重组血管基膜衍生多功能肽（rVBMDMP）抗非小细胞肺癌的作用及机制研究
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摘要
背景与目的肿瘤抑素(tumstatin)是一种由胶原Ⅳ分子α3链的中间三股螺旋区域共244个氨基酸组成的具有抑制血管生成和抗肿瘤细胞增殖作用的蛋白质,其活性区域位于N端的74-98氨基酸功能肽(抗血管生成作用)和197-215氨基酸功能肽(抗肿瘤作用)。但完整的tumstatin蛋白立体结构中,197-215氨基酸功能肽被其他肽段遮盖而不能发挥直接的抗肿瘤作用。因此本课题组在前期研究中,将来源于tumstatin N端74-98氨基酸功能肽通过人IgG3上游铰链区序列与Tumstatin N端197-215氨基酸功能肽连接获得了一种融合肽,命名为重组血管基膜衍生多功能肽(Recombinant Vascular Basement-derived Multifunctional Peptide, rVBMDMP),并初步证实其具有抑制人脐静脉内皮细胞和结肠癌细胞的双重作用。本研究将在此基础上进一步系统观察rVBMDMP抑制肺癌细胞生长作用和可能机制,为开发这一新型抗肿瘤蛋白药物提供理论依据。
方法(1)MTS法检测rVBMDMP对体外培养人肺腺癌(A549)细胞系,大细胞肺癌(H460)细胞系,小细胞肺癌(H446)细胞系、肺鳞状细胞癌(H520)和人胚肺二倍体细胞(KMB-17)细胞系增殖活性的影响以及对化疗药物顺铂(DDP)抗肺癌细胞的增敏作用；平皿克隆法测定rVBMDMP对A549细胞克隆形成率的影响；DNA琼脂糖凝胶电泳、AO/EB双染及Hoechst染色等方法观察rVBMDMP对A549细胞凋亡的影响；划痕法及transwell小室法测定rVBMDMP对A549细胞体外迁移及侵袭转移能力的影响；(2)采用功能分类基因芯片—癌通路发现者芯片检测rVBMDMP作用肺癌细胞后凋亡与侵袭转移相关基因的改变；并应用real-time PCR和western bloting技术验证芯片结果；(3)应用免疫共沉淀技术检测rVBMDMP与整合素(integrin)αVβ3的相互作用；Western blotting检测rVBMDMP作用A549细胞后FAK/PI3K信号通路和Fas/caspase-8信号通路相关分子表达情况；免疫组织化学检测rVBMDMP作用后裸鼠移植瘤内FAK/PI3K信号通路和Fas/caspase-8信号通路相关分子表达情况；TUNEL法检测rVBMDMP作用后裸鼠移植瘤细胞凋亡情况；Western blotting检测rVBMDMP作用A549/DDP细胞后磷酸化PI3K/Akt,耐药相关蛋白MRP,抗凋亡蛋白bcl-2和caspase-3的表达情况。
结果(1) rVBMDMP能不同程度选择性抑制肺癌细胞的增殖活性,其中对A549的抑制作用最强；(2) rVBMDMP促进A549细胞发生时间依赖型DNA非随机性剪切和剂量依赖型凋亡形态学改变；显著抑制A549细胞体外迁移和侵袭能力；(3)当与DDP合用时,10.0μM的rVBMDMP使DDP对A549细胞的IC50由4.614μg/mL下降为1.320μg/mL (P<0.05),对A549/DDP细胞(DDP耐受细胞)的IC50由31.19μg/mL下降为11.82μg／mL(P<0.05)；(4)10.0μMrVBMDMP作用后,A549细胞中p27基因(CDKN1B),粒酶A(GZMA),转移抑制基因KISS-1,信号转导和转录因子(RAF1,RASA1,SRC),细胞周期蛋白D1(CCND1)、整合素受体IntegrinαⅤ、α1、α2、α6等16个基因表达上调,信号转导和转录因子(CTNNB1, JUN, MYC, MAP2K1),凋亡蛋白酶激活因子(APAF1),调控血管发生的基因(FGF2,IGF1,THBS1),侵袭和转移相关基因(SERPINB2, SERPINE1, SERPINB5, uPA, uPAR)等21个基因表达下调；其中CDC25A、uPA、uPAR、IntegrinαⅤ、KISS1等基因的验证结果与芯片结果一致；(5) rVBMDMP能与A549细胞中integrinαⅤ/β3相互结合,抑制integrinαⅤβ3和下游的FAK、PI3K和Akt等蛋白的磷酸化,rVBMDMP干预后的裸鼠移植瘤内的免疫组化验证结果与细胞检测结果一致；(6) rVBMDMP作用早期(12h)能致A549细胞Fas表达上调,caspase-8活化；24h后,能使bcl-2、MRP表达下调caspase-3活化,rVBMDMP处理的裸鼠移植瘤免疫组化和TUNEL检测结果与细胞结果一致。
结论(1) rVBMDMP能显著抑制人肺腺癌A549细胞体外生长增殖和侵袭转移能力,诱导其凋亡；(2)建立了rVBMDMP作用A549细胞的差异基因表达谱,共获得37个差异表达基因；(3) rVBMDMP抑制A549细胞生长、诱导其凋亡作用可能与其结合integrin aVβ3,抑制integrin aVβ3/FAK/PI3K/Akt的蛋白磷酸化有关；(4) rVBMDMP诱导凋亡作用可能与上调Fas表达、抑制bcl-2表达有关；(5) rVBMDMP可能通过上调KISS-1的表达,下调uPA和uPAR的表达来抑制人肺癌细胞的侵袭和转移；(6) rVBMDMP能增加A549和A549/DDP细胞对DDP的敏感性,其作用可能与上述机制及抑制MRP表达有关。
Background and purpose
