蛋白激酶Cξ在胶质瘤细胞和单核/巨噬细胞趋化运动中的功能研究
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摘要
研究背景和目的:
脑胶质瘤是神经系统发病率最高的肿瘤,其侵袭性的生长方式,是胶质瘤预后欠佳的重要原因。本研究第一部分探讨PKCξ在EGF诱导的两种人胶质瘤细胞运动和侵袭中的作用及其相关分子机制,以阐明PKCξ基因与胶质瘤细胞运动和侵袭、细胞外基质黏附、肌动蛋白聚合和解聚之间的关系。
大量研究发现,在肺癌、乳腺癌等肿瘤组织中,巨噬细胞不仅不能清除肿瘤,反而主动抑制机体免疫应答,在肿瘤的发生、进展和转移等过程中起了促进作用。在本研究第二部分中,进一步利用小RNA干扰技术降低PKC在细胞中的表达水平,通过比较正常单核/巨噬细胞和转染干扰PKCξ表达质粒的单核/巨噬细胞,探讨PKC降表达对单核/巨噬细胞趋化运动能力的影响及其相关分子机制,明确PKCξ基因在单核/巨噬细胞趋化运动中的作用。
研究方法:
1)应用PKC家族抑制剂探讨非典型PKC亚家族在胶质瘤细胞和单核/巨噬细胞趋化运动中的作用。建立稳定转染空载体,稳定转染PKCξ降表达的胶质瘤细胞和单核/巨噬细胞。
2)趋化运动实验和趋化动力学实验,探讨PKC降表达后对胶质瘤细胞和单核/巨噬细胞趋化运动能力的影响。
3)肌动蛋白聚合实验,探讨趋化因子刺激不同时间后肌动蛋白聚合的变化,采用磷酸化特异性抗体检测不同PKCξ表达对趋化因子刺激后LIMK和cofilin磷酸化水平的影响。
4)应用豆蔻酰化的PKCξ的特异性假底物进一步探讨PKC对胶质瘤细胞或单核/巨噬细胞趋化运动能力和肌动蛋白聚合的影响。
5)应用Stealth~(TM) RNA降低PKC在小鼠腹腔巨噬细胞的表达,探讨PKC对CSF-1和MCP-1诱导的巨噬细胞趋化运动能力的影响。
6)黏附实验检测PKC降表达对胶质瘤细胞黏附能力的影响,同时采用磷酸化特异性抗体检测不同PKCξ表达对EGF刺激后integrinβ1磷酸化水平的影响。
7)体外侵袭实验检测PKC降表达对胶质瘤细胞侵袭能力的影响,同时将PKC降表达的胶质瘤细胞接种到裸鼠体内,观察PKC对体内胶质瘤细胞侵袭能力的影响。
结果:
1)应用PKC各亚型的抑制剂证实了非典型PKC在胶质瘤细胞和单核/巨噬细胞趋化运动中起到重要作用。
2)应用小RNA干扰技术转染胶质瘤细胞和单核/巨噬细胞后,PKC的mRNA和蛋白水平均明显下降。
3) PKC降表达的胶质瘤细胞和单核/巨噬细胞趋化运动能力比对照组细胞明显减弱(P<0.05)。
4) PKC降表达的胶质瘤细胞和单核/巨噬细胞F-actin聚合比对照组细胞减少(P<0.05)。Western blotting证实,降低PKC的表达能够明显减低与F-actin聚合和解聚相关的LIMK和cofilin的磷酸化水平。
5) PKC降表达的胶质瘤细胞比对照组的黏附数量明显减少(P<0.05),而且与黏附功能相关的磷酸化integrinβ1的表达也明显降低。
6)体内和体外实验均证实PKC降表达的胶质瘤细胞侵袭能力比对照组细胞明显减弱(P<0.05),同时与细胞侵袭相关的MMP-9的表达也明显降低, MMP-2的表达没有检测到变化。
7)应用化学合成的小RNA干扰技术转染小鼠腹腔巨噬细胞后,PKC降表达的巨噬细胞修复划痕的速度比对照细胞慢(P<0.05)。
8) PKC降表达的巨噬细胞在CSF-1和MCP-1诱导的趋化运动能力比对照细胞明显减弱(P<0.05)
结论:
1) PKC参与了EGF诱导的胶质瘤细胞的运动和侵袭。PKC是通过调节LIMK/cofilin和integrinβ1的活化来调节胶质瘤细胞骨架重排和细胞黏附的。
2) PKC参与了CSF-1诱导的单核/巨噬细胞的趋化运动。PKC是通过调节LIMK/cofilin的活化来调节单核/巨噬细胞细胞骨架重排的。
3) PKC是G蛋白耦联受体和酪氨酸激酶受体两条信号传导通路的共同信号分子。
Background and Objective
Brain glioma is the highest morbidity tumors in nervous system.We aimed toexplain the relationship between PKCζand cell migration,adhesion and actinpolymerization.
