人肺腺癌干细胞的分离、培养与鉴定及PI3K/AKT信号传导通路对其增殖及自我更新的影响
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摘要
第一部分PI3K/AKT信号传导通路蛋白在非小细胞肺癌中的表达及临床意义
目的：探讨磷脂酰肌醇3-激酶(PI3K)，磷酸化蛋白激酶B(p-AKT)在非小细胞肺癌(NSCLC)组织中的表达及其临床意义。
方法：回顾性分析157例NSCLC患者的临床资料，其中鳞癌75例，腺癌82例，Ⅰ-ⅢA期70例，ⅢB-Ⅳ期87例，并收集30例手术切除肺癌癌旁组织标本。应用免疫组织化学方法检测PI3K和p-AKT蛋白在NSCLC癌组织和手术切除的肺癌癌旁组织中的表达，分析PI3K和p-AKT蛋白表达与NSCLC患者临床资料变量的关系，同时分析PI3K和p-AKT蛋白表达与ⅢB-Ⅳ期NSCLC预后的关系。
结果：PI3K和p-AKT在Ⅰ-ⅢA期NSCLC中的表达明显高于癌旁组织（χ2=14.8455，P=0.000；χ2=14.2615，P=0.000）。p-AKT表达与Ⅰ-ⅢA期NSCLC的淋巴结转移、TNM分期呈正相关(χ2=6.1189,P=0.013，χ2=8.9752,P=0.011)，而与肿瘤的性别、年龄、病理类型、分化程度无关。p-AKT表达与ⅢB-Ⅳ期NSCLC的TNM分期呈正相关（χ2=5.7501,P=0.016），与肿瘤的性别、年龄、病理类型、分化程度、体力状态（PS）评分无关。PI3K表达与上述临床特征无关。在ⅢB-Ⅳ期NSCLC中，PI3K阴性表达组的中位数生存时间明显优于阳性表达组[17.699月(95%CI15.114-20.283)/13.426月(95%CI11.832-15.021)，P=0.004]，p-AKT阴性表达组的中位数生存时间明显亦优于阳性表达组[17.134月(95%CI14.927-19.341)/13.067月(95%CI11.316-14.817)，P=0.007]。多变量Cox’s回归分析显示PI3K [HR=2.143(95%CI1.211-3.790)，P=0.009]， p-AKT [HR=1.991(95%CI1.009-3.927)，P=0.047]，TNM分期[HR=4.788(95%CI2.591-8.848)， P=0.000]， PS评分[HR=3.272(95%CI1.701-6.296)，P=0.000]是ⅢB-Ⅳ期NSCLC的独立不利预后因素。
结论： p-AKT与NSCLC不良预后因素密切相关， PI3K、p-AKT的高表达是晚期NSCLC预后的独立不利因素。
第二部分人肺腺癌干细胞的分离、培养与鉴定
目的：从人肺腺癌组织中分离、培养及鉴定具有干细胞特征的高致瘤性类肺癌干细胞。
方法：采用磁性细胞分选(magnetic activated cell sorting，MACS)技术从人肺腺癌
组织单细胞悬液中分离CD133阳性细胞，无血清培养基富集CD133阳性细胞，流式细胞仪及免疫荧光检测富集后细胞的CD133的表达，并通过NOD/SCID小鼠移植评估其致瘤性。
结果：人肺腺癌组织CD133阳性细胞成功分离，无血清培养法可用于分离的CD133阳性细胞的培养及富集，其具有自我更新，多项分化及高致瘤能力，在NOD/SCID小鼠中仅需移植100个细胞即可形成肿瘤。
结论：MACS联用无血清培养法是人类肺癌干细胞分离和富集的有效方法。
第三部分SiRNA沉默AKTl、PI3K P85基因对肺癌干细胞增殖及自我更新的影响
目的：探讨RNAi(RNA interference)技术下调肺癌干细胞中AKTl和PI3K P85亚基的表达对肺癌干细胞增殖和自我更新的影响。
方法：实时荧光定量PCR检测肺癌干细胞中AKTl和PI3K P85mRNA的表达。将包含AKT1、PI3K P85两种siRNA开放阅读框的短发夹RNA(shRNA)重组腺病毒质粒表达载体rAd5-siAKTl-siPI3K P85转染至肺癌干细胞中。应用Western blotting检测转染后目的基因蛋白的表达水平，并用Western blotting检测目的基因被沉默后PCNA、cyclinD1和P53的表达情况。分别采用MTT增殖实验、细胞球形成实验和异种移植瘤形成实验观察各组差异，并用流式细胞仪检测各组细胞的细胞周期。
结果：肺癌干细胞AKT1和PI3K P85亚基的mRNA表达明显高于肺癌原代细胞，重组腺病毒质粒表达载体rAd5-siAKTl-siPI3K P85介导的靶向AKTl，PI3K P85shRNA可以有效下调目的基因AKT1和PI3K P85的蛋白表达；下游相关因子PCNA、cyclin D1的表达亦下调，P53表达则上调。MTT增殖实验、细胞球形成实验和异种移植瘤形成实验发现肺癌干细胞增殖、自我更新、体外致瘤能力都显著降低。
结论：AKTl和PI3K P85基因在肺癌干细胞高表达，靶向AKTl/PI3K P85亚基的shRNA技术可以抑制肺癌干细胞中AKTl、PI3K P85亚基的表达，抑制肺癌干细胞的体外增殖及自我更新能力。
Part I Expression and clinical significance of the PI3K/AKT signaltransduction pathway in non-small cell lung carcinoma
