制瘤素对卵巢癌细胞的影响及其机制的体外研究
摘要
目的本研究的目的是探讨重组人OSM(rH-OSM)对人卵巢癌SKOV3细胞的影响,以及ERK1/2、p38、STAT3是否参与了它的信号通路。
方法将SKOV3细胞置于含有2%胎牛血清(FBS)的RPMI-1640培养基中培养,通过MTT分析rH(重组人)-OSM不同浓度,不同刺激时间对卵巢癌SKOV3细胞的影响。分别应用Hoechst 33342/PI染色、AO/EB染色观察析rH-OSM是否会引起卵巢癌SKOV3细胞凋亡。通过western blot蛋白印迹分析rH-OSM诱导的卵巢癌SKOV3细胞中p-ERK1/2、p-p-38, p-STAT3蛋白表达的变化。然后我们检测rH-OSM引起的卵巢癌SKOV3细胞变化是否是由活化的ERK1/2、p-38, p-STAT3介导的。MEK抑制剂U0126(40nmol/ml)能阻止p-ERK的激活,用U0126评估p-pERK的抑制是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。使用p-p38激酶抑制剂SB202190 (50nmol/ml/)能特异阻断p-p38的活化。SB202190被用来评估p-p38的抑制是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。通过RNAi技术沉默STAT3基因来评估P-STAT3的沉默是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。
结果Hoechst33342/PI染色和AO/EB染色未见到rH-OSM治疗组与对照组有明显不同,表明rH-OSM不能诱导SKOV3细胞凋亡；MTT结果显示50ng/ml以上的rH-OSM才能够促进卵巢癌SKOV3细胞增殖,表明一定剂量的rH-OSM才能够诱导SKOV3细胞的增殖；而且培养3天后才看到有统计学意义的增殖,表明rH-OSM长期刺激可以促进卵巢癌细胞增殖；细胞周期显示rH-OSM处理组在18 h和42 h的G2/M+S期细胞百分率较对照组明显高,表明它可能是通过加速细胞周期来促进SKOV3细胞增殖；免疫蛋白印迹分析表明rH-OSM诱导SKOV3细胞中p-STAT3、p-ERK1/2和p-p38的蛋白水平增加。p-p38和p-ERK1/2的抑制剂抑制了rH-OSM的诱导SKOV3细胞的增殖。免疫蛋白印迹分析表明p-p38的抑制剂阻止了rH-OSM诱导的卵巢癌SKOV3细胞中p-STAT3蛋白的表达；并且ERK1/2抑制剂也阻止了rH-OSM诱导的SKOV3细胞p-STAT3的表达,表明p-p38和p-ERK调节着p-STAT3蛋白表达。然而,RANi干扰沉默STAT3基因后,再用rH-OSM刺激SKOV3细胞,细胞显出轻微增殖但与sh-STAT3组比无统计学意义,表明沉默STAT3阻止了rH-OSM诱导的SKOV3细胞的增殖能力。p-ERK1/2和p-p38蛋白表达水平与未沉默STAT3基因前一样,表明沉默STAT3没有影响到rH-OSM诱导的SKOV3细胞中p-ERK和p-p38蛋白表达。
结论长时间的rH-OSM刺激可以促进卵巢癌SKOV3细胞增殖。并且rH-OSM促进SKOV3细胞增殖活性可以与不同的信号通路有关,如p-STAT3、p-ERK1/2和p-p38。ERK1/2和p38调节着SKOV3细胞中STAT3蛋白的表达,而STAT3可能是rH-OSM诱导SKOV3细胞体外增殖的关键因素。
purpose The purpose of this study was to investigate the possible role of recombinant human OSM (rH-OSM) in human ovarian cancer SKOV3 cells,and if the ERK1/2, p38, STAT3 signaling pathways are involved.
Methods The cells were treated with rH-OSM (100 ng/mL) in RPMI-1640 medium with 2% FBS, SKOV3 cells measured in using MTT assays after treatment with different concentrations rH-OSM in different times; SKOV3 cells treated with rH-OSM analyze by Hoechst 33342/PI staining and AO/EB staining in order to show if proliferation of SKOV3 cells induce by rH-OSM; p-ERK1/2,p-p38, p-STAT3 protein expression in treated SKOV3 cells analyse by western blot. And then we investigated whether rH-OSM-induced change is mediated by activation of p-ERK1/2, p-p38, p-STAT3 in ovarian cancer cell line SKOV3. The MEK inhibitor U0126 was used, and found to specifically block p-ERK activation. An inhibitor of p-p38 kinase, SB202190, was used. SB202190 (50 nmol/mL) was able to specifically block p-p38 activation. So U0126 and SB202190 was utilized to assess the role of p-ERK and p-p38 in rH-OSM induced growth of SKOV3 cells. STAT3 also was silenced by RNAi to assess the role of p-STAT3 in rH-OSM induced growth of SKOV3 cells.
