HGF通过MEK/ERK和PI3K/AKT信号途径影响人大肠癌细胞侵袭能力及VEGF表达
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摘要
目的：
1．检测临床大肠癌患者及正常人HGF及VEGF血清水平，并初步分析其与临床病理资料相关性及二者相关性。
2．观察HGF对大肠癌细胞Lovo、SW480、Colo205粘附、迁移及侵袭能力的影响。
3．检测HGF对大肠癌细胞及正常肠上皮细胞VEGF表达的影响。
4．探讨MEK／ERK1／2和PI3K／AKT信号转导通路在HGF影响大肠癌细胞侵袭能力及VEGF表达过程中可能的作用。
方法：
1．应用ELISA方法检测大肠癌患者及正常对照者HGF、VEGF血清学水平。
2．细胞培养：大肠癌细胞Lovo、SW480、Colo205及正常肠上皮细胞系按常规方法培养。
3．细胞经外源性HGF处理后，应用MTT法检测Lovo、SW480、Colo205及正常肠上皮细胞粘附能力变化，Transwell小室结合倒置显微镜观察肿瘤细胞迁移能力变化，Transwell小室结合Matrix胶检测肿瘤细胞侵袭能力的变化；HGF、c-Met磷酸化抑制剂Herbimycin A(HA)、MEK／ERK1／2信号通路特异性抑制剂UO126、PI3K／AKT信号通路特异性抑制剂LY294002分别处理细胞后，检测细胞侵袭能力变化并应用ELISA及RT-PCR方法检测细胞VEGF表达变化。
4．Western blot方法检测HGF、HA、UO126及LY294002处理后细胞VEGF蛋白表达水平的变化，同时检测c-Met及信号通路相关信号分子蛋白水平及磷酸化水平的变化。
结果：
1．大肠癌患者HGF、VEGF血清水平分别是正常人的约2.8倍、2.5倍(P＜0.01)，相关分析显示大肠癌患者血清HGF水平与临床病理分期、淋巴结转移相关(P＜0.01)，而与病理类型和分化程度无相关性(P＞0.05)；VEGF水平与病理分期、淋巴结转移、病理类型相关(P＜0.05)，而与分化程度无相关性(P＞0.05)；HGF血清水平与VEGF血清水平呈正相关(r=0.76，P＜0.01)。
2．外源性HGF明显增加大肠癌细胞Lovo、SW480、Colo205粘附比率、迁移及侵袭细胞数量，40ng的HGF作用4h后，粘附细胞比率较对照组分别增加63.33％、40.63％、39.13％(P＜0.05)；24h迁移细胞数量较对照组分别增加88.05％、124.13％、127.08％(P＜0.05)；24h侵袭细胞数量较对照组分别增加101.27％、89.46％、91.82％(P＜0.05)，而正常肠上皮细胞无明显变化(P＞0.05)。c-Met磷酸化抑制剂HA、MEK／ERK1／2信号通路特异性抑制剂UO126及PI3K／AKT信号通路特异性抑制剂LY294002均显著抑制由HGF诱导的大肠癌细胞粘附、迁移及侵袭能力(P＜0.05)。
3．ELISA、RT-PCR结果显示：大肠癌细胞有VEGF蛋白及mRNA转录水平表达，应用10ng、40ng、100ng HGF处理后，VEGF蛋白及mRNA转录水平均显著增加且与HGF浓度之间存在明显相关性，而正常肠上皮细胞无明显变化。HA、UO126及LY294002均显著抑制由HGF诱导的大肠癌细胞VEGF表达，HA 1.0μg、UO126合用LY294002 30μM时均几乎完全抑制HGF诱导的大肠癌细胞VEGF表达。
4．Western blot结果示：大肠癌细胞c-Met表达，而正常肠上皮细胞未检测到其表达；外源性HGF诱导大肠癌细胞c-Met、ERK1／2、AKT磷酸化及VEGF蛋白表达，且与HGF剂量有关。HA降低HGF所引起的c-Met磷酸化水平，1.0μg时完全抑制HGF所诱导的c-Met磷酸化；UO126、LY294002均显著降低由HGF所诱导的大肠癌细胞ERK1／2、AKT磷酸化水平，且两者之间无交叉抑制性。
结论：
1．大肠癌患者HGF、VEGF血清水平高于正常人血清水平，HGF可能与大肠癌局部浸润、转移及肿瘤细胞VEGF表达有关。
2．HGF可显著提高大肠癌细胞的粘附、迁移及侵袭能力，HGF促进肿瘤细胞粘附、迁移及侵袭可能与激活MEK／ERK1／2、PI3K／AKT信号通路有关。
3．大肠癌细胞c-Met过表达，HGF可活化其受体c-Met，进而激活MEK／RK1／2、PI3K／AKT信号转导通路，增加肿瘤细胞VEGF mRNA转录及蛋白表达，达到促进局部血管或淋巴管增殖、增加肿瘤细胞血供、增强肿瘤细胞远处转移能力的效果。
Objective:
1. To evaluate the clinical pathological effects of serum VEGF and HGFin patients with Colorectal Carcinoma.
2. To identify whether HGF can promote adhesion, migration andinvasion of human colorectal carcinoma cell lines in vitro.
3. To investigate the transcription of VEGF mRNA and expression ofVEGF protein in human colorectal carcinoma cell lines after treatedwith extraneous HGF in vitro.
4. To investigate the role of c-Met、MEK/ERK1/2 and PI3K/AKT signaltransduction pathways in the effect exerted by HGF on adhesion、migration and invasion abilities and VEGF expression of humancolorectal carcinoma cell lines.
Methods:
1. The serum levels of hepatocyte growth factor and vascular endothelialgrowth factor in patients with colorectal carcinoma and controlsubjects were measured by ELISA.
2. The cell adhesion ability was tested by MTT assay, cell migrationability was identified by Transwell plate and invasion ability wasobserved by a Matrix gel coated Transwell plate.
3. The mRNA level of vascular endothelial growth factor was analyzedby reverse-transcription PCR.
4. Western blot assay was performed to assess c-Met and many other proteins involved in the MEK and PI3K signaling pathwayscontributing to cell invasion and expression of VEGF in colorectalcarcinoma cells.
Results:
1. The serum levels of HGF and VEGF in patients with colorectalcarcinoma increased nearly 2.8-fold and 2.5-fold than those of controlsubjects, respectively; In addition, the levels of serum HGF and VEGFcorrelated with tumor stage and lymph node metastasis respectively;the level of serum VEGF correlated positively with the serum level ofHGF in patients with colorectal carcinoma.
2. Human colorectal carcinoma cells adhesion ratio, migration ratio andinvasion ratio were all increased rapidly after treated with extrinsicsource 40ng HGF. A significant decreased ratio of cell adhesion,migration and invasion could be detected after Herbimycin A, UO 126and LY294002 were added to the culture media respectively.
3. A small quantity of VEGF mRNA and protein were detected incolorectal carcinoma cell lines by reverse-transcription PCR andWestern blot. In vitro, extraneous hepatocyte growth factor markedlyupregulated protein and mRNA levels of vascular endothelial growthfactor in colorectal carcinoma cells.
4. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2and AKT in a dose-dependent manner respectively. Specific inhibitorson MEK and PI3K inhibited the hepatocyte growth factor-inducingexpression of vascular endothelial growth factor in colorectalcarcinoma cells.
Conclusions:
1. The serum levels of HGF and VEGF in patients with colorectalcarcinoma increased; moreover, the level of serum HGF probably correlated with tumor local invasion and metastasis; the level ofserum VEGF probably correlated positively with the serum level ofHGF.
2. HGF can significantly promote the adhesion, migration and invasionabilities of human colorectal carcinoma cell lines.
3. HGF can increase VEGF mRNA transcription and VEGF proteinexpression in human colorectal carcinoma cell lines.
4. The elevation of human colorectal carcinoma cells invasion abilityand VEGF production induced by HGF may be caused by theHGF-inducing activation of MEK/ERK1/2 and PI3K/AKT signalingpathways.
