PGE2对肝癌细胞生长与侵袭能力的影响及相关机制的研究
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摘要
研究背景:
前列腺素E_2(PGE_2)是花生四烯酸代谢产物,国内外研究表明PGE_2合成增加与多种肿瘤的生长与扩散有关。PGE_2合成关键酶为环加氧酶(cyclooxygenase, COX),目前已发现三种环加氧酶,其中COX-2主要由某些细胞因子、激素等诱导合成,因而在炎症与肿瘤组织中往往呈高表达。所合成的PGE2主要通过与细胞膜表面的四种EP受体(EP1、EP2、EP3、EP4)结合,激活下游信号转导通路,而发挥生物学调节作用。本实验室前期实验证明肝细胞癌细胞表面同时表达四种EP受体;COX-2过表达或外源性PGE2都有促进肝细胞癌细胞存活、生长的作用;而选择性COX-2抑制剂celecoxib则可抑制肝癌细胞存活,促进细胞凋亡。
本课题在此基础上继续探讨PGE_2对肝细胞癌细胞生长、粘附与侵袭能力的影响。
研究目的:
1.阐明PGE_2对肝细胞癌细胞生长的影响。
2.探讨PGE_2及相关EP受体通路对肝细胞癌细胞中存活素(survivin)表达的影响。
3.研究PGE_2对肝细胞癌细胞粘附、迁移与侵袭能力的影响。
4.探讨粘着斑激酶(FAK)信号转导通路在PGE2诱导的肝细胞癌细胞粘附与迁移等过程中的作用。
研究方法:
1.常规方法培养肝细胞癌细胞株HUH-7、Hep3B与HepG2,以及人胚肾细胞株HEK293。
2.采用WST法检测PGE_2或EP1受体激动剂(17-PT-PGE_2)对肝细胞癌细胞生长与粘附能力的影响。
3.采用Transwell小室的方法检测PGE_2对肝细胞癌细胞生长、粘附与侵袭能力的影响。
4.采用质粒转染实验获得过表达COX-2蛋白的HUH-7细胞,采用质粒转染实验结合筛选稳定表达株的方法获得稳定表达EP1受体蛋白的HEK293细胞,研究其对细胞生物学活性的影响。
5.采用RNA干扰实验抑制肝癌细胞中EP1受体或FAK蛋白的表达,研究其对细胞生物学活性的影响。
6.采用realtime PCR实验检测survivin mRNA水平的变化;采用Western Blot实验分析survivin、FAK、paxillin等蛋白水平的变化,并检测EGFR、Akt、FAK、paxillin、ERK的磷酸化水平的变化。
研究结果:
1.采用5μM PGE_2分别处理HUH-7、Hep3B与HepG2,24 h后WST法检测发现细胞活性分别增加到123%、112%与109%。而用50μM选择性COX-2抑制剂celecoxib分别处理三种细胞,24 h后细胞活性下降至对照组的5.4%、1.2%及25.6%。
2.采用5μM PGE_2处理HUH-7细胞,8 h后细胞中survivin蛋白水平增加至230%;COX-2过表达实验可引起相似的survivin蛋白水平增高的现象,而celecoxib 50μM作用下此现象完全被阻断。
3.采用5μM 17-P-T-PGE_2处理HUH-7细胞或转染EP1受体的HEK293细胞,细胞中survivin蛋白水平都增加2倍以上;而选择性EP1受体阻断剂或EP1受体RNA干扰实验完全抑制PGE_2诱导的survivin蛋白水平增加。
4. 17-P-T-PGE_2处理HUH-7细胞中,EGFR与Akt磷酸化水平明显增加,而选择性EGFR与PI3K抑制剂显著抑制17-P-T-PGE_2诱导的survivin蛋白水平增加。
5. PGE2处理HUH-7细胞,24h后检测发现粘附、迁移与侵袭细胞数分别增加158%、122%与128%。
6. PGE_2促进HUH-7细胞中FAK蛋白表达与磷酸化水平分别增加170%与263%。而FAK RNA干扰实验抑制PGE2诱导的HUH-7细胞的粘附与迁移。
7. PGE_2促进HUH-7细胞中FAK下游蛋白paxillin与ERK磷酸化水平增加,选择性ERK抑制剂(PD98059)显著抑制PGE_2诱导的HUH-7细胞的粘附与迁移。
结论:
PGE_2明显促进肝细胞癌细胞生长、粘附、迁移与侵袭,其中可通过EP1受体/ EGFR/ PI3K通路上调survivin蛋白水平而促进细胞生长,并通过FAK/ paxillin/ ERK通路上调细胞粘附、迁移与侵袭的能力。
Background:
Prostaglandin E_2 (PGE_2) one of predominant metabolic products of arachidonic acid. It is widely known that PGE_2 synthesis is associated with cell growth and spread in many cancer cells. Cyclooxygenase (COX) is known as prostaglandin endoperoxide synthase. Cyclooxygenase has three isoforms: COX-1, COX-2 and COX-3. Among them, COX-2 is induced by a lot of stimuli such as cytokines, hormones, mitogens, and growth factors, which explains its up-regulation in various inflammatory diseases and human cancers. PGE_2 mediates its effects by binding to and activating 4 different G-protein-coupled receptors, EP1, EP2, EP3 and EP4. In our previous studies, all of the 4 EP receptors were expressed on the surface of hepatocellular carcinoma cells. Both COX-2 overexpression and exogenous PGE_2 improved cell growth, while the selective COX-2 inhibitor, celecoxib, suppressed cell survival and induced cell apoptosis in hepatocellular carcinoma cells.
