0.05),细胞凋亡增加;过表达NICD的细胞则相反,细胞未见明显凋亡。阻断Notch-1后,U251细胞的cyclin D1、CDK-4、Bcl-2、MCL-1、PARP-1蛋白的表达受到抑制(P < 0.05),P27、caspase-3、caspase-9蛋白的表达上调(P < 0.05),而在过表达NICD的U251细胞其结果则相反。
第三部分:Notch-1对胶质瘤侵袭和血管发生的影响及机制研究
利用基质胶包被的Transwell小室检测U251细胞侵袭能力,内皮细胞小管形成实验观察瘤细胞培养上清对血管形成的影响,同时用Western-blot法检测瘤细胞侵袭相关蛋白MMP-2、MMP-3、MMP-7的表达,RT-PCR和ELASA法检测VEGF的表达,结果显示:阻断Notch-1可抑制U251细胞的侵袭能力和MMP-2、MMP-3的表达,过表达NICD促进肿瘤侵袭能力和侵袭相关蛋白MMP-2、MMP-7的表达;虽然血管发生和VEGF的表达未受影响,但是阻断Notch-1能抑制U87细胞VEGFR-2的表达。
第四部分:Notch-1对Akt-mTOR通路调控的研究
采用Western-blot法检测Notch-1干扰和NICD过表达的U251细胞中Akt-mTOR通路的主要蛋白T-Akt、p-Akt、p-mTOR、p-70S6K、p-4EBP1的表达情况,结果显示:阻断Notch-1能抑制p-Akt、p-mTOR、p-70S6K的表达,过表达NICD的结果则相反。
结论
阻断Notch-1能抑制胶质瘤生长,促进细胞凋亡和周期阻滞,降低胶质瘤的侵袭能力;促增殖的cyclin D1、CDK-4蛋白和抗凋亡的Bcl-2、MCL-1、PARP-1蛋白表达受到抑制,而抑制增殖的P27蛋白和促凋亡的caspase-3、caspase-9蛋白表达上调;并能抑制Akt-mTOR通路的p-Akt、p-mTOR、p-70S6K蛋白的表达。因此,Notch-1可能通过调控Akt-mTOR信号及其下游靶点来影响胶质瘤的存活、增殖和侵袭能力。
Notch signaling system plays an important role in the tumorigenesis and developments. Previous studies in our laboratory have found that notch-1 gene expression was significantly higher and involved in the glioma-genesis. However, which kind of the biological behavior of glioma is regulated by Notch-1 and the mechanism is still not clear. In this study, we constructed lentivirus to express Notch-1 intracellular domain NICD (active form of Notch-1), and in the previous works we have build notch-1 gene RNA interference lentivirus. We used the two lentivirus to infection human glioma U251 cells, observed the effects of Notch-1 on glioma cell proliferation, apoptosis, invasion, angiogenesis and researched the mechanism.
The research including four parts:
Part I: cloning of notch-1 gene intracellular domain NICD and lentiviral packaging
Using a long fragment cloning method, we extracted the mRNA from human U251 glioma cells and then reverse transcribed it into cDNA which contain notch-1 gene intracellular domain NICD, amplificated it by polymerase chain reaction (PCR) and linked with TA cloning vector pCR-XL-TOPO. After sequenced, the correct sequence of NICD was digested and recombined with pNL-IRES2-EGFP lentiviral plasmid. The lentivirus were generated from 293T cells which co-transfection of pNL-NICD-IRES2-EGFP plasmid, packaging plasmids Helper and VSVG. Through ultrafiltration and centrifuge method, we got 2.00E+8 TU/ml of high-titer lentivirus. U251 glioma cells were infected with the lentivirus and transfection effeciency were observed by fluorescence microscope. The expression of NICD mRNA and protein were analyzed by RT-PCR and Western-blot. The results showed an increase about 1.6 times of mRNA and 1.4 times of protein in infected NICD-lentiviral U251 glioma cells compared with control. All these proved that we have succeed in cloning the segment of NICD and expressing it effectently in U251 glioma cells.
