mTORC2/Rictor调控非小细胞肺癌转移的分子机制研究
摘要
目的：
肺癌是严重危害人类健康的恶性肿瘤之一,在我国肺癌的发病率和死亡人数位于恶性肿瘤的第一位。目前的研究认为转移的发生是导致临床肿瘤患者治疗失败和死亡的主要原因,而癌细胞的趋化运动和上皮间质转化(EMT)在肿瘤转移过程起非常重要的作用,因此明确调控癌细胞趋化运动和EMT发生的详细分子机制对于研究肿瘤转移具有非常重要的意义,同时可以为临床转移肿瘤的诊断和治疗提供新的潜在靶点。
本课题组前期研究发现构成雷帕霉素不敏感的蛋白激酶复合体mTORC2的关键分子Rictor在多种癌组织中高表达,而且与患者出现转移密切相关,目前对mTORC2/Rictor在肿瘤发生发展中的详细作用机制并不清楚。在本次研究中我们拟采用小RNA干扰等一系列分子生物学和细胞生物学研究技术、并结合EGF诱导的肺癌细胞趋化运动和TGFβ诱导的肺癌细胞EMT发生模型,分析探讨mTORC2/Rictor在调节肺癌细胞迁移和转移能力中的作用机制,最后在免疫缺陷小鼠转移模型中验证Rictor表达下调对肺癌细胞体内转移能力的影响。
方法：
1)采用基于慢病毒的小RNA干扰技术下调Rictor在肺癌细胞中的表达水平,研究其表达下调对EGF诱导的肺癌细胞趋化运动能力的影响；
2)采用伤口愈合实验分析Rictor表达下调对划痕诱导的肺癌细胞极化和定向迁移能力的影响；采用粘附实验观察肺癌细胞中Rictor表达下调对细胞外基质粘附能力的影响；分析Rictor表达下调对EGF诱导的细胞骨架蛋白F-actin聚合能力的影响；
3)采用Western blotting的方法研究Rictor表达下调对EGF诱导的下游信号分子激活的影响；
4)采用免疫荧光染色和Western blotting的方法研究Rictor表达下调对TGFβ诱导的肺癌细胞EMT发生的影响；
5)采用免疫荧光染色和Western blotting的方法分析Rictor表达下调对TGFβ诱导的经典Smads通路和非经典Smads通路中mTORC2/Akt、Erk1/2和GSK3β/β-catenin信号通路激活的影响；
6)采用免疫荧光染色和Western blotting的方法研究抑制GSK3β活性对TGFβ诱导的肺癌细胞EMT发生的影响；
7)采用免疫荧光染色和Western blotting的方法分析下调β-catenin的表达对TGFβ诱导的肺癌细胞EMT发生的影响；
8)采用免疫组织化学的方法分析Rictor在肺癌组织中的表达情况；
9)在免疫缺陷小鼠转移模型中研究下调Rictor的表达对肺癌细胞转移能力的影响；
结果：
1)下调Rictor的表达明显抑制了EGF诱导的蛋白激酶Akt的磷酸化,同时抑制了EGF诱导的肺癌细胞的趋化运动能力和划痕诱导细胞极性的重新建立和定向迁移能力；而且Rictor降表达的细胞对Fibronectin的粘附能力明显降低,对EGF诱导的F-actin聚合能力也明显下降；
2)下调肺癌细胞A549中Rictor的表达导致细胞中上皮标志性蛋白E-cadheirn表达升高和间质标志性蛋白Vimentin的表达下降即细胞发生类MET变化；
3)下调Rictor的表达明显抑制了TGFβ诱导的非小细胞肺癌A549和H358细胞EMT的发生；
4)下调Rictor的表达对TGFβ诱导的经典Smads通路以及Erk1/2的激活没有明显影响,但是抑制了TGFβ诱导的Akt473位点的磷酸化和GSK3β的磷酸化,同时抑制了TGFβ诱导的β-catenin向细胞核转位；
5)采用GSK3β的抑制剂LiCl抑制Rictor表达下降细胞中GSK3β的活性可以恢复TGFβ诱导的EMT的发生；
6)下调P-catenin的表达可以明显抑制TGFβ诱导肺癌细胞EMT的发生,但是对TGFβ诱导的经典Smads通路和非经典Smads通路没有明显影响；
7)免疫组化的结果显示Rictor在肺癌组织中表达上调,而且Rictor表达上调与患者出现远处转移相关,但是与患者的年龄、性别、TNM分期和淋巴结状态没有明显相关性；
8)免疫缺陷小鼠体内转移模型显示下调Rictor的表达明显抑制了肺癌细胞的转移能力。
结论：
下调Rictor的表达可以明显抑制非小细胞肺癌细胞在体外的迁移能力和免疫缺陷小鼠体内的转移能力,表明Rictor是调节癌细胞迁移和转移能力的一个非常关键的因子。进一步的研究发现Rictor主要通过调节癌细胞的趋化运动和肿瘤的上皮间质转化两个方面从而促进肿瘤转移的发生。一方面,Rictor调节肺癌细胞的趋化运动主要通过与mTOR形成的蛋白激酶复合体mTORC2而实现,Rictor/mTORC2通过调节蛋白激酶Akt的活性继而传递了EGF诱导的趋化运动信号通路。下调Rictor的表达抑制了划痕诱导的癌细胞极性重新建立和定向迁移能力；癌细胞对细胞外基质的粘附能力以及细胞迁移过程中细胞骨架蛋白F-actin的重构能力从而抑制了细胞的趋化运动。