In current studies, we went on to explore the effects of PGE_2 on cell growth, adhesion, migration and invasion in hepatocellular carcinoma cells.
Aims:
1. To clarify the effects of PGE_2 on cell growth in hepatocellular carcinoma cells.
2. To explore the effects of PGE_2 and related EP receptor on survivin expression in hepatocellular carcinoma cells.
3. To investigate the effects of PGE_2 on cell adhesion, migration and invasion in hepatocellular carcinoma cells.
4. To define a role of focal adhesion kinase (FAK) in PGE_2-induced cell adhesion and migration in hepatocellular carcinoma cells.
Materials and methods:
1. The hepatocellular carcinoma cell lines HUH-7, Hep3B and HepG2 cells, and human embryonic kidney HEK293 cells, were all cultured in conventional conditions.
2. The WST reagents were used to detect the cell viability rate and relative adhesion rate in hepatocellular carcinoma cells with PGE_2 or selective EP1 agonist (17-P-T-PGE_2) treatments.
3. 12-well transwell units were used to detect relative migration rate and invasion rate in hepatocellular carcinoma cells with PGE_2 treatments.
4. The pcDNA3 plasmid encoding human COX-2 (COX-2-pcDNA3) and EP1 receptor (EP1R-pcDNA3) were transfected in HUH-7 cells and HEK293 cells, respectively, to gain COX-2-overexpressed cells and EP1 receptor-stably expressed cells.
5. RNA interference was used to suppress EP1 receptor or FAK protein expression in HUH-7 cells, in order to study the effects of these protein on cell biologic activities.
6. Realtime PCR was used to detect survivin mRNA level in HUH-7 cells. Western Blot was used to detect the protein level of survivin, FAK and paxillin, and the phosphorylation of EGFR, Akt, FAK, paxillin and ERK.
Results:
1. In WST assays, the cell viabilities were increased to 123%, 112% and 109% in HUH-7, Hep3B and HepG2 cells when treated with 5μM PGE_2 for 24 h. However, 50μM celecoxib suppressed the cell viabilities to 5.4%, 1.2% and 25.6% of control, respectively.
2. 5μM PGE_2 treatment increased survivin expression 2.3-fold in HUH-7 cell. COX-2 overexpression caused similar survivin upregulation, which was suppressed by 50μM celecoxib.
3. 5μM selective EP1 agonist (17-P-T-PGE_2) or EP1 receptor transfection increased survivin expression more than 2 fold. Conversely, the PGE_2-induced survivin upregulation was blocked by selective EP1 antagonist or EP1 RNA interference.
4. The phosphorylation of EGFR and Akt were elevated in 17-P-T-PGE_2-treated cells, while both EGFR and PI3K inhibitors suppressed survivin upregulation induced by 17-P-T-PGE_2.
5. PGE_2 treatment significantly increased the relative adhesion rate, migration rate, and invasive rate by 158%, 122% and 128% in HUH-7 cells.
6. PGE_2 treatment increased the synthesis and phosphorylation of FAK by 170% and 263%. RNA interference targeting FAK suppressed PGE_2-mediated cell adhesion and migration.
7. PGE_2 treatment increased the phosphorylation of paxillin and Erk2, the down stream protein of FAK. PD98059, the specific inhibitor of MEK, suppressed PGE_2-mediated cell adhesion and migration.
Conclusion:
PGE_2 improved cell growth, adhesion, migration and invasion in hepatocellular carcinoma cells. The PGE_2/EP1/EGFR/PI3K pathway promoted cell growth by upregulating survivin expression. And the FAK/paxillin/ERK pathway was associated with PGE_2-induced cell adhesion, migration, and invasion.