Part II: Effects of Notch-1 on glioma proliferation, cell cycle, apoptosis and their mechanisms
U251 glioma cells were infected with Notch-1 RNA interference or over-expression NICD lentivirus. The cell proliferation was assayed with MTT, cell cycle was determined by flow cytometry, apoptosis was checked by Annexin-V labeling and AO/EB staining, The expression of cell cycle-related proteins cyclin D1, CDK-4, P27 and apoptosis-related proteins Bcl-2, MCL-1, PARP-1, caspase-3, caspase-9 were examined by Western-blot. It was found that down-regulation of Notch-1 expression inhibited U251 glioma cell growth, cells were blocked in G1-phase (P< 0.05) and S-phase cells were decreased (P<0.05), apoptotic cells were increased, over-expression of Notch-1 have the contrary results. Down-regulation of Notch-1 expression inhibited cyclin D1, CDK-4, Bcl-2, MCL-1, PARP-1 and increased P27, caspase-3, caspase-9 protein expression in U251 glioma cells, whereas we got the contrary results in U251 glioma cells over-expressed NICD.
Part III: Effects of Notch-1 on glioma cell invasion, angiogenesis and their mechanisms
The effects of Notch-1 gene on U251 glioma cell invasion were examined with matrigel coated transwell chambers, angiogenesis of tumor cell supernatant were measured through endothelial cell tube formation examine. The invasion-related protein MMP-2, MMP-3 and MMP-7 were analyzed by Western-blot, VEGF expression was detected with RT-PCR and ELASA. Results showed that down-regulation of Notch-1 expression inhibited U251 glioma cells invasion and MMP-2, MMP-3 expression, over-expression of NICD promotes U251 glioma cells invasion and invasion-related protein MMP-2 and MMP-7 expression, but there is no change in angiogenesis and VEGF expression. However, Results indicated VEGFR-2 expression was decreased in Notch-1 down-regulated U87 glioma cells.
Part IV: Effects of Notch-1 on Akt-mTOR signaling pathway
We observed the effects of notch-1 gene down-regulation and over-expression on the T-Akt, p-Akt, p-mTOR, p-70S6K and p-4EBP1 in U251 glioma cells using Western-blot analysis, which are the major components of Akt-mTOR signaling. Results showed that down-regulation of Notch-1 expression inhibited p-Akt, p-mTOR and p-70S6K expression. Whereas we got the contrary results in U251 glioma cells over-expressed NICD.
Conclusion
Down-regulation of Notch-1 expression inhibites U251 glioma cell proliferation, results in cell cycle arrest, promotes cell apoptosis and reduces tumor cell invasion. The expression of proliferation accelerating proteins cyclin D1, CDK-4 and anti-apoptosis protein Bcl-2, MCL-1, PARP-1 were inhibited, while the expression of proliferation inhibiting protein P27 and pro-apoptosis proteins caspase-3, caspase-9 were up-regulated. The Akt-mTOR pathway composition including p-Akt, p-mTOR, p-70S6K were inhibited. So Notch-1 probably promotes glioma cell survival, proliferation and invasion through regulating Akt-mTOR signaling and its downstream targets.