Tumstatin, a 244 amino acids domain fragment of typeⅣcollagenα3 chain, possess two active regions. The one consisting of amino acids 74-98 is associated with anti-angiogenic properties and the other one consisting of amino acids 197-215 is associated with anti-tumor activity. However, tumstatin does not show a direct anti-tumor effect because its anti-tumor effect region (197-215aa) is masked with another peptide. In previous study, we have constructed a fusion protein based on the above two tumstatin-derived sequences linked with the human IgG3 upper hinge region, named recombined vascular basement membrane derived multifunctional peptide (rVBMDMP), and preliminarily confirmed its double inhibition effects on human umbilical vein endothelial cells and colon cancer cells. Based on our previous work, the present study will be further systematicly observe inhibition effect of rVBMDMP on the growth of lung cancer cell and analysis possible mechanism so that provide a theoretical basis for the development of new anti-tumor protein drugs.
Methods
(1) MTS assay was peformed to measure the effect of rVBMDMP on the proliferation of human lung adenocarcinoma (A549) cell lines, large cell lung cancer (H460) cell lines, small cell lung cancer (H446) cell lines, lung squamous cell carcinoma (H520) and human diploid fibroblasts (KMB-17) cell line. Plate cloning method was used to detect inhibitory effect of rVBMDMP on A549 cell. AO and EB duel stain under fluorescence microscope and DNA agarose gel electrophoresis were employed to detect apoptosis induction of rVBMDMP on A549 cells. Scratching assay and transwell method were used to measure the effect of rVBMDMP on the migration and invasion/metastasis abilities of A549 cells in vitro respectively. (2) Functional classification using genechips-cancer pathway finder microarray was employed to identify gene expression change induced by rVBMDMP at the transcriptional level. Then Real-time PCR and weatern bloting technology were used to confirm the results of cDNA microarray. (3) Immunoprecipitation was applied to detect interaction between rVBMDMP and integrinαⅤβ3. The changes of FAK/PI3K signal transduction and the Fas/caspase-8 signaling pathway related molecules expression after rVBMDMP treatment in A549 cells were surveyed by Western blotting, and within nude mice tumor were surveyed by immunohistochemistry. TUNEL assay was adopted to detect apoptosis of tumor tissue in nude mice. Western blotting was used to detect phosphorylation of PI3K/Akt, drug resistance associated protein MRP, anti-apoptotic protein bcl-2 and caspase-3 expression change in A549/DDP cells after rVBMDMP exposure.