前列腺素E_2(PGE_2)是花生四烯酸代谢产物,国内外研究表明PGE_2合成增加与多种肿瘤的生长与扩散有关。PGE_2合成关键酶为环加氧酶(cyclooxygenase, COX),目前已发现三种环加氧酶,其中COX-2主要由某些细胞因子、激素等诱导合成,因而在炎症与肿瘤组织中往往呈高表达。所合成的PGE2主要通过与细胞膜表面的四种EP受体(EP1、EP2、EP3、EP4)结合,激活下游信号转导通路,而发挥生物学调节作用。本实验室前期实验证明肝细胞癌细胞表面同时表达四种EP受体;COX-2过表达或外源性PGE2都有促进肝细胞癌细胞存活、生长的作用;而选择性COX-2抑制剂celecoxib则可抑制肝癌细胞存活,促进细胞凋亡。
本课题在此基础上继续探讨PGE_2对肝细胞癌细胞生长、粘附与侵袭能力的影响。
研究目的:
1.阐明PGE_2对肝细胞癌细胞生长的影响。
2.探讨PGE_2及相关EP受体通路对肝细胞癌细胞中存活素(survivin)表达的影响。
3.研究PGE_2对肝细胞癌细胞粘附、迁移与侵袭能力的影响。
4.探讨粘着斑激酶(FAK)信号转导通路在PGE2诱导的肝细胞癌细胞粘附与迁移等过程中的作用。
研究方法:
1.常规方法培养肝细胞癌细胞株HUH-7、Hep3B与HepG2,以及人胚肾细胞株HEK293。
2.采用WST法检测PGE_2或EP1受体激动剂(17-PT-PGE_2)对肝细胞癌细胞生长与粘附能力的影响。
3.采用Transwell小室的方法检测PGE_2对肝细胞癌细胞生长、粘附与侵袭能力的影响。
4.采用质粒转染实验获得过表达COX-2蛋白的HUH-7细胞,采用质粒转染实验结合筛选稳定表达株的方法获得稳定表达EP1受体蛋白的HEK293细胞,研究其对细胞生物学活性的影响。
5.采用RNA干扰实验抑制肝癌细胞中EP1受体或FAK蛋白的表达,研究其对细胞生物学活性的影响。
6.采用realtime PCR实验检测survivin mRNA水平的变化;采用Western Blot实验分析survivin、FAK、paxillin等蛋白水平的变化,并检测EGFR、Akt、FAK、paxillin、ERK的磷酸化水平的变化。
研究结果:
1.采用5μM PGE_2分别处理HUH-7、Hep3B与HepG2,24 h后WST法检测发现细胞活性分别增加到123%、112%与109%。而用50μM选择性COX-2抑制剂celecoxib分别处理三种细胞,24 h后细胞活性下降至对照组的5.4%、1.2%及25.6%。
2.采用5μM PGE_2处理HUH-7细胞,8 h后细胞中survivin蛋白水平增加至230%;COX-2过表达实验可引起相似的survivin蛋白水平增高的现象,而celecoxib 50μM作用下此现象完全被阻断。
3.采用5μM 17-P-T-PGE_2处理HUH-7细胞或转染EP1受体的HEK293细胞,细胞中survivin蛋白水平都增加2倍以上;而选择性EP1受体阻断剂或EP1受体RNA干扰实验完全抑制PGE_2诱导的survivin蛋白水平增加。
4. 17-P-T-PGE_2处理HUH-7细胞中,EGFR与Akt磷酸化水平明显增加,而选择性EGFR与PI3K抑制剂显著抑制17-P-T-PGE_2诱导的survivin蛋白水平增加。
5. PGE2处理HUH-7细胞,24h后检测发现粘附、迁移与侵袭细胞数分别增加158%、122%与128%。
6. PGE_2促进HUH-7细胞中FAK蛋白表达与磷酸化水平分别增加170%与263%。而FAK RNA干扰实验抑制PGE2诱导的HUH-7细胞的粘附与迁移。
7. PGE_2促进HUH-7细胞中FAK下游蛋白paxillin与ERK磷酸化水平增加,选择性ERK抑制剂(PD98059)显著抑制PGE_2诱导的HUH-7细胞的粘附与迁移。
结论:
PGE_2明显促进肝细胞癌细胞生长、粘附、迁移与侵袭,其中可通过EP1受体/ EGFR/ PI3K通路上调survivin蛋白水平而促进细胞生长,并通过FAK/ paxillin/ ERK通路上调细胞粘附、迁移与侵袭的能力。
Background:
Prostaglandin E_2 (PGE_2) one of predominant metabolic products of arachidonic acid. It is widely known that PGE_2 synthesis is associated with cell growth and spread in many cancer cells. Cyclooxygenase (COX) is known as prostaglandin endoperoxide synthase. Cyclooxygenase has three isoforms: COX-1, COX-2 and COX-3. Among them, COX-2 is induced by a lot of stimuli such as cytokines, hormones, mitogens, and growth factors, which explains its up-regulation in various inflammatory diseases and human cancers. PGE_2 mediates its effects by binding to and activating 4 different G-protein-coupled receptors, EP1, EP2, EP3 and EP4. In our previous studies, all of the 4 EP receptors were expressed on the surface of hepatocellular carcinoma cells. Both COX-2 overexpression and exogenous PGE_2 improved cell growth, while the selective COX-2 inhibitor, celecoxib, suppressed cell survival and induced cell apoptosis in hepatocellular carcinoma cells.