本研究共分为四部分:
第一部分:notch-1基因胞内段NICD的克隆和慢病毒包装
采用长片段克隆的方法,从胶质瘤U251细胞中提取RNA,经逆转录获得人Notch-1胞内段NICD的cDNA,PCR扩增后将其连接入TA克隆载体pCR-XL-TOPO质粒,测序正确后,经酶切、连接,构建pNL-NICD-IRES2-EGFP慢病毒表达质粒,再和辅助包装质粒Helper和VSVG共转染293T细胞,超滤离心浓缩后,获得滴度为2.0E+8 TU/ml的慢病毒。该病毒感染U251胶质瘤细胞后,荧光显微镜观察感染效率,RT-PCR和Western-blot检测NICD的表达,结果表明NICD的mRNA和蛋白表达量较对照组分别增加约1.6和1.4倍(P < 0.05),说明notch-1基因胞内段NICD克隆成功,并能在细胞内稳定高效表达。
第二部分:Notch-1对胶质瘤细胞增殖、细胞周期和凋亡的影响及机制研究
用notch-1基因RNA干扰或高表达NICD的慢病毒分别感染U251胶质瘤细胞后,用MTT检测细胞增殖、流式细胞术检测细胞周期、Annexin-V法和AO-EB染色检测细胞凋亡、Western-blot法检测周期相关蛋白cyclin D1、CDK-4、P27和凋亡相关蛋白Bcl-2、MCL-1、PARP-1、caspase-3、caspase-9的变化。结果表明:阻断Notch-1能抑制U251细胞的生长,细胞阻滞于G1期(P < 0.05),S期细胞减少(P < 0.05),细胞凋亡增加;过表达NICD的细胞则相反,细胞未见明显凋亡。阻断Notch-1后,U251细胞的cyclin D1、CDK-4、Bcl-2、MCL-1、PARP-1蛋白的表达受到抑制(P < 0.05),P27、caspase-3、caspase-9蛋白的表达上调(P < 0.05),而在过表达NICD的U251细胞其结果则相反。
第三部分:Notch-1对胶质瘤侵袭和血管发生的影响及机制研究
利用基质胶包被的Transwell小室检测U251细胞侵袭能力,内皮细胞小管形成实验观察瘤细胞培养上清对血管形成的影响,同时用Western-blot法检测瘤细胞侵袭相关蛋白MMP-2、MMP-3、MMP-7的表达,RT-PCR和ELASA法检测VEGF的表达,结果显示:阻断Notch-1可抑制U251细胞的侵袭能力和MMP-2、MMP-3的表达,过表达NICD促进肿瘤侵袭能力和侵袭相关蛋白MMP-2、MMP-7的表达;虽然血管发生和VEGF的表达未受影响,但是阻断Notch-1能抑制U87细胞VEGFR-2的表达。
第四部分:Notch-1对Akt-mTOR通路调控的研究
采用Western-blot法检测Notch-1干扰和NICD过表达的U251细胞中Akt-mTOR通路的主要蛋白T-Akt、p-Akt、p-mTOR、p-70S6K、p-4EBP1的表达情况,结果显示:阻断Notch-1能抑制p-Akt、p-mTOR、p-70S6K的表达,过表达NICD的结果则相反。
结论
阻断Notch-1能抑制胶质瘤生长,促进细胞凋亡和周期阻滞,降低胶质瘤的侵袭能力;促增殖的cyclin D1、CDK-4蛋白和抗凋亡的Bcl-2、MCL-1、PARP-1蛋白表达受到抑制,而抑制增殖的P27蛋白和促凋亡的caspase-3、caspase-9蛋白表达上调;并能抑制Akt-mTOR通路的p-Akt、p-mTOR、p-70S6K蛋白的表达。因此,Notch-1可能通过调控Akt-mTOR信号及其下游靶点来影响胶质瘤的存活、增殖和侵袭能力。
Notch signaling system plays an important role in the tumorigenesis and developments. Previous studies in our laboratory have found that notch-1 gene expression was significantly higher and involved in the glioma-genesis. However, which kind of the biological behavior of glioma is regulated by Notch-1 and the mechanism is still not clear. In this study, we constructed lentivirus to express Notch-1 intracellular domain NICD (active form of Notch-1), and in the previous works we have build notch-1 gene RNA interference lentivirus. We used the two lentivirus to infection human glioma U251 cells, observed the effects of Notch-1 on glioma cell proliferation, apoptosis, invasion, angiogenesis and researched the mechanism.
