胆管癌67kDa层粘素受体调控Fas配体表达的分子机制研究
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摘要
研究背景：Fas配体(FasL)是一种分子量约4万道尔顿的跨膜蛋白，属于肿瘤坏死因子超家族，当其与受体Fas结合后能够启动细胞凋亡。目前，大量研究显示：FasL不但在激活的T淋巴细胞上表达，而且在多种肿瘤细胞中表达，在人胆管癌细胞中，FasL也呈过表达。我们的研究及其它一些研究均显示，当高表达FasL的肿瘤细胞与Fas +的T淋巴细胞共培养时，可诱导Fas +的T淋巴细胞发生凋亡。这些研究结果提示肿瘤细胞的免疫逃逸与肿瘤细胞表达FasL有关。然而，关于肿瘤细胞FasL表达的信号调节及转录调控，目前研究仍不透彻。我们以往的研究显示在人胆管癌细胞中67kDa的层粘素受体( 67kDa laminin receptor，67-kDa LNR)过表达可诱导FasL的表达，但其信号调节及转录调控机制目前不清楚。
67 kDa层粘素受体( 67kDa laminin receptor，67-kDa LNR)广泛存在于上皮细胞、内皮细胞、周围神经细胞、巨噬细胞及大部分肿瘤细胞表面，结合位点为LNβ1链的YIGSR序列。67-kDa LNR的高表达，可使癌细胞与基底膜的黏附力增强，有利于肿瘤的侵袭和转移。67-kDa LNR与LN的结合诱导了一系列跨膜信号传导系统的变化，最近的一项研究发现，层粘连蛋白的信号通路参与了有丝分裂原活化蛋白激酶(MAPK的)级联反应。这些结果提示：67-kDa LNR表达上调可能激活MAPK信号转导通路，且MAPK/ERK1/2被激活后，可将信号传递到细胞核内转录因子，从而增加与DNA的结合，促进和调节有关的基因表达。而肿瘤细胞67-kDa LNR激活MAPK信号转导通路是否可调节肿瘤细胞FasL的表达目前还不清楚。
在T淋巴细胞中，FasL基因表达是受转录因子调控，包括NF-KB，AP-1，c-Myc等。然而，在肿瘤细胞中，FasL的转录调控受哪些转录因子的影响目前仍不清楚。c-Myc是一种原癌基因，与肿瘤的分化和发展密切相关，它和异二聚体Max一起形成转录因子复合体，介导了许多肿瘤生长基因的表达。而且，c-Myc不但可以引起细胞的增殖，且可以诱导凋亡，而其诱导凋亡的作用与Fas和FasL的表达有关，Brunner etal.揭示了c-Myc通过直接与FasL启动子相互作用，诱导活化T细胞FasL表达。在肿瘤细胞中，c-Myc是否可以调控FasL的表达目前还知之甚少。
基于以上研究结果和思路，所以在本实验中，我们主要应用MAPK/ERKkinase(MEK)特异抑制剂PD98059，来观察肿瘤细胞67-kDa LNR能否通过MAPK/ERK1 /2信号通路，影响转录因子c-Myc的活性，从而调控人胆管癌细胞FasL的表达，进而影响Jurkat T细胞的凋亡。
来材料与方法：
1.用RT-PCR和Western-bolt检测PD98059处理组及未处理组人胆管癌细胞(QBC939)中c-Myc、p-c-Myc和FasL的表达。
2.采用脂质体转染法转染c-Myc干扰质粒至人胆管癌细胞，用RT-PCR和Western-bolt检测c-Myc和FasL的表达。
3.构建含FasL启动子及c-Myc结合位点(-127/-121)的FasL启动子的突变体的荧光素酶报告基因质粒，分别与pRL-TK表达质粒一起瞬时转染人胆管癌细胞，检测荧光素酶相对活性，比较PD98059处理组及PD98059未处理组人胆管癌细胞FasL启动子活性的变化情况；比较c-Myc结合位点突变前后的FasL启动子活性变化。
4.染色质免疫共沉淀(ChIP)技术分析p-c-Myc与活体人胆管癌细胞中FasL基因启动子的结合情况。
5.建立人胆管癌细胞与人Jurkat T细胞Transwell?小室旁分泌共培养模型，用TUNEL法检测胆管癌细胞PD98059处理组及PD98059未处理组对Jurkat T细胞凋亡的影响。
结果:
1. PD98059处理组人胆管癌细胞(QBC939细胞)磷酸化c-Myc(p-c-Myc)和FasL的表达均明显降低，而c-Myc未见明显变化；c-Myc干扰组胆管癌细胞c-Myc和FasL的表达均明显降低。
2.构建包含FasL启动子的PGL3- FasL-pro荧光素酶报告质粒并有c-Myc结合位点突变的PGL3- FasL-proM荧光素酶报告质粒，均经酶切及测序鉴定，表明PGL3-FasL-pro和PGL3- FasL-proM荧光素酶报告载体质粒构建成功。
3.运用荧火虫酶活性分析技术证实PD98059处理组人胆管癌细胞(QBC939细胞)荧光素酶活性(FasL基因启动子活性)与对照组相比明显下降；c-Myc干扰组及突变体组荧光素酶活性(FasL基因启动子活性)与对照组相比分别下降约80%和70%。
4.用染色质免疫共沉淀技术证实了在人胆管癌细胞(QBC939细胞)中，p-c-Myc与FasL基因启动子存在结合关系。