Objective:To investigate the expression of phosphatidylinositol3-kinase(PI3K) andphosphorylated AKT B (p-AKT) protein and its clinical significance in non-small-cell lungcarcinoma (NSCLC).
Methods: The clinical records of157patients with NSCLC（70cases inⅠ-ⅢA stageand87cases in ⅢB-Ⅳ stage）, consisting of75cases of squamous cell carcinoma (SCC)and82cases of adenocarcinoma (AdC), together with30cases of resection of lung cancertumor-adjacent tissues, were retrospectively evaluated. PI3K and p-AKT expression inNSCLC cancer tissues and tumor-adjacent tissues were measured using animmunohistochemical method and its association with clinicopathological data andprognosis in advanced NSCLC were also evaluated.
Results: PI3K and p-AKT expression were significantly higher in cancer tissues thanthose in tumor-adjacent tissues （χ2=14.8455， P=0.000； χ2=14.2615， P=0.000;respectively). The overexpression of p-AKT in NSCLC withⅠ-ⅢA stage wasrelated to lymph node metastasis and TNM stage (χ2=6.1189,P=0.013，χ2=8.9752,P=0.011;respectively) and no correlation was observed with gender, age,histological categories or histological grade. The overexpression of p-AKT in NSCLC withⅢB-Ⅳ stage was only related to TNM stage（χ2=5.7501,P=0.016） and no correlationwas observed with gender, age, histological categories,histological grade or ECOGperformance status. The overexpression of PI3K was not related to above clinicopathological variables in all patients. Survival rates are significantly better inadvanced NSCLC with PI3K and p-AKT negative expression than positive expression[17.699months (95%CI15.114-20.283)/13.426months (95%CI11.832-15.021),P=0.004and17.134months (95%CI14.927-19.341)/13.067months (95%CI11.316-14.817),P=0.007]. Multivariate analysis showed that PI3K [HR=2.143(95%CI1.211-3.790)，P=0.009]， p-AKT [HR=1.991(95%CI1.009-3.927)，P=0.047]，TNM stage[HR=4.788(95%CI2.591-8.848)，P=0.000]， ECOG performance status [HR=3.272(95%CI1.701-6.296)，P=0.000] were independent predictors for survival in NSCLC with ⅢB-Ⅳ stage.
Conclusion: p-AKT overexpression is closely correlated with unfavorable prognosticfactors in NSCLC. PI3K and p-AKT overexpression are independent poor prognosticmarkers in advanced NSCLC.