The research including four parts:
Part I: cloning of notch-1 gene intracellular domain NICD and lentiviral packaging
Using a long fragment cloning method, we extracted the mRNA from human U251 glioma cells and then reverse transcribed it into cDNA which contain notch-1 gene intracellular domain NICD, amplificated it by polymerase chain reaction (PCR) and linked with TA cloning vector pCR-XL-TOPO. After sequenced, the correct sequence of NICD was digested and recombined with pNL-IRES2-EGFP lentiviral plasmid. The lentivirus were generated from 293T cells which co-transfection of pNL-NICD-IRES2-EGFP plasmid, packaging plasmids Helper and VSVG. Through ultrafiltration and centrifuge method, we got 2.00E+8 TU/ml of high-titer lentivirus. U251 glioma cells were infected with the lentivirus and transfection effeciency were observed by fluorescence microscope. The expression of NICD mRNA and protein were analyzed by RT-PCR and Western-blot. The results showed an increase about 1.6 times of mRNA and 1.4 times of protein in infected NICD-lentiviral U251 glioma cells compared with control. All these proved that we have succeed in cloning the segment of NICD and expressing it effectently in U251 glioma cells.
Part II: Effects of Notch-1 on glioma proliferation, cell cycle, apoptosis and their mechanisms
U251 glioma cells were infected with Notch-1 RNA interference or over-expression NICD lentivirus. The cell proliferation was assayed with MTT, cell cycle was determined by flow cytometry, apoptosis was checked by Annexin-V labeling and AO/EB staining, The expression of cell cycle-related proteins cyclin D1, CDK-4, P27 and apoptosis-related proteins Bcl-2, MCL-1, PARP-1, caspase-3, caspase-9 were examined by Western-blot. It was found that down-regulation of Notch-1 expression inhibited U251 glioma cell growth, cells were blocked in G1-phase (P< 0.05) and S-phase cells were decreased (P<0.05), apoptotic cells were increased, over-expression of Notch-1 have the contrary results. Down-regulation of Notch-1 expression inhibited cyclin D1, CDK-4, Bcl-2, MCL-1, PARP-1 and increased P27, caspase-3, caspase-9 protein expression in U251 glioma cells, whereas we got the contrary results in U251 glioma cells over-expressed NICD.
Part III: Effects of Notch-1 on glioma cell invasion, angiogenesis and their mechanisms
The effects of Notch-1 gene on U251 glioma cell invasion were examined with matrigel coated transwell chambers, angiogenesis of tumor cell supernatant were measured through endothelial cell tube formation examine. The invasion-related protein MMP-2, MMP-3 and MMP-7 were analyzed by Western-blot, VEGF expression was detected with RT-PCR and ELASA. Results showed that down-regulation of Notch-1 expression inhibited U251 glioma cells invasion and MMP-2, MMP-3 expression, over-expression of NICD promotes U251 glioma cells invasion and invasion-related protein MMP-2 and MMP-7 expression, but there is no change in angiogenesis and VEGF expression. However, Results indicated VEGFR-2 expression was decreased in Notch-1 down-regulated U87 glioma cells.
Part IV: Effects of Notch-1 on Akt-mTOR signaling pathway
We observed the effects of notch-1 gene down-regulation and over-expression on the T-Akt, p-Akt, p-mTOR, p-70S6K and p-4EBP1 in U251 glioma cells using Western-blot analysis, which are the major components of Akt-mTOR signaling. Results showed that down-regulation of Notch-1 expression inhibited p-Akt, p-mTOR and p-70S6K expression. Whereas we got the contrary results in U251 glioma cells over-expressed NICD.
Conclusion
Down-regulation of Notch-1 expression inhibites U251 glioma cell proliferation, results in cell cycle arrest, promotes cell apoptosis and reduces tumor cell invasion. The expression of proliferation accelerating proteins cyclin D1, CDK-4 and anti-apoptosis protein Bcl-2, MCL-1, PARP-1 were inhibited, while the expression of proliferation inhibiting protein P27 and pro-apoptosis proteins caspase-3, caspase-9 were up-regulated. The Akt-mTOR pathway composition including p-Akt, p-mTOR, p-70S6K were inhibited. So Notch-1 probably promotes glioma cell survival, proliferation and invasion through regulating Akt-mTOR signaling and its downstream targets.
引文
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