In our study,we aimed to explain the influence of PKCζdown-regulation onmonocytes/macrophages chemotaxis and the related molecular mechanism.
Methods
1)We studied the role of atypical PKC chemokine-mediated chemotaxis of gliomaand monocytes/macrophages by using various PKC specific inhibitors.
2)Chemotaxis assay and chemokinesis assay demonstrated the influence of PKCζon the chemotaxis ability of glioma cells and monocytes/macrophages.
3)F-actin polymerization assay explained the changes of actin polymerizationstimulated by chemokines in different times.Western blotting assay detected theexpression ofphospho-LIMK and cofilin in siPKCζcells and control cells.
4)Treated the cells by the specific myristolated PKCζpseudosubstrate to furtherdemonstrate the influence of PKCζon the cell migration.
5)Using a small interference RNA strategy to attenuate PKCζexpression in mouseperitoneal macrophages and demonstrated the influence of PKCζon macrophage.
6)Adhesion assay detected the influence of down-regulated PKCζon the adhesionof glioma cells.Western blotting assay detected the expression ofphospho-integrinβ1 siPKCζglioma cells and control glioma cells.
7)We used the subcutaneous mouse xenograft model and invasion in vitro assay tovalidate the role of PKCζin glioblastoma invasion in vivo.
Results
1)Using specific inhibitors of PKC isotypes demonstrated that atypical PKC playsan important role in glioma cells and monocytes/macrophages chemotaxis.
2)After transfected glioma and monocytes/macrophages by small interference RNA, the exression of PKCζsignificantly decreased.
3)PKCζ-reduced glioma cells and monocytes/macrophages showed decreasedchemotaxis ability compared with control cells (P＜0.05).
4)PKCζ-reduced glioma cells and monocytes/macrophages showed decreased actinpolymerization ability compared with the control cells (P＜0.05).The expressionofphospho-LIMK/cofilin was down regulated.
5)The adherent cell of PKCζ-reduced glioma cells is significantly reducedcompared with control cells (P＜0.05).The expression of phospho-integrinβ1 wasdown regulated.
6)Both in vivo and in vitro assay demonstrated that the invasion ability ofPKCζ-reduced glioma cells is significantly reduced compared with controlcells(P＜0.05).The expression of MMP-9 was also down regulated in siPKCζcells.
7)When knock-down of PKCζby Stealth~(TM)RNA in mouse peritoneal macrophages,it took the PKCζ-reduced macrophages a longer time to fill the gap (P＜0.05).
8)The chemotaxis ability of PKCζ-reduced mouse peritoneal macrophages issignificantly decreased compared with control cells induced by CSF-1 andMCP-1 (P＜0.05).
Conclusions
1)PKCζparticipated in EGF-induced glioma cells migration and invasion.PKCζaccommodated the activation of LIMK/cofilin and integrinβ1 to controlcytoskeletal rearrangement and adhesion.
2)PKCζparticipated in CSF-1 induced monocytes/macrophages chemotaxis.PKCζaccommodate the activation of LIMK/cofilin to control cytoskeletalrearrangement.