PartⅡ Isolation, cultivation and identification of human lungadenocarcinoma stem cells
Objective：Isolation, cultivation and identification the highly tumorigenic cancerstem-like cells with stem cell features from the tissues of lung adenocarcinoma．
Methods：The CD133(+) cells were isolated from the single cell suspension of the lungadenocarcinoma tissue by using magnetic activated cell sorting(MACS) technique, andenriched by serum free cultures．The markers of CD133on the isolated and enriched cellswere detected by using flow cytometry instrument and immunofluorescence． Thetumorigenic potent of the isolated cells was evaluated via the transplantation intoNOD-SCID mice．
Results：The CD133(+) cells were successfully isolated by using MACS technique,and enriched by serum free cultures,and had capacity for self-renewal,multi-potentdifferentiation, and induction of xenograft tumors in vivo. Tumor could be induced inNOD-SCID mice by transplantation of100stem-like cells per mouse．
Conclusion： MACS combined with serum-free culture are effective methods to isolate and enrich the human lung cancer stem cells.
Part Ⅲ RNAi targeting AKTl and PI3K P85suppresses proliferation andself-renewal of lung cancer stem cells
Objective: To investigate the effect of RNA interference(RNAi) targeting AKTl andPI3K P85on the proliferation and self-renewal of lung cancer stem cells.
Methods: Real-time PCR was carried out to detect the expression pattern of AKTland PI3K P85in lung cancer stem cells.The recombinant adenovirus expressionvector,which contained short hairpin RNA(shRNA) targeting open reading frames of AKTland PI3K P85(rAd5-siAKTl-siPI3K P85)，was transfected into lung cancer stem cells.AKTl and P13K P85protein expressions were detected by Western blotting analysis.Theexpressions of PCNA,cyclin Dl,and P53were also detected by Western blottinganalysis．The effects of AKTl and PI3K P85on self-renewal and proliferation of lungcancer stem cells were investigated using MTT assay,sphere forming assay and xenograftformation. In addition, cell cycle assay was also detected using flow cytometry after AKTland PI3K P85silence in lung cancer stem cells.
Results: AKTl and PI3K P85expressions are up-regulated in lung cancer stem cellscompared with the lung cancer primary cells in mRNA level. Recombinant adenovirusvector rAd5-siAKTl-siPI3K P85significantly down-regulated AKTl and PI3K P85mRNAand protein expressions in lung cancer stem cells；The downstream factors PCNA andcyclin D1were also down-regulated，while P53was up-regulated. Following silence ofAKTl and PI3K P85, cell proliferation, tumor sphere self-renewal and tumor formation inNOD/SCID mice was reduced.
Conclusion: AKTl and PI3K P85expressions are up-regulated in lung cancer stemcells. shRNA targeting AKTl and P13K P85can significantly down-regulate theexpression of AKT1and PI3K P85in lung cancer stem cells,and inhibit the proliferation,self-renewal of lung cancer stem cells in vitro．