5.人胆管癌细胞(QBC939细胞)与Jurkat T细胞共培养后，Jurkat T细胞的凋亡指数明显增加；而PD98059处理人胆管癌细胞(QBC939细胞)后，JurkatT细胞的凋亡指数明显降低。
结论:
1.人胆管癌细胞(QBC939细胞)中，MAPK-ERK是67kDa层粘素受体(67-kDaLNR)诱导FasL的表达进而诱导Jurkat T细胞凋亡的主要信号通路之一。
2.人胆管癌细胞(QBC939细胞)中，67-kDa LNR诱导增强FasL基因启动子的活性有赖于转录因子c-Myc的参与，且可能与MAPK-ERK信号通路的活化后增强c-Myc的磷酸化有关。
Backbround: Fas ligand (FasL) is an approximately 40-kDa transmembrane proteinbelongings to the tumor necrosis factor(TNF) superfamily that can trigger apoptotic celldeath by binding to its receptor，Fas (CD95/APO-1) . FasL is expressed not only byactivated T cells but also by various tumors . We have found that a humancholangiocarcinoma cell line (QBC-939 cells) expresses various levels of functional FasL.We have also observed that higher expression levels of FasL in QBC-939 cells resulted inincreased apoptosis of T lymphocytes when both cell types were co-cultured. This result isconsistent with the hypothesis that tumors gain immune privilege by upregulating FasLexpression in order to“counterattack”and kill Fas-expressing infiltrating lymphocytes.Moreover，our previous study showed that 67-kDa laminin receptor(67-kDa LNR) andLn-1 play a definite role in the upregulation of FasL in QBC-939 cells.
67-kDa laminin receptor (67-kDa LNR) is thought to be a major laminin receptor thatis upregulated in neoplastic cells compared to their normal counterparts. Our previous studyshowed that human cholangiocarcinoma cells expressed a higher level of 67-kDa LNR thannormal epithelial cells. It has been shown that a cell-laminin interaction via the 67-kDaLNR is an important step in signal transduction pathways and that laminin and 67-kDa LNRare likely involved in MAPK (mitogen-activated protein kinase)- and DUSP(dual-specificity MAPK phosphatase)-mediated laminin signaling in human melanomacells . In human glioma cell lines，MEK inhibitors have been shown to decreasephosphorylated extracellular signal-regulated kinase (pERK) levels caused by stimulationwith either ligand or activating antibody to Fas. Based on our previous studies and the workof other researchers，we investigated the effect of the MAPK-ERK cascade on 67-kDaLNR- and Ln-1-induced FasL upregulation in QBC-939 cells.