Result The study showed that rH-OSM promoted the proliferation of SKOV3 ovarian cancer cells. Western blot analysis showed that p-STAT3, phosphorylated-extracellular regulated protein kinase 1/2(p-ERK1/2), p-p38 protein levels were increased in the cell lines treated with rH-OSM. Proliferation in SKOV3 cells induced by rH-OSM was suppressed by inhibitors of p-p38 or p-ERK 1/2. Western blot analysis showed that p-STAT3 protein was decreased in SKOV3 cells treated by inhibitors of p-p38 prior to treatment with rH-OSM. Also, p-STAT3 was not increased in the cells treated by inhibitors of ERK1/2 prior to treatment with rH-OSM. Cell proliferation showed a moderate increase in sh-STAT3+rh-OSM control group compared with sh-STAT3 group. And after cells treated with rh-OSM, p-ERK1/2 and p-p38 protein expression was similarly affected in sh-STAT3+rh-OSM group compared with SKOV3 cells with STAT3.
Conclusion These data demonstrate that rH-OSM promotes the proliferation of SKOV3 ovarian cancer cells and the growth-promoting activity of rH-OSM can be mediated through different signaling pathways. ERK1/2 and p38 proteins regulate STAT3 expression in SKOV3 cells, while STAT3 may be pivotal to the proliferation of SKOV3 cells in vitro.
方法将SKOV3细胞置于含有2%胎牛血清(FBS)的RPMI-1640培养基中培养,通过MTT分析rH(重组人)-OSM不同浓度,不同刺激时间对卵巢癌SKOV3细胞的影响。分别应用Hoechst 33342/PI染色、AO/EB染色观察析rH-OSM是否会引起卵巢癌SKOV3细胞凋亡。通过western blot蛋白印迹分析rH-OSM诱导的卵巢癌SKOV3细胞中p-ERK1/2、p-p-38, p-STAT3蛋白表达的变化。然后我们检测rH-OSM引起的卵巢癌SKOV3细胞变化是否是由活化的ERK1/2、p-38, p-STAT3介导的。MEK抑制剂U0126(40nmol/ml)能阻止p-ERK的激活,用U0126评估p-pERK的抑制是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。使用p-p38激酶抑制剂SB202190 (50nmol/ml/)能特异阻断p-p38的活化。SB202190被用来评估p-p38的抑制是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。通过RNAi技术沉默STAT3基因来评估P-STAT3的沉默是否会影响rH-OSM诱导的卵巢癌SKOV3细胞增殖及蛋白表达变化。
结果Hoechst33342/PI染色和AO/EB染色未见到rH-OSM治疗组与对照组有明显不同,表明rH-OSM不能诱导SKOV3细胞凋亡；MTT结果显示50ng/ml以上的rH-OSM才能够促进卵巢癌SKOV3细胞增殖,表明一定剂量的rH-OSM才能够诱导SKOV3细胞的增殖；而且培养3天后才看到有统计学意义的增殖,表明rH-OSM长期刺激可以促进卵巢癌细胞增殖；细胞周期显示rH-OSM处理组在18 h和42 h的G2/M+S期细胞百分率较对照组明显高,表明它可能是通过加速细胞周期来促进SKOV3细胞增殖；免疫蛋白印迹分析表明rH-OSM诱导SKOV3细胞中p-STAT3、p-ERK1/2和p-p38的蛋白水平增加。p-p38和p-ERK1/2的抑制剂抑制了rH-OSM的诱导SKOV3细胞的增殖。免疫蛋白印迹分析表明p-p38的抑制剂阻止了rH-OSM诱导的卵巢癌SKOV3细胞中p-STAT3蛋白的表达；并且ERK1/2抑制剂也阻止了rH-OSM诱导的SKOV3细胞p-STAT3的表达,表明p-p38和p-ERK调节着p-STAT3蛋白表达。然而,RANi干扰沉默STAT3基因后,再用rH-OSM刺激SKOV3细胞,细胞显出轻微增殖但与sh-STAT3组比无统计学意义,表明沉默STAT3阻止了rH-OSM诱导的SKOV3细胞的增殖能力。p-ERK1/2和p-p38蛋白表达水平与未沉默STAT3基因前一样,表明沉默STAT3没有影响到rH-OSM诱导的SKOV3细胞中p-ERK和p-p38蛋白表达。
结论长时间的rH-OSM刺激可以促进卵巢癌SKOV3细胞增殖。并且rH-OSM促进SKOV3细胞增殖活性可以与不同的信号通路有关,如p-STAT3、p-ERK1/2和p-p38。ERK1/2和p38调节着SKOV3细胞中STAT3蛋白的表达,而STAT3可能是rH-OSM诱导SKOV3细胞体外增殖的关键因素。
purpose The purpose of this study was to investigate the possible role of recombinant human OSM (rH-OSM) in human ovarian cancer SKOV3 cells,and if the ERK1/2, p38, STAT3 signaling pathways are involved.
Methods The cells were treated with rH-OSM (100 ng/mL) in RPMI-1640 medium with 2% FBS, SKOV3 cells measured in using MTT assays after treatment with different concentrations rH-OSM in different times; SKOV3 cells treated with rH-OSM analyze by Hoechst 33342/PI staining and AO/EB staining in order to show if proliferation of SKOV3 cells induce by rH-OSM; p-ERK1/2,p-p38, p-STAT3 protein expression in treated SKOV3 cells analyse by western blot. And then we investigated whether rH-OSM-induced change is mediated by activation of p-ERK1/2, p-p38, p-STAT3 in ovarian cancer cell line SKOV3. The MEK inhibitor U0126 was used, and found to specifically block p-ERK activation. An inhibitor of p-p38 kinase, SB202190, was used. SB202190 (