目的：探讨磷脂酰肌醇3-激酶(PI3K)，磷酸化蛋白激酶B(p-AKT)在非小细胞肺癌(NSCLC)组织中的表达及其临床意义。
方法：回顾性分析157例NSCLC患者的临床资料，其中鳞癌75例，腺癌82例，Ⅰ-ⅢA期70例，ⅢB-Ⅳ期87例，并收集30例手术切除肺癌癌旁组织标本。应用免疫组织化学方法检测PI3K和p-AKT蛋白在NSCLC癌组织和手术切除的肺癌癌旁组织中的表达，分析PI3K和p-AKT蛋白表达与NSCLC患者临床资料变量的关系，同时分析PI3K和p-AKT蛋白表达与ⅢB-Ⅳ期NSCLC预后的关系。
结果：PI3K和p-AKT在Ⅰ-ⅢA期NSCLC中的表达明显高于癌旁组织（χ2=14.8455，P=0.000；χ2=14.2615，P=0.000）。p-AKT表达与Ⅰ-ⅢA期NSCLC的淋巴结转移、TNM分期呈正相关(χ2=6.1189,P=0.013，χ2=8.9752,P=0.011)，而与肿瘤的性别、年龄、病理类型、分化程度无关。p-AKT表达与ⅢB-Ⅳ期NSCLC的TNM分期呈正相关（χ2=5.7501,P=0.016），与肿瘤的性别、年龄、病理类型、分化程度、体力状态（PS）评分无关。PI3K表达与上述临床特征无关。在ⅢB-Ⅳ期NSCLC中，PI3K阴性表达组的中位数生存时间明显优于阳性表达组[17.699月(95%CI15.114-20.283)/13.426月(95%CI11.832-15.021)，P=0.004]，p-AKT阴性表达组的中位数生存时间明显亦优于阳性表达组[17.134月(95%CI14.927-19.341)/13.067月(95%CI11.316-14.817)，P=0.007]。多变量Cox’s回归分析显示PI3K [HR=2.143(95%CI1.211-3.790)，P=0.009]， p-AKT [HR=1.991(95%CI1.009-3.927)，P=0.047]，TNM分期[HR=4.788(95%CI2.591-8.848)， P=0.000]， PS评分[HR=3.272(95%CI1.701-6.296)，P=0.000]是ⅢB-Ⅳ期NSCLC的独立不利预后因素。
结论： p-AKT与NSCLC不良预后因素密切相关， PI3K、p-AKT的高表达是晚期NSCLC预后的独立不利因素。
第二部分人肺腺癌干细胞的分离、培养与鉴定
目的：从人肺腺癌组织中分离、培养及鉴定具有干细胞特征的高致瘤性类肺癌干细胞。
方法：采用磁性细胞分选(magnetic activated cell sorting，MACS)技术从人肺腺癌
组织单细胞悬液中分离CD133阳性细胞，无血清培养基富集CD133阳性细胞，流式细胞仪及免疫荧光检测富集后细胞的CD133的表达，并通过NOD/SCID小鼠移植评估其致瘤性。
结果：人肺腺癌组织CD133阳性细胞成功分离，无血清培养法可用于分离的CD133阳性细胞的培养及富集，其具有自我更新，多项分化及高致瘤能力，在NOD/SCID小鼠中仅需移植100个细胞即可形成肿瘤。
结论：MACS联用无血清培养法是人类肺癌干细胞分离和富集的有效方法。
第三部分SiRNA沉默AKTl、PI3K P85基因对肺癌干细胞增殖及自我更新的影响
目的：探讨RNAi(RNA interference)技术下调肺癌干细胞中AKTl和PI3K P85亚基的表达对肺癌干细胞增殖和自我更新的影响。
方法：实时荧光定量PCR检测肺癌干细胞中AKTl和PI3K P85mRNA的表达。将包含AKT1、PI3K P85两种siRNA开放阅读框的短发夹RNA(shRNA)重组腺病毒质粒表达载体rAd5-siAKTl-siPI3K P85转染至肺癌干细胞中。应用Western blotting检测转染后目的基因蛋白的表达水平，并用Western blotting检测目的基因被沉默后PCNA、cyclinD1和P53的表达情况。分别采用MTT增殖实验、细胞球形成实验和异种移植瘤形成实验观察各组差异，并用流式细胞仪检测各组细胞的细胞周期。
结果：肺癌干细胞AKT1和PI3K P85亚基的mRNA表达明显高于肺癌原代细胞，重组腺病毒质粒表达载体rAd5-siAKTl-siPI3K P85介导的靶向AKTl，PI3K P85shRNA可以有效下调目的基因AKT1和PI3K P85的蛋白表达；下游相关因子PCNA、cyclin D1的表达亦下调，P53表达则上调。MTT增殖实验、细胞球形成实验和异种移植瘤形成实验发现肺癌干细胞增殖、自我更新、体外致瘤能力都显著降低。
结论：AKTl和PI3K P85基因在肺癌干细胞高表达，靶向AKTl/PI3K P85亚基的shRNA技术可以抑制肺癌干细胞中AKTl、PI3K P85亚基的表达，抑制肺癌干细胞的体外增殖及自我更新能力。
Part I Expression and clinical significance of the PI3K/AKT signaltransduction pathway in non-small cell lung carcinoma
Objective:To investigate the expression of phosphatidylinositol3-kinase(PI3K) andphosphorylated AKT B (p-AKT) protein and its clinical significance in non-small-cell lungcarcinoma (NSCLC).
Methods: The clinical records of157patients with NSCLC（70cases inⅠ-ⅢA stageand87cases in ⅢB-Ⅳ stage）, consisting of75cases of squamous cell carcinoma (SCC)and82cases of adenocarcinoma (AdC), together with30cases of resection of lung cancertumor-adjacent tissues, were retrospectively evaluated. PI3K and p-AKT expression inNSCLC cancer tissues and tumor-adjacent tissues were measured using animmunohistochemical method and its association with clinicopathological data andprognosis in advanced NSCLC were also evaluated.