3)PKCζmay be required for both GPCR and RTK mediated chemotaxis signalingpathways.
脑胶质瘤是神经系统发病率最高的肿瘤,其侵袭性的生长方式,是胶质瘤预后欠佳的重要原因。本研究第一部分探讨PKCξ在EGF诱导的两种人胶质瘤细胞运动和侵袭中的作用及其相关分子机制,以阐明PKCξ基因与胶质瘤细胞运动和侵袭、细胞外基质黏附、肌动蛋白聚合和解聚之间的关系。
大量研究发现,在肺癌、乳腺癌等肿瘤组织中,巨噬细胞不仅不能清除肿瘤,反而主动抑制机体免疫应答,在肿瘤的发生、进展和转移等过程中起了促进作用。在本研究第二部分中,进一步利用小RNA干扰技术降低PKC在细胞中的表达水平,通过比较正常单核/巨噬细胞和转染干扰PKCξ表达质粒的单核/巨噬细胞,探讨PKC降表达对单核/巨噬细胞趋化运动能力的影响及其相关分子机制,明确PKCξ基因在单核/巨噬细胞趋化运动中的作用。
研究方法:
1)应用PKC家族抑制剂探讨非典型PKC亚家族在胶质瘤细胞和单核/巨噬细胞趋化运动中的作用。建立稳定转染空载体,稳定转染PKCξ降表达的胶质瘤细胞和单核/巨噬细胞。
2)趋化运动实验和趋化动力学实验,探讨PKC降表达后对胶质瘤细胞和单核/巨噬细胞趋化运动能力的影响。
3)肌动蛋白聚合实验,探讨趋化因子刺激不同时间后肌动蛋白聚合的变化,采用磷酸化特异性抗体检测不同PKCξ表达对趋化因子刺激后LIMK和cofilin磷酸化水平的影响。
4)应用豆蔻酰化的PKCξ的特异性假底物进一步探讨PKC对胶质瘤细胞或单核/巨噬细胞趋化运动能力和肌动蛋白聚合的影响。
5)应用Stealth~(TM) RNA降低PKC在小鼠腹腔巨噬细胞的表达,探讨PKC对CSF-1和MCP-1诱导的巨噬细胞趋化运动能力的影响。
6)黏附实验检测PKC降表达对胶质瘤细胞黏附能力的影响,同时采用磷酸化特异性抗体检测不同PKCξ表达对EGF刺激后integrinβ1磷酸化水平的影响。
7)体外侵袭实验检测PKC降表达对胶质瘤细胞侵袭能力的影响,同时将PKC降表达的胶质瘤细胞接种到裸鼠体内,观察PKC对体内胶质瘤细胞侵袭能力的影响。
结果:
1)应用PKC各亚型的抑制剂证实了非典型PKC在胶质瘤细胞和单核/巨噬细胞趋化运动中起到重要作用。
2)应用小RNA干扰技术转染胶质瘤细胞和单核/巨噬细胞后,PKC的mRNA和蛋白水平均明显下降。
3) PKC降表达的胶质瘤细胞和单核/巨噬细胞趋化运动能力比对照组细胞明显减弱(P<0.05)。
4) PKC降表达的胶质瘤细胞和单核/巨噬细胞F-actin聚合比对照组细胞减少(P<0.05)。Western blotting证实,降低PKC的表达能够明显减低与F-actin聚合和解聚相关的LIMK和cofilin的磷酸化水平。
5) PKC降表达的胶质瘤细胞比对照组的黏附数量明显减少(P<0.05),而且与黏附功能相关的磷酸化integrinβ1的表达也明显降低。
6)体内和体外实验均证实PKC降表达的胶质瘤细胞侵袭能力比对照组细胞明显减弱(P<0.05),同时与细胞侵袭相关的MMP-9的表达也明显降低, MMP-2的表达没有检测到变化。
7)应用化学合成的小RNA干扰技术转染小鼠腹腔巨噬细胞后,PKC降表达的巨噬细胞修复划痕的速度比对照细胞慢(P<0.05)。
8) PKC降表达的巨噬细胞在CSF-1和MCP-1诱导的趋化运动能力比对照细胞明显减弱(P<0.05)
结论:
1) PKC参与了EGF诱导的胶质瘤细胞的运动和侵袭。PKC是通过调节LIMK/cofilin和integrinβ1的活化来调节胶质瘤细胞骨架重排和细胞黏附的。
2) PKC参与了CSF-1诱导的单核/巨噬细胞的趋化运动。PKC是通过调节LIMK/cofilin的活化来调节单核/巨噬细胞细胞骨架重排的。
3) PKC是G蛋白耦联受体和酪氨酸激酶受体两条信号传导通路的共同信号分子。
Background and Objective
Brain glioma is the highest morbidity tumors in nervous system.We aimed toexplain the relationship between PKCζand cell migration,adhesion and actinpolymerization.