FasL gene expression is controlled by transcription factor–DNA interactions at the FasL promoter. c-Myc belongs to the Myc family of transcription factors and c-Myc mRNAand protein are overexpressed in many cancer cells，including human cholangiocarcinomacells. Numerous signal transduction pathways are involved in the control of c-Myctranscription. Bermudez et al. reported that EGF activates c-Myc transcription via theRas/MEK/ERK pathway. Because relatively little is known about c-Myc regulation of FasLexpression outside of the immune system，we focused on the role of c-Myc in 67-kDaLNR and laminin-induced FasL upregulation in QBC-939 cells. And in other aspect，weset out to investigate the role of MAPK-ERK pathway in 67-kDa LNR induced FasLexpression and FasL-mediated apoptosis in human cholangiocarcinoma cells.
MethodsMethods: (1) The parent QBC-939 cells were pretreated with or without PD98059 (20μM) or DMSO (Vehicle) for 4 h and then incubated with Ln-1 (100μg/ml) for 24 h，theexpression of c-Myc and FasL were analyzed by immunohistochemistry，RT-PCR andWestern blotting. (2) To assess FasL promoter activity，the construct of pGL3-FasL-Prluciferase reporter gene vector and mutant construct were generated and wereco-transfected into QBC-939 cells with pRL-TK plasmid for 24h respectively. After that，the luciferase activity were measured using a luminometer. (3) Chromatinimmunoprecipitation assays was used to show the binding of phosphorylated c-Myc to thehuman FasL promoter in vivo. (4) We also examined the human cholangiocarcinomacells-induced apoptosis of Fas-sensitive Jurkat T cells using TUNEL assay after the parentQBC-939 cells were pretreated with or without PD98059 (20μM) or DMSO (Vehicle) for 4h and then incubated with Ln-1 (100μg/ml) for 24 h.
Results : (1) PD98059 significantly attenuated phosphorylation of c-Myc on Ser-62and FasL upregulation in QBC-939 cells and these cells showed decreased cytotoxicityagainst Fas-sensitive Jurkat T cells. (2) A luciferase reporter assay revealed that levels ofFasL promoter activity were significantly reduced after the parent QBC-939 cells werepretreated with PD98059 (20μM) . (3) Furthermore，mutational analysis of the c-Mycsites located on FasL promoter suggested that these sites are required for FasL promoteractivity in QBC-939 cells. (4) In addition，chromatin immunoprecipitation assays showedthe binding of phosphorylated c-Myc to the human FasL promoter in vivo.
ConclusionsConclusions: Based on these results，we conclude that:
1. MAPK-ERK pathway in 67-kDa LNR induced FasL expression and FasL-mediatedapoptosis take an important role in human cholangiocarcinoma cells.
2. 67-kDa LNR may increase the activation of the FasL promoter by phosphorylatingof c-Myc on Ser-62 to bind to the human FasL promoter in vivo in humancholangiocarcinoma cells.