Results: PI3K and p-AKT expression were significantly higher in cancer tissues thanthose in tumor-adjacent tissues （χ2=14.8455， P=0.000； χ2=14.2615， P=0.000;respectively). The overexpression of p-AKT in NSCLC withⅠ-ⅢA stage wasrelated to lymph node metastasis and TNM stage (χ2=6.1189,P=0.013，χ2=8.9752,P=0.011;respectively) and no correlation was observed with gender, age,histological categories or histological grade. The overexpression of p-AKT in NSCLC withⅢB-Ⅳ stage was only related to TNM stage（χ2=5.7501,P=0.016） and no correlationwas observed with gender, age, histological categories,histological grade or ECOGperformance status. The overexpression of PI3K was not related to above clinicopathological variables in all patients. Survival rates are significantly better inadvanced NSCLC with PI3K and p-AKT negative expression than positive expression[17.699months (95%CI15.114-20.283)/13.426months (95%CI11.832-15.021),P=0.004and17.134months (95%CI14.927-19.341)/13.067months (95%CI11.316-14.817),P=0.007]. Multivariate analysis showed that PI3K [HR=2.143(95%CI1.211-3.790)，P=0.009]， p-AKT [HR=1.991(95%CI1.009-3.927)，P=0.047]，TNM stage[HR=4.788(95%CI2.591-8.848)，P=0.000]， ECOG performance status [HR=3.272(95%CI1.701-6.296)，P=0.000] were independent predictors for survival in NSCLC with ⅢB-Ⅳ stage.
Conclusion: p-AKT overexpression is closely correlated with unfavorable prognosticfactors in NSCLC. PI3K and p-AKT overexpression are independent poor prognosticmarkers in advanced NSCLC.
PartⅡ Isolation, cultivation and identification of human lungadenocarcinoma stem cells
Objective：Isolation, cultivation and identification the highly tumorigenic cancerstem-like cells with stem cell features from the tissues of lung adenocarcinoma．
Methods：The CD133(+) cells were isolated from the single cell suspension of the lungadenocarcinoma tissue by using magnetic activated cell sorting(MACS) technique, andenriched by serum free cultures．The markers of CD133on the isolated and enriched cellswere detected by using flow cytometry instrument and immunofluorescence． Thetumorigenic potent of the isolated cells was evaluated via the transplantation intoNOD-SCID mice．
Results：The CD133(+) cells were successfully isolated by using MACS technique,and enriched by serum free cultures,and had capacity for self-renewal,multi-potentdifferentiation, and induction of xenograft tumors in vivo. Tumor could be induced inNOD-SCID mice by transplantation of100stem-like cells per mouse．
Conclusion： MACS combined with serum-free culture are effective methods to isolate and enrich the human lung cancer stem cells.
Part Ⅲ RNAi targeting AKTl and PI3K P85suppresses proliferation andself-renewal of lung cancer stem cells
Objective: To investigate the effect of RNA interference(RNAi) targeting AKTl andPI3K P85on the proliferation and self-renewal of lung cancer stem cells.
Methods: Real-time PCR was carried out to detect the expression pattern of AKTland PI3K P85in lung cancer stem cells.The recombinant adenovirus expressionvector,which contained short hairpin RNA(shRNA) targeting open reading frames of AKTland PI3K P85(rAd5-siAKTl-siPI3K P85)，was transfected into lung cancer stem cells.AKTl and P13K P85protein expressions were detected by Western blotting analysis.Theexpressions of PCNA,cyclin Dl,and P53were also detected by Western blottinganalysis．The effects of AKTl and PI3K P85on self-renewal and proliferation of lungcancer stem cells were investigated using MTT assay,sphere forming assay and xenograftformation. In addition, cell cycle assay was also detected using flow cytometry after AKTland PI3K P85silence in lung cancer stem cells.