In our study,we aimed to explain the influence of PKCζdown-regulation onmonocytes/macrophages chemotaxis and the related molecular mechanism.
Methods
1)We studied the role of atypical PKC chemokine-mediated chemotaxis of gliomaand monocytes/macrophages by using various PKC specific inhibitors.
2)Chemotaxis assay and chemokinesis assay demonstrated the influence of PKCζon the chemotaxis ability of glioma cells and monocytes/macrophages.
3)F-actin polymerization assay explained the changes of actin polymerizationstimulated by chemokines in different times.Western blotting assay detected theexpression ofphospho-LIMK and cofilin in siPKCζcells and control cells.
4)Treated the cells by the specific myristolated PKCζpseudosubstrate to furtherdemonstrate the influence of PKCζon the cell migration.
5)Using a small interference RNA strategy to attenuate PKCζexpression in mouseperitoneal macrophages and demonstrated the influence of PKCζon macrophage.
6)Adhesion assay detected the influence of down-regulated PKCζon the adhesionof glioma cells.Western blotting assay detected the expression ofphospho-integrinβ1 siPKCζglioma cells and control glioma cells.
7)We used the subcutaneous mouse xenograft model and invasion in vitro assay tovalidate the role of PKCζin glioblastoma invasion in vivo.
Results
1)Using specific inhibitors of PKC isotypes demonstrated that atypical PKC playsan important role in glioma cells and monocytes/macrophages chemotaxis.
2)After transfected glioma and monocytes/macrophages by small interference RNA, the exression of PKCζsignificantly decreased.
3)PKCζ-reduced glioma cells and monocytes/macrophages showed decreasedchemotaxis ability compared with control cells (P＜0.05).
4)PKCζ-reduced glioma cells and monocytes/macrophages showed decreased actinpolymerization ability compared with the control cells (P＜0.05).The expressionofphospho-LIMK/cofilin was down regulated.
5)The adherent cell of PKCζ-reduced glioma cells is significantly reducedcompared with control cells (P＜0.05).The expression of phospho-integrinβ1 wasdown regulated.
6)Both in vivo and in vitro assay demonstrated that the invasion ability ofPKCζ-reduced glioma cells is significantly reduced compared with controlcells(P＜0.05).The expression of MMP-9 was also down regulated in siPKCζcells.
7)When knock-down of PKCζby Stealth~(TM)RNA in mouse peritoneal macrophages,it took the PKCζ-reduced macrophages a longer time to fill the gap (P＜0.05).
8)The chemotaxis ability of PKCζ-reduced mouse peritoneal macrophages issignificantly decreased compared with control cells induced by CSF-1 andMCP-1 (P＜0.05).
Conclusions
1)PKCζparticipated in EGF-induced glioma cells migration and invasion.PKCζaccommodated the activation of LIMK/cofilin and integrinβ1 to controlcytoskeletal rearrangement and adhesion.
2)PKCζparticipated in CSF-1 induced monocytes/macrophages chemotaxis.PKCζaccommodate the activation of LIMK/cofilin to control cytoskeletalrearrangement.
3)PKCζmay be required for both GPCR and RTK mediated chemotaxis signalingpathways.
引文
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