67 kDa层粘素受体( 67kDa laminin receptor，67-kDa LNR)广泛存在于上皮细胞、内皮细胞、周围神经细胞、巨噬细胞及大部分肿瘤细胞表面，结合位点为LNβ1链的YIGSR序列。67-kDa LNR的高表达，可使癌细胞与基底膜的黏附力增强，有利于肿瘤的侵袭和转移。67-kDa LNR与LN的结合诱导了一系列跨膜信号传导系统的变化，最近的一项研究发现，层粘连蛋白的信号通路参与了有丝分裂原活化蛋白激酶(MAPK的)级联反应。这些结果提示：67-kDa LNR表达上调可能激活MAPK信号转导通路，且MAPK/ERK1/2被激活后，可将信号传递到细胞核内转录因子，从而增加与DNA的结合，促进和调节有关的基因表达。而肿瘤细胞67-kDa LNR激活MAPK信号转导通路是否可调节肿瘤细胞FasL的表达目前还不清楚。
在T淋巴细胞中，FasL基因表达是受转录因子调控，包括NF-KB，AP-1，c-Myc等。然而，在肿瘤细胞中，FasL的转录调控受哪些转录因子的影响目前仍不清楚。c-Myc是一种原癌基因，与肿瘤的分化和发展密切相关，它和异二聚体Max一起形成转录因子复合体，介导了许多肿瘤生长基因的表达。而且，c-Myc不但可以引起细胞的增殖，且可以诱导凋亡，而其诱导凋亡的作用与Fas和FasL的表达有关，Brunner etal.揭示了c-Myc通过直接与FasL启动子相互作用，诱导活化T细胞FasL表达。在肿瘤细胞中，c-Myc是否可以调控FasL的表达目前还知之甚少。
基于以上研究结果和思路，所以在本实验中，我们主要应用MAPK/ERKkinase(MEK)特异抑制剂PD98059，来观察肿瘤细胞67-kDa LNR能否通过MAPK/ERK1 /2信号通路，影响转录因子c-Myc的活性，从而调控人胆管癌细胞FasL的表达，进而影响Jurkat T细胞的凋亡。
来材料与方法：
1.用RT-PCR和Western-bolt检测PD98059处理组及未处理组人胆管癌细胞(QBC939)中c-Myc、p-c-Myc和FasL的表达。
2.采用脂质体转染法转染c-Myc干扰质粒至人胆管癌细胞，用RT-PCR和Western-bolt检测c-Myc和FasL的表达。
3.构建含FasL启动子及c-Myc结合位点(-127/-121)的FasL启动子的突变体的荧光素酶报告基因质粒，分别与pRL-TK表达质粒一起瞬时转染人胆管癌细胞，检测荧光素酶相对活性，比较PD98059处理组及PD98059未处理组人胆管癌细胞FasL启动子活性的变化情况；比较c-Myc结合位点突变前后的FasL启动子活性变化。
4.染色质免疫共沉淀(ChIP)技术分析p-c-Myc与活体人胆管癌细胞中FasL基因启动子的结合情况。
5.建立人胆管癌细胞与人Jurkat T细胞Transwell?小室旁分泌共培养模型，用TUNEL法检测胆管癌细胞PD98059处理组及PD98059未处理组对Jurkat T细胞凋亡的影响。
结果:
1. PD98059处理组人胆管癌细胞(QBC939细胞)磷酸化c-Myc(p-c-Myc)和FasL的表达均明显降低，而c-Myc未见明显变化；c-Myc干扰组胆管癌细胞c-Myc和FasL的表达均明显降低。
2.构建包含FasL启动子的PGL3- FasL-pro荧光素酶报告质粒并有c-Myc结合位点突变的PGL3- FasL-proM荧光素酶报告质粒，均经酶切及测序鉴定，表明PGL3-FasL-pro和PGL3- FasL-proM荧光素酶报告载体质粒构建成功。
3.运用荧火虫酶活性分析技术证实PD98059处理组人胆管癌细胞(QBC939细胞)荧光素酶活性(FasL基因启动子活性)与对照组相比明显下降；c-Myc干扰组及突变体组荧光素酶活性(FasL基因启动子活性)与对照组相比分别下降约80%和70%。
4.用染色质免疫共沉淀技术证实了在人胆管癌细胞(QBC939细胞)中，p-c-Myc与FasL基因启动子存在结合关系。
5.人胆管癌细胞(QBC939细胞)与Jurkat T细胞共培养后，Jurkat T细胞的凋亡指数明显增加；而PD98059处理人胆管癌细胞(QBC939细胞)后，JurkatT细胞的凋亡指数明显降低。
结论:
1.人胆管癌细胞(QBC939细胞)中，MAPK-ERK是67kDa层粘素受体(67-kDaLNR)诱导FasL的表达进而诱导Jurkat T细胞凋亡的主要信号通路之一。
2.人胆管癌细胞(QBC939细胞)中，67-kDa LNR诱导增强FasL基因启动子的活性有赖于转录因子c-Myc的参与，且可能与MAPK-ERK信号通路的活化后增强c-Myc的磷酸化有关。
Backbround: Fas ligand (FasL) is an approximately 40-kDa transmembrane proteinbelongings to the tumor necrosis factor(TNF) superfamily that can trigger apoptotic celldeath by binding to its receptor，Fas (CD95/APO-1) . FasL is expressed not only byactivated T cells but also by various tumors . We have found that a humancholangiocarcinoma cell line (QBC-939 cells) expresses various levels of functional FasL.We have also observed that higher expression levels of FasL in QBC-939 cells resulted inincreased apoptosis of T lymphocytes when both cell types were co-cultured. This result isconsistent with the hypothesis that tumors gain immune privilege by upregulating FasLexpression in order to“counterattack”and kill Fas-expressing infiltrating lymphocytes.Moreover，our previous study showed that 67-kDa laminin receptor(67-kDa LNR) andLn-1 play a definite role in the upregulation of FasL in QBC-939 cells.