Results
(1) rVBMDMP can inhibit proliferative activity of NSCLC cells in different degrees, in which the strongest inhibition was on the A549. (2) rVBMDMP can promote DNA non-random cut in a time-dependent manner and morphological changes of apoptosis in a time-dependent manner in A549 cells. (3) 10.0μM rVBMDMP can lead to IC50 values of cisplatin reduction in A549 cells from 4.614μg/mL to 1.320μg/mL and that in A549/DDP cells from 31.19μg/mL to 11.82μg/mL. (4) After treatment with10.0μM rVBMDMP, cDNA microarray showed that expression of total of 16 genes including p27 gene, granzyme A, metastasis suppressor gene KISS-1, signal transduction and transcription factor(RAF1, RASA1, SRC), cyclin D1, IntegrinαⅤ,α1,α2,α6 were up-regulated; expression of total of 21 genes including Signal transduction and transcription factors(CTNNB1, JUN, MYC, MAP2K1), apoptosis protease activating factor(APAF1), angiogenesis gene regulation(FGF2, IGF1, THBS1), invasion and metastasis related gene(SERPINB2, SERPINE1, SERPINB5, uPA, uPAR) were down-regulated. Among these genes, the test results of CDC25A, uPA, uPAR, IntegrinαV and KISS1 were consistent with microarray results. (5) rVBMDMP can interact with integrinαⅤ/β3, then inhibits phosphorylation of integrinαV/β3 and downstream of FAK, PI3K and Akt in the A549 cell. Immunohistochemical test results in nude mice xenograft tumor were consistent with the cell detection. (6) In early stage (12h), rVBMDMP can up-regulate the expressions of Fas and activate caspase-8, and down-regulate the expressions of bcl-2 and MRP and activate caspase-3 24h later. Immunohistochemical test and TUNEL results in nude mice xenograft tumor were consistent with the cell detection too.
Conclusion
(1) rVBMDMP can inhibit the proliferation and abilities of migration and invasion/metastasis in vitro of lung adenocarcinoma A549 cell and directly induce apoptosis. (2) The effects of growth inhibition and apoptosis induction of rVBMDMP on A549 cells may be related to binding to integrinαVβ3 and then inhibition of protein phosphorylation of integrinαVβ3/FAK/PI3K/Akt. (3) Induction of Apoptosis by rVBMDMP may be associated with upregulation of Fas and inhibition of bcl-2. (4) rVBMDMP suppressed invasion and metastasis of human lung cancer cell by upregulating the expression of KISS-1 and downregulating the expression of uPA and uPAR. (5) rVBMDMP can increase the sensitivity of A549 and A549/DDP cells to DDP, which may be related to the above-mentioned mechanism and inhibition of MRP expression. (6) Established a gene expression profiles of rVBMDMP acting on A549 cell, and obtained 37 differentially expressed genes.