1．检测临床大肠癌患者及正常人HGF及VEGF血清水平，并初步分析其与临床病理资料相关性及二者相关性。
2．观察HGF对大肠癌细胞Lovo、SW480、Colo205粘附、迁移及侵袭能力的影响。
3．检测HGF对大肠癌细胞及正常肠上皮细胞VEGF表达的影响。
4．探讨MEK／ERK1／2和PI3K／AKT信号转导通路在HGF影响大肠癌细胞侵袭能力及VEGF表达过程中可能的作用。
方法：
1．应用ELISA方法检测大肠癌患者及正常对照者HGF、VEGF血清学水平。
2．细胞培养：大肠癌细胞Lovo、SW480、Colo205及正常肠上皮细胞系按常规方法培养。
3．细胞经外源性HGF处理后，应用MTT法检测Lovo、SW480、Colo205及正常肠上皮细胞粘附能力变化，Transwell小室结合倒置显微镜观察肿瘤细胞迁移能力变化，Transwell小室结合Matrix胶检测肿瘤细胞侵袭能力的变化；HGF、c-Met磷酸化抑制剂Herbimycin A(HA)、MEK／ERK1／2信号通路特异性抑制剂UO126、PI3K／AKT信号通路特异性抑制剂LY294002分别处理细胞后，检测细胞侵袭能力变化并应用ELISA及RT-PCR方法检测细胞VEGF表达变化。
4．Western blot方法检测HGF、HA、UO126及LY294002处理后细胞VEGF蛋白表达水平的变化，同时检测c-Met及信号通路相关信号分子蛋白水平及磷酸化水平的变化。
结果：
1．大肠癌患者HGF、VEGF血清水平分别是正常人的约2.8倍、2.5倍(P＜0.01)，相关分析显示大肠癌患者血清HGF水平与临床病理分期、淋巴结转移相关(P＜0.01)，而与病理类型和分化程度无相关性(P＞0.05)；VEGF水平与病理分期、淋巴结转移、病理类型相关(P＜0.05)，而与分化程度无相关性(P＞0.05)；HGF血清水平与VEGF血清水平呈正相关(r=0.76，P＜0.01)。
2．外源性HGF明显增加大肠癌细胞Lovo、SW480、Colo205粘附比率、迁移及侵袭细胞数量，40ng的HGF作用4h后，粘附细胞比率较对照组分别增加63.33％、40.63％、39.13％(P＜0.05)；24h迁移细胞数量较对照组分别增加88.05％、124.13％、127.08％(P＜0.05)；24h侵袭细胞数量较对照组分别增加101.27％、89.46％、91.82％(P＜0.05)，而正常肠上皮细胞无明显变化(P＞0.05)。c-Met磷酸化抑制剂HA、MEK／ERK1／2信号通路特异性抑制剂UO126及PI3K／AKT信号通路特异性抑制剂LY294002均显著抑制由HGF诱导的大肠癌细胞粘附、迁移及侵袭能力(P＜0.05)。
3．ELISA、RT-PCR结果显示：大肠癌细胞有VEGF蛋白及mRNA转录水平表达，应用10ng、40ng、100ng HGF处理后，VEGF蛋白及mRNA转录水平均显著增加且与HGF浓度之间存在明显相关性，而正常肠上皮细胞无明显变化。HA、UO126及LY294002均显著抑制由HGF诱导的大肠癌细胞VEGF表达，HA 1.0μg、UO126合用LY294002 30μM时均几乎完全抑制HGF诱导的大肠癌细胞VEGF表达。
4．Western blot结果示：大肠癌细胞c-Met表达，而正常肠上皮细胞未检测到其表达；外源性HGF诱导大肠癌细胞c-Met、ERK1／2、AKT磷酸化及VEGF蛋白表达，且与HGF剂量有关。HA降低HGF所引起的c-Met磷酸化水平，1.0μg时完全抑制HGF所诱导的c-Met磷酸化；UO126、LY294002均显著降低由HGF所诱导的大肠癌细胞ERK1／2、AKT磷酸化水平，且两者之间无交叉抑制性。
结论：
1．大肠癌患者HGF、VEGF血清水平高于正常人血清水平，HGF可能与大肠癌局部浸润、转移及肿瘤细胞VEGF表达有关。
2．HGF可显著提高大肠癌细胞的粘附、迁移及侵袭能力，HGF促进肿瘤细胞粘附、迁移及侵袭可能与激活MEK／ERK1／2、PI3K／AKT信号通路有关。
3．大肠癌细胞c-Met过表达，HGF可活化其受体c-Met，进而激活MEK／RK1／2、PI3K／AKT信号转导通路，增加肿瘤细胞VEGF mRNA转录及蛋白表达，达到促进局部血管或淋巴管增殖、增加肿瘤细胞血供、增强肿瘤细胞远处转移能力的效果。
Objective:
1. To evaluate the clinical pathological effects of serum VEGF and HGFin patients with Colorectal Carcinoma.
2. To identify whether HGF can promote adhesion, migration andinvasion of human colorectal carcinoma cell lines in vitro.
3. To investigate the transcription of VEGF mRNA and expression ofVEGF protein in human colorectal carcinoma cell lines after treatedwith extraneous HGF in vitro.
4. To investigate the role of c-Met、MEK/ERK1/2 and PI3K/AKT signaltransduction pathways in the effect exerted by HGF on adhesion、migration and invasion abilities and VEGF expression of humancolorectal carcinoma cell lines.
Methods:
1. The serum levels of hepatocyte growth factor and vascular endothelialgrowth factor in patients with colorectal carcinoma and controlsubjects were measured by ELISA.
2. The cell adhesion ability was tested by MTT assay, cell migrationability was identified by Transwell plate and invasion ability wasobserved by a Matrix gel coated Transwell plate.
3. The mRNA level of vascular endothelial growth factor was analyzedby reverse-transcription PCR.
4. Western blot assay was performed to assess c-Met and many other proteins involved in the MEK and PI3K signaling pathwayscontributing to cell invasion and expression of VEGF in colorectalcarcinoma cells.
Results:
1. The serum levels of HGF and VEGF in patients with colorectalcarcinoma increased nearly 2.8-fold and 2.5-fold than those of controlsubjects, respectively; In addition, the levels of serum HGF and VEGFcorrelated with tumor stage and lymph node metastasis respectively;the level of serum VEGF correlated positively with the serum level ofHGF in patients with colorectal carcinoma.
2. Human colorectal carcinoma cells adhesion ratio, migration ratio andinvasion ratio were all increased rapidly after treated with extrinsicsource 40ng HGF. A significant decreased ratio of cell adhesion,migration and invasion could be detected after Herbimycin A, UO 126and LY294002 were added to the culture media respectively.
3. A small quantity of VEGF mRNA and protein were detected incolorectal carcinoma cell lines by reverse-transcription PCR andWestern blot. In vitro, extraneous hepatocyte growth factor markedlyupregulated protein and mRNA levels of vascular endothelial growthfactor in colorectal carcinoma cells.
4. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2and AKT in a dose-dependent manner respectively. Specific inhibitorson MEK and PI3K inhibited the hepatocyte growth factor-inducingexpression of vascular endothelial growth factor in colorectalcarcinoma cells.
Conclusions:
1. The serum levels of HGF and VEGF in patients with colorectalcarcinoma increased; moreover, the level of serum HGF probably correlated with tumor local invasion and metastasis; the level ofserum VEGF probably correlated positively with the serum level ofHGF.
2. HGF can significantly promote the adhesion, migration and invasionabilities of human colorectal carcinoma cell lines.
3. HGF can increase VEGF mRNA transcription and VEGF proteinexpression in human colorectal carcinoma cell lines.
4. The elevation of human colorectal carcinoma cells invasion abilityand VEGF production induced by HGF may be caused by theHGF-inducing activation of MEK/ERK1/2 and PI3K/AKT signalingpathways.
引文
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7. Maeshima A, Zhang YQ, Furukawa M, Naruse T, Kojima I: Hepatocyte growth factor induces branching tubulogenesis in MDCK cells by modulating the activin-follistatin system. Kidney international 2000, 58(4):1511-1522.
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