另一方面下调Rictor的表达诱导肺癌细胞A549发生类MET变化,说明mTORC2是维持间质细胞表型所必须的。机理方面的研究发现mTORC2/Rictor介导TGFP诱导肺癌细胞EMT发生主要通过交叉激活Wnt通路中的GSK3β/β-catenin信号通路,从而调节EMT发生相关基因的转录而实现。我们的研究结果提示Rictor/mTORC2调节癌细胞的EMT和趋化运动两者之间是相互促进和相互协作的,Rictor一方面通过促进肿瘤细胞EMT的发生使得肿瘤细胞脱离原发灶,获得了类似于间质细胞的迁移侵袭能力；另一方面Rictor还可以增强癌细胞的趋化运动能力,而且这种癌细胞沿着趋化因子浓度梯度而发生的定向迁移能力则是导致肿瘤细胞发生器官或者组织特异性转移的关键因素。
Objectives
The incidence of lung cancer has increased as the most frequently diagnosed cancer and the leading cause of cancer death in China. Metastasis is one of main causes of treatment failure and death in cancer patients, most evidences have demonstrated that chemotaxis and Epithelial-Mesenchymal Transition (EMT) play critical roles in promoting cancer cell metastasis. However, the detailed mechanism remains largely unknown. Our previous studies have found that Rictor, a key component of mTORC2, was up-regulated in several cancer tissues, and its elevated expression correlated with metastasis of cancer patients. However, how Rictor regulates cancer cell metastasis is unclear. In the present study, we aim to investigate the role of Rictor in EGF induced chemotaxis of non small cell lung cancer cells, and to explore the potential function of Rictor/mTORC2in the mediation of TGFβ induced EMT of NSCLC cells. We also examine the effect of Rictor deletion on metastasis of lung cancer cells in an in vivo SCID mouse model.
Methods
1) Lentivirus mediated shRNA delivery system was used to knockdown the expression of Rictor in lung cancer cells, then chemotaxis assay, cell polarization and directed cell migration assay, cell adhesion assay and F-actin polymerization assay was used to examine the effect of Rictor deletion on EGF induced chemotaxis and cell migration of NSCLC cells.
2) Immunofluresence staining and western blotting methods were used to investigate the effect of Rictor or β-catenin deletion on TGFP induced EMT and activation of canonical Smads and non-canonical pathways in lung cancer cells.
3) Immunofluresence staining and western blotting methods were used to exmine the effect of GSK3β inhibition by LiCl on TGFβ induced EMT in Rictor knockdown cells.