方法(1)MTS法检测rVBMDMP对体外培养人肺腺癌(A549)细胞系,大细胞肺癌(H460)细胞系,小细胞肺癌(H446)细胞系、肺鳞状细胞癌(H520)和人胚肺二倍体细胞(KMB-17)细胞系增殖活性的影响以及对化疗药物顺铂(DDP)抗肺癌细胞的增敏作用；平皿克隆法测定rVBMDMP对A549细胞克隆形成率的影响；DNA琼脂糖凝胶电泳、AO/EB双染及Hoechst染色等方法观察rVBMDMP对A549细胞凋亡的影响；划痕法及transwell小室法测定rVBMDMP对A549细胞体外迁移及侵袭转移能力的影响；(2)采用功能分类基因芯片—癌通路发现者芯片检测rVBMDMP作用肺癌细胞后凋亡与侵袭转移相关基因的改变；并应用real-time PCR和western bloting技术验证芯片结果；(3)应用免疫共沉淀技术检测rVBMDMP与整合素(integrin)αVβ3的相互作用；Western blotting检测rVBMDMP作用A549细胞后FAK/PI3K信号通路和Fas/caspase-8信号通路相关分子表达情况；免疫组织化学检测rVBMDMP作用后裸鼠移植瘤内FAK/PI3K信号通路和Fas/caspase-8信号通路相关分子表达情况；TUNEL法检测rVBMDMP作用后裸鼠移植瘤细胞凋亡情况；Western blotting检测rVBMDMP作用A549/DDP细胞后磷酸化PI3K/Akt,耐药相关蛋白MRP,抗凋亡蛋白bcl-2和caspase-3的表达情况。
结果(1) rVBMDMP能不同程度选择性抑制肺癌细胞的增殖活性,其中对A549的抑制作用最强；(2) rVBMDMP促进A549细胞发生时间依赖型DNA非随机性剪切和剂量依赖型凋亡形态学改变；显著抑制A549细胞体外迁移和侵袭能力；(3)当与DDP合用时,10.0μM的rVBMDMP使DDP对A549细胞的IC50由4.614μg/mL下降为1.320μg/mL (P<0.05),对A549/DDP细胞(DDP耐受细胞)的IC50由31.19μg/mL下降为11.82μg／mL(P<0.05)；(4)10.0μMrVBMDMP作用后,A549细胞中p27基因(CDKN1B),粒酶A(GZMA),转移抑制基因KISS-1,信号转导和转录因子(RAF1,RASA1,SRC),细胞周期蛋白D1(CCND1)、整合素受体IntegrinαⅤ、α1、α2、α6等16个基因表达上调,信号转导和转录因子(CTNNB1, JUN, MYC, MAP2K1),凋亡蛋白酶激活因子(APAF1),调控血管发生的基因(FGF2,IGF1,THBS1),侵袭和转移相关基因(SERPINB2, SERPINE1, SERPINB5, uPA, uPAR)等21个基因表达下调；其中CDC25A、uPA、uPAR、IntegrinαⅤ、KISS1等基因的验证结果与芯片结果一致；(5) rVBMDMP能与A549细胞中integrinαⅤ/β3相互结合,抑制integrinαⅤβ3和下游的FAK、PI3K和Akt等蛋白的磷酸化,rVBMDMP干预后的裸鼠移植瘤内的免疫组化验证结果与细胞检测结果一致；(6) rVBMDMP作用早期(12h)能致A549细胞Fas表达上调,caspase-8活化；24h后,能使bcl-2、MRP表达下调caspase-3活化,rVBMDMP处理的裸鼠移植瘤免疫组化和TUNEL检测结果与细胞结果一致。
结论(1) rVBMDMP能显著抑制人肺腺癌A549细胞体外生长增殖和侵袭转移能力,诱导其凋亡；(2)建立了rVBMDMP作用A549细胞的差异基因表达谱,共获得37个差异表达基因；(3) rVBMDMP抑制A549细胞生长、诱导其凋亡作用可能与其结合integrin aVβ3,抑制integrin aVβ3/FAK/PI3K/Akt的蛋白磷酸化有关；(4) rVBMDMP诱导凋亡作用可能与上调Fas表达、抑制bcl-2表达有关；(5) rVBMDMP可能通过上调KISS-1的表达,下调uPA和uPAR的表达来抑制人肺癌细胞的侵袭和转移；(6) rVBMDMP能增加A549和A549/DDP细胞对DDP的敏感性,其作用可能与上述机制及抑制MRP表达有关。
Background and purpose
Tumstatin, a 244 amino acids domain fragment of typeⅣcollagenα3 chain, possess two active regions. The one consisting of amino acids 74-98 is associated with anti-angiogenic properties and the other one consisting of amino acids 197-215 is associated with anti-tumor activity. However, tumstatin does not show a direct anti-tumor effect because its anti-tumor effect region (197-215aa) is masked with another peptide. In previous study, we have constructed a fusion protein based on the above two tumstatin-derived sequences linked with the human IgG3 upper hinge region, named recombined vascular basement membrane derived multifunctional peptide (rVBMDMP), and preliminarily confirmed its double inhibition effects on human umbilical vein endothelial cells and colon cancer cells. Based on our previous work, the present study will be further systematicly observe inhibition effect of rVBMDMP on the growth of lung cancer cell and analysis possible mechanism so that provide a theoretical basis for the development of new anti-tumor protein drugs.