In current studies, we went on to explore the effects of PGE_2 on cell growth, adhesion, migration and invasion in hepatocellular carcinoma cells.
Aims:
1. To clarify the effects of PGE_2 on cell growth in hepatocellular carcinoma cells.
2. To explore the effects of PGE_2 and related EP receptor on survivin expression in hepatocellular carcinoma cells.
3. To investigate the effects of PGE_2 on cell adhesion, migration and invasion in hepatocellular carcinoma cells.
4. To define a role of focal adhesion kinase (FAK) in PGE_2-induced cell adhesion and migration in hepatocellular carcinoma cells.
Materials and methods:
1. The hepatocellular carcinoma cell lines HUH-7, Hep3B and HepG2 cells, and human embryonic kidney HEK293 cells, were all cultured in conventional conditions.
2. The WST reagents were used to detect the cell viability rate and relative adhesion rate in hepatocellular carcinoma cells with PGE_2 or selective EP1 agonist (17-P-T-PGE_2) treatments.
3. 12-well transwell units were used to detect relative migration rate and invasion rate in hepatocellular carcinoma cells with PGE_2 treatments.
4. The pcDNA3 plasmid encoding human COX-2 (COX-2-pcDNA3) and EP1 receptor (EP1R-pcDNA3) were transfected in HUH-7 cells and HEK293 cells, respectively, to gain COX-2-overexpressed cells and EP1 receptor-stably expressed cells.
5. RNA interference was used to suppress EP1 receptor or FAK protein expression in HUH-7 cells, in order to study the effects of these protein on cell biologic activities.
6. Realtime PCR was used to detect survivin mRNA level in HUH-7 cells. Western Blot was used to detect the protein level of survivin, FAK and paxillin, and the phosphorylation of EGFR, Akt, FAK, paxillin and ERK.
Results:
1. In WST assays, the cell viabilities were increased to 123%, 112% and 109% in HUH-7, Hep3B and HepG2 cells when treated with 5μM PGE_2 for 24 h. However, 50μM celecoxib suppressed the cell viabilities to 5.4%, 1.2% and 25.6% of control, respectively.
2. 5μM PGE_2 treatment increased survivin expression 2.3-fold in HUH-7 cell. COX-2 overexpression caused similar survivin upregulation, which was suppressed by 50μM celecoxib.
3. 5μM selective EP1 agonist (17-P-T-PGE_2) or EP1 receptor transfection increased survivin expression more than 2 fold. Conversely, the PGE_2-induced survivin upregulation was blocked by selective EP1 antagonist or EP1 RNA interference.
4. The phosphorylation of EGFR and Akt were elevated in 17-P-T-PGE_2-treated cells, while both EGFR and PI3K inhibitors suppressed survivin upregulation induced by 17-P-T-PGE_2.
5. PGE_2 treatment significantly increased the relative adhesion rate, migration rate, and invasive rate by 158%, 122% and 128% in HUH-7 cells.
6. PGE_2 treatment increased the synthesis and phosphorylation of FAK by 170% and 263%. RNA interference targeting FAK suppressed PGE_2-mediated cell adhesion and migration.
7. PGE_2 treatment increased the phosphorylation of paxillin and Erk2, the down stream protein of FAK. PD98059, the specific inhibitor of MEK, suppressed PGE_2-mediated cell adhesion and migration.
Conclusion:
PGE_2 improved cell growth, adhesion, migration and invasion in hepatocellular carcinoma cells. The PGE_2/EP1/EGFR/PI3K pathway promoted cell growth by upregulating survivin expression. And the FAK/paxillin/ERK pathway was associated with PGE_2-induced cell adhesion, migration, and invasion.
引文
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[4] Han C, Michalopoulos GK, Wu T. Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells. J Cell Physiol, 2006, 207: 261-270.
[5] Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem, 2003, 278: 35451-35457.
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