67-kDa laminin receptor (67-kDa LNR) is thought to be a major laminin receptor thatis upregulated in neoplastic cells compared to their normal counterparts. Our previous studyshowed that human cholangiocarcinoma cells expressed a higher level of 67-kDa LNR thannormal epithelial cells. It has been shown that a cell-laminin interaction via the 67-kDaLNR is an important step in signal transduction pathways and that laminin and 67-kDa LNRare likely involved in MAPK (mitogen-activated protein kinase)- and DUSP(dual-specificity MAPK phosphatase)-mediated laminin signaling in human melanomacells . In human glioma cell lines，MEK inhibitors have been shown to decreasephosphorylated extracellular signal-regulated kinase (pERK) levels caused by stimulationwith either ligand or activating antibody to Fas. Based on our previous studies and the workof other researchers，we investigated the effect of the MAPK-ERK cascade on 67-kDaLNR- and Ln-1-induced FasL upregulation in QBC-939 cells.
FasL gene expression is controlled by transcription factor–DNA interactions at the FasL promoter. c-Myc belongs to the Myc family of transcription factors and c-Myc mRNAand protein are overexpressed in many cancer cells，including human cholangiocarcinomacells. Numerous signal transduction pathways are involved in the control of c-Myctranscription. Bermudez et al. reported that EGF activates c-Myc transcription via theRas/MEK/ERK pathway. Because relatively little is known about c-Myc regulation of FasLexpression outside of the immune system，we focused on the role of c-Myc in 67-kDaLNR and laminin-induced FasL upregulation in QBC-939 cells. And in other aspect，weset out to investigate the role of MAPK-ERK pathway in 67-kDa LNR induced FasLexpression and FasL-mediated apoptosis in human cholangiocarcinoma cells.
MethodsMethods: (1) The parent QBC-939 cells were pretreated with or without PD98059 (20μM) or DMSO (Vehicle) for 4 h and then incubated with Ln-1 (100μg/ml) for 24 h，theexpression of c-Myc and FasL were analyzed by immunohistochemistry，RT-PCR andWestern blotting. (2) To assess FasL promoter activity，the construct of pGL3-FasL-Prluciferase reporter gene vector and mutant construct were generated and wereco-transfected into QBC-939 cells with pRL-TK plasmid for 24h respectively. After that，the luciferase activity were measured using a luminometer. (3) Chromatinimmunoprecipitation assays was used to show the binding of phosphorylated c-Myc to thehuman FasL promoter in vivo. (4) We also examined the human cholangiocarcinomacells-induced apoptosis of Fas-sensitive Jurkat T cells using TUNEL assay after the parentQBC-939 cells were pretreated with or without PD98059 (20μM) or DMSO (Vehicle) for 4h and then incubated with Ln-1 (100μg/ml) for 24 h.
Results : (1) PD98059 significantly attenuated phosphorylation of c-Myc on Ser-62and FasL upregulation in QBC-939 cells and these cells showed decreased cytotoxicityagainst Fas-sensitive Jurkat T cells. (2) A luciferase reporter assay revealed that levels ofFasL promoter activity were significantly reduced after the parent QBC-939 cells werepretreated with PD98059 (20μM) . (3) Furthermore，mutational analysis of the c-Mycsites located on FasL promoter suggested that these sites are required for FasL promoteractivity in QBC-939 cells. (4) In addition，chromatin immunoprecipitation assays showedthe binding of phosphorylated c-Myc to the human FasL promoter in vivo.
ConclusionsConclusions: Based on these results，we conclude that:
1. MAPK-ERK pathway in 67-kDa LNR induced FasL expression and FasL-mediatedapoptosis take an important role in human cholangiocarcinoma cells.
2. 67-kDa LNR may increase the activation of the FasL promoter by phosphorylatingof c-Myc on Ser-62 to bind to the human FasL promoter in vivo in humancholangiocarcinoma cells.
引文
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