4) Immunohistochemistry method was used to detect the expression status of Rictor in lung cancer tissues; A SCID mouse model was used to evaluate the effect of Rictor knockdown on the metastatic ability of lung cancer cells.
Results
1) Rictor knockdown impaired EGF induced phoshorylation of Akt, and inhibited EGF induced chemotaxis of lung cancer cells along with defects in cell polarization, directed cell migration, cell adherion and F-actin polymerization.
2) Loss of Rictor expression in A549cells results in an up-regulation of epithelial maker E-cadherin and a decrease of mesenchymal protein vimentin, which indicating a mesenchymal to epithelial transtion, meanwhile, Rictor knockdown also impaired TGFβ induced EMT of lung cancer cells.
3) Knockdown of Rictor in A549cells has no significant effect on TGFβ induced activation of canonical Smad2/3and Erkl/2, but phosphorylation of Akt at473sites and GSK3β at ser9sites were decreased, along with a reduction of nuclear translocation of β-catenin.
4) Inhibition of GSK3β activity by LiCl in Rictor depletion cells rescued TGFβ induced EMT; knockdown of β-catenin impaired TGFβ induced EMT of lung cancer cells without affecting canonical Smads and non-canonical pathways;
5) Elevated expression of Rictor was observed in lung cancer tissues compared with tumor-adjacent normal tissues, and high expression of Rictor correlated with distant metatasis of cancer patients.
6) Rictor depletion inhibited lung cancer cell metastsis in an in vivo mouse model.
Conclusions
Our results support Rictor as a key regulator for lung cancer cell migration and metastasis. Rictor mediates cancer cell metastasis by regulating chemotaxis and Epithelial-Mesenchymal Transition of cancer cells. Rictor knockdown impaired EGF induced chemotaxis and phosphorylation of Akt, pivitol melecules in chemotaxis signaling, in parallel, cell polarization and directed cell migration was also decreased. Further, Rictor/mTORC2is required for TGFβinduced EMT of NSCLC cells through cross activation of GSK3β/β catenin pathway.
肺癌是严重危害人类健康的恶性肿瘤之一,在我国肺癌的发病率和死亡人数位于恶性肿瘤的第一位。目前的研究认为转移的发生是导致临床肿瘤患者治疗失败和死亡的主要原因,而癌细胞的趋化运动和上皮间质转化(EMT)在肿瘤转移过程起非常重要的作用,因此明确调控癌细胞趋化运动和EMT发生的详细分子机制对于研究肿瘤转移具有非常重要的意义,同时可以为临床转移肿瘤的诊断和治疗提供新的潜在靶点。
本课题组前期研究发现构成雷帕霉素不敏感的蛋白激酶复合体mTORC2的关键分子Rictor在多种癌组织中高表达,而且与患者出现转移密切相关,目前对mTORC2/Rictor在肿瘤发生发展中的详细作用机制并不清楚。在本次研究中我们拟采用小RNA干扰等一系列分子生物学和细胞生物学研究技术、并结合EGF诱导的肺癌细胞趋化运动和TGFβ诱导的肺癌细胞EMT发生模型,分析探讨mTORC2/Rictor在调节肺癌细胞迁移和转移能力中的作用机制,最后在免疫缺陷小鼠转移模型中验证Rictor表达下调对肺癌细胞体内转移能力的影响。
方法：
1)采用基于慢病毒的小RNA干扰技术下调Rictor在肺癌细胞中的表达水平,研究其表达下调对EGF诱导的肺癌细胞趋化运动能力的影响；
2)采用伤口愈合实验分析Rictor表达下调对划痕诱导的肺癌细胞极化和定向迁移能力的影响；采用粘附实验观察肺癌细胞中Rictor表达下调对细胞外基质粘附能力的影响；分析Rictor表达下调对EGF诱导的细胞骨架蛋白F-actin聚合能力的影响；
3)采用Western blotting的方法研究Rictor表达下调对EGF诱导的下游信号分子激活的影响；