Results: AKTl and PI3K P85expressions are up-regulated in lung cancer stem cellscompared with the lung cancer primary cells in mRNA level. Recombinant adenovirusvector rAd5-siAKTl-siPI3K P85significantly down-regulated AKTl and PI3K P85mRNAand protein expressions in lung cancer stem cells；The downstream factors PCNA andcyclin D1were also down-regulated，while P53was up-regulated. Following silence ofAKTl and PI3K P85, cell proliferation, tumor sphere self-renewal and tumor formation inNOD/SCID mice was reduced.
Conclusion: AKTl and PI3K P85expressions are up-regulated in lung cancer stemcells. shRNA targeting AKTl and P13K P85can significantly down-regulate theexpression of AKT1and PI3K P85in lung cancer stem cells,and inhibit the proliferation,self-renewal of lung cancer stem cells in vitro．
引文
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[1] Jemal A, Bray F, Center MM,et al.Global cancer statistics[J]. CA Cancer JClin.2011;61(2):69-90.
[2] Roccaro AM, Sacco A, Husu EN,et al. Dual targeting of the PI3K/AKT/mTORpathway as an antitumor strategy in Waldenstrom macroglobulinemia[J]. Blood.2010;115(3):559-569.
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[3] Yang L,Parkin DM,Ferlay J,et a1.Estimates of cancer incidence in China for2000andprojections for2005[J].Cancer Epidemiol Biomarkers Prev.2005;14(1):243-250．
[4] Zhou XD, Wang XY, Qu FJ, et al. Detection of cancer stem cells from the C6gliomacell line[J]. J Int Med Res.2009;37(2):503-510.
[5] Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic,stem-like neural precursors from human glioblastoma[J].Cancer Res.2004;64(19):7011–7021.
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[8] O'Brien CA, Pollett A, Gallinger S,et al. A human colon cancer cell capable ofinitiating tumour growth in immunodeficient mice[J]. Nature.2007;445(7123):106-110.
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[1]Molina JR,Yang P,Cassivi SD,et a1.Non-small cell lung cancer:epidemiology,riskfactors,treatment, and survivorship[J].Mayo Clin Proe.2008;83(5):584-594.
[2]Yang L,Parkin DM,Ferlay J,et a1.Estimates of cancer incidence in China for2000andprojections for2005[J].Cancer Epidemiol Biomarkers Prev.2005;14(1):243-250．
[3]Jemal A, Bray F, Center MM, et a1. Global cancer statistics[J].CA Cancer J Clin.2011;61(2):69-90.
[4]Zhou XD, Wang XY, Qu FJ, et al. Detection of cancer stem cells from the C6gliomacell line[J]. J Int Med Res.2009;37(2):503-510.
[5]Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic,stem-like neural precursors from human glioblastoma[J].Cancer Res.2004;64(19):7011–7021.
[6]Hwang-Verslues WW, Kuo WH, Chang PH, et al. Multiple lineages of human breastcancer stem/progenitor cells identified by profiling with stem cell markers[J]. PLoSONE.2009;4(12): e8377.
[7]Collins AT, Berry PA, Hyde C, et a1. Prospective identification of tumorigenic prostatecancer stem cells[J]. Cancer Res.2005;65(23):10946-10951.
[8]O'Brien CA, Pollett A, Gallinger S,et al. A human colon cancer cell capable of initiatingtumour growth in immunodeficient mice[J]. Nature.2007;445(7123):106-110.
[9]Suetsugu A, Nagaki M, Aoki H, et al. Characterization of CD133+hepatocellularcarcinoma cells as cancer stem/progenitor cells[J]. Biochem Biophys Res Commun.2006;351(4):820-824.
[10]Varnat F, Duquet A, Malerba M, et al. Human colon cancer epithelial cells harbouractive HEDGEHOG-GLI signalling that is essential for tumour growth,recurrence,metastasis and stem cell survival and expansion[J]. EMBO Mol Med.2009;1(6-7):338-351.
[11]Reya T,Morrison SJ,Clarke MF,et a1.Stem cells,cancer,and cancer stemcells[J].Nature.2001;414(6859):105-111.
[12]Sullivan JP, Minna JD and Shay JW.Evidence for self-renewing lung cancer stem cellsand their implications in tumour initiation, progression, and targeted therapy[J].Cancer Metastasis Rev.2010;29(1):61-72.
[13]Otto WR.Lung epithelial stem cells[J]. J Pathol.2002;197(4):527-535.
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