Methods
(1) MTS assay was peformed to measure the effect of rVBMDMP on the proliferation of human lung adenocarcinoma (A549) cell lines, large cell lung cancer (H460) cell lines, small cell lung cancer (H446) cell lines, lung squamous cell carcinoma (H520) and human diploid fibroblasts (KMB-17) cell line. Plate cloning method was used to detect inhibitory effect of rVBMDMP on A549 cell. AO and EB duel stain under fluorescence microscope and DNA agarose gel electrophoresis were employed to detect apoptosis induction of rVBMDMP on A549 cells. Scratching assay and transwell method were used to measure the effect of rVBMDMP on the migration and invasion/metastasis abilities of A549 cells in vitro respectively. (2) Functional classification using genechips-cancer pathway finder microarray was employed to identify gene expression change induced by rVBMDMP at the transcriptional level. Then Real-time PCR and weatern bloting technology were used to confirm the results of cDNA microarray. (3) Immunoprecipitation was applied to detect interaction between rVBMDMP and integrinαⅤβ3. The changes of FAK/PI3K signal transduction and the Fas/caspase-8 signaling pathway related molecules expression after rVBMDMP treatment in A549 cells were surveyed by Western blotting, and within nude mice tumor were surveyed by immunohistochemistry. TUNEL assay was adopted to detect apoptosis of tumor tissue in nude mice. Western blotting was used to detect phosphorylation of PI3K/Akt, drug resistance associated protein MRP, anti-apoptotic protein bcl-2 and caspase-3 expression change in A549/DDP cells after rVBMDMP exposure.
Results
(1) rVBMDMP can inhibit proliferative activity of NSCLC cells in different degrees, in which the strongest inhibition was on the A549. (2) rVBMDMP can promote DNA non-random cut in a time-dependent manner and morphological changes of apoptosis in a time-dependent manner in A549 cells. (3) 10.0μM rVBMDMP can lead to IC50 values of cisplatin reduction in A549 cells from 4.614μg/mL to 1.320μg/mL and that in A549/DDP cells from 31.19μg/mL to 11.82μg/mL. (4) After treatment with10.0μM rVBMDMP, cDNA microarray showed that expression of total of 16 genes including p27 gene, granzyme A, metastasis suppressor gene KISS-1, signal transduction and transcription factor(RAF1, RASA1, SRC), cyclin D1, IntegrinαⅤ,α1,α2,α6 were up-regulated; expression of total of 21 genes including Signal transduction and transcription factors(CTNNB1, JUN, MYC, MAP2K1), apoptosis protease activating factor(APAF1), angiogenesis gene regulation(FGF2, IGF1, THBS1), invasion and metastasis related gene(SERPINB2, SERPINE1, SERPINB5, uPA, uPAR) were down-regulated. Among these genes, the test results of CDC25A, uPA, uPAR, IntegrinαV and KISS1 were consistent with microarray results. (5) rVBMDMP can interact with integrinαⅤ/β3, then inhibits phosphorylation of integrinαV/β3 and downstream of FAK, PI3K and Akt in the A549 cell. Immunohistochemical test results in nude mice xenograft tumor were consistent with the cell detection. (6) In early stage (12h), rVBMDMP can up-regulate the expressions of Fas and activate caspase-8, and down-regulate the expressions of bcl-2 and MRP and activate caspase-3 24h later. Immunohistochemical test and TUNEL results in nude mice xenograft tumor were consistent with the cell detection too.
Conclusion
(1) rVBMDMP can inhibit the proliferation and abilities of migration and invasion/metastasis in vitro of lung adenocarcinoma A549 cell and directly induce apoptosis. (2) The effects of growth inhibition and apoptosis induction of rVBMDMP on A549 cells may be related to binding to integrinαVβ3 and then inhibition of protein phosphorylation of integrinαVβ3/FAK/PI3K/Akt. (3) Induction of Apoptosis by rVBMDMP may be associated with upregulation of Fas and inhibition of bcl-2. (4) rVBMDMP suppressed invasion and metastasis of human lung cancer cell by upregulating the expression of KISS-1 and downregulating the expression of uPA and uPAR. (5) rVBMDMP can increase the sensitivity of A549 and A549/DDP cells to DDP, which may be related to the above-mentioned mechanism and inhibition of MRP expression. (6) Established a gene expression profiles of rVBMDMP acting on A549 cell, and obtained 37 differentially expressed genes.
引文
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