4)采用免疫荧光染色和Western blotting的方法研究Rictor表达下调对TGFβ诱导的肺癌细胞EMT发生的影响；
5)采用免疫荧光染色和Western blotting的方法分析Rictor表达下调对TGFβ诱导的经典Smads通路和非经典Smads通路中mTORC2/Akt、Erk1/2和GSK3β/β-catenin信号通路激活的影响；
6)采用免疫荧光染色和Western blotting的方法研究抑制GSK3β活性对TGFβ诱导的肺癌细胞EMT发生的影响；
7)采用免疫荧光染色和Western blotting的方法分析下调β-catenin的表达对TGFβ诱导的肺癌细胞EMT发生的影响；
8)采用免疫组织化学的方法分析Rictor在肺癌组织中的表达情况；
9)在免疫缺陷小鼠转移模型中研究下调Rictor的表达对肺癌细胞转移能力的影响；
结果：
1)下调Rictor的表达明显抑制了EGF诱导的蛋白激酶Akt的磷酸化,同时抑制了EGF诱导的肺癌细胞的趋化运动能力和划痕诱导细胞极性的重新建立和定向迁移能力；而且Rictor降表达的细胞对Fibronectin的粘附能力明显降低,对EGF诱导的F-actin聚合能力也明显下降；
2)下调肺癌细胞A549中Rictor的表达导致细胞中上皮标志性蛋白E-cadheirn表达升高和间质标志性蛋白Vimentin的表达下降即细胞发生类MET变化；
3)下调Rictor的表达明显抑制了TGFβ诱导的非小细胞肺癌A549和H358细胞EMT的发生；
4)下调Rictor的表达对TGFβ诱导的经典Smads通路以及Erk1/2的激活没有明显影响,但是抑制了TGFβ诱导的Akt473位点的磷酸化和GSK3β的磷酸化,同时抑制了TGFβ诱导的β-catenin向细胞核转位；
5)采用GSK3β的抑制剂LiCl抑制Rictor表达下降细胞中GSK3β的活性可以恢复TGFβ诱导的EMT的发生；
6)下调P-catenin的表达可以明显抑制TGFβ诱导肺癌细胞EMT的发生,但是对TGFβ诱导的经典Smads通路和非经典Smads通路没有明显影响；
7)免疫组化的结果显示Rictor在肺癌组织中表达上调,而且Rictor表达上调与患者出现远处转移相关,但是与患者的年龄、性别、TNM分期和淋巴结状态没有明显相关性；
8)免疫缺陷小鼠体内转移模型显示下调Rictor的表达明显抑制了肺癌细胞的转移能力。
结论：
下调Rictor的表达可以明显抑制非小细胞肺癌细胞在体外的迁移能力和免疫缺陷小鼠体内的转移能力,表明Rictor是调节癌细胞迁移和转移能力的一个非常关键的因子。进一步的研究发现Rictor主要通过调节癌细胞的趋化运动和肿瘤的上皮间质转化两个方面从而促进肿瘤转移的发生。一方面,Rictor调节肺癌细胞的趋化运动主要通过与mTOR形成的蛋白激酶复合体mTORC2而实现,Rictor/mTORC2通过调节蛋白激酶Akt的活性继而传递了EGF诱导的趋化运动信号通路。下调Rictor的表达抑制了划痕诱导的癌细胞极性重新建立和定向迁移能力；癌细胞对细胞外基质的粘附能力以及细胞迁移过程中细胞骨架蛋白F-actin的重构能力从而抑制了细胞的趋化运动。另一方面下调Rictor的表达诱导肺癌细胞A549发生类MET变化,说明mTORC2是维持间质细胞表型所必须的。机理方面的研究发现mTORC2/Rictor介导TGFP诱导肺癌细胞EMT发生主要通过交叉激活Wnt通路中的GSK3β/β-catenin信号通路,从而调节EMT发生相关基因的转录而实现。我们的研究结果提示Rictor/mTORC2调节癌细胞的EMT和趋化运动两者之间是相互促进和相互协作的,Rictor一方面通过促进肿瘤细胞EMT的发生使得肿瘤细胞脱离原发灶,获得了类似于间质细胞的迁移侵袭能力；另一方面Rictor还可以增强癌细胞的趋化运动能力,而且这种癌细胞沿着趋化因子浓度梯度而发生的定向迁移能力则是导致肿瘤细胞发生器官或者组织特异性转移的关键因素。
Objectives
The incidence of lung cancer has increased as the most frequently diagnosed cancer and the leading cause of cancer death in China. Metastasis is one of main causes of treatment failure and death in cancer patients, most evidences have demonstrated that chemotaxis and Epithelial-Mesenchymal Transition (EMT) play critical roles in promoting cancer cell metastasis. However, the detailed mechanism remains largely unknown. Our previous studies have found that Rictor, a key component of mTORC2, was up-regulated in several cancer tissues, and its elevated expression correlated with metastasis of cancer patients. However, how Rictor regulates cancer cell metastasis is unclear. In the present study, we aim to investigate the role of Rictor in EGF induced chemotaxis of non small cell lung cancer cells, and to explore the potential function of Rictor/mTORC2in the mediation of TGFβ induced EMT of NSCLC cells. We also examine the effect of Rictor deletion on metastasis of lung cancer cells in an in vivo SCID mouse model.
Methods
1) Lentivirus mediated shRNA delivery system was used to knockdown the expression of Rictor in lung cancer cells, then chemotaxis assay, cell polarization and directed cell migration assay, cell adhesion assay and F-actin polymerization assay was used to examine the effect of Rictor deletion on EGF induced chemotaxis and cell migration of NSCLC cells.
2) Immunofluresence staining and western blotting methods were used to investigate the effect of Rictor or β-catenin deletion on TGFP induced EMT and activation of canonical Smads and non-canonical pathways in lung cancer cells.
3) Immunofluresence staining and western blotting methods were used to exmine the effect of GSK3β inhibition by LiCl on TGFβ induced EMT in Rictor knockdown cells.
4) Immunohistochemistry method was used to detect the expression status of Rictor in lung cancer tissues; A SCID mouse model was used to evaluate the effect of Rictor knockdown on the metastatic ability of lung cancer cells.
Results
1) Rictor knockdown impaired EGF induced phoshorylation of Akt, and inhibited EGF induced chemotaxis of lung cancer cells along with defects in cell polarization, directed cell migration, cell adherion and F-actin polymerization.
2) Loss of Rictor expression in A549cells results in an up-regulation of epithelial maker E-cadherin and a decrease of mesenchymal protein vimentin, which indicating a mesenchymal to epithelial transtion, meanwhile, Rictor knockdown also impaired TGFβ induced EMT of lung cancer cells.
3) Knockdown of Rictor in A549cells has no significant effect on TGFβ induced activation of canonical Smad2/3and Erkl/2, but phosphorylation of Akt at473sites and GSK3β at ser9sites were decreased, along with a reduction of nuclear translocation of β-catenin.
4) Inhibition of GSK3β activity by LiCl in Rictor depletion cells rescued TGFβ induced EMT; knockdown of β-catenin impaired TGFβ induced EMT of lung cancer cells without affecting canonical Smads and non-canonical pathways;
5) Elevated expression of Rictor was observed in lung cancer tissues compared with tumor-adjacent normal tissues, and high expression of Rictor correlated with distant metatasis of cancer patients.
6) Rictor depletion inhibited lung cancer cell metastsis in an in vivo mouse model.
Conclusions
Our results support Rictor as a key regulator for lung cancer cell migration and metastasis. Rictor mediates cancer cell metastasis by regulating chemotaxis and Epithelial-Mesenchymal Transition of cancer cells. Rictor knockdown impaired EGF induced chemotaxis and phosphorylation of Akt, pivitol melecules in chemotaxis signaling, in parallel, cell polarization and directed cell migration was also decreased. Further, Rictor/mTORC2is required for TGFβinduced EMT of NSCLC cells through cross activation of GSK3β/β catenin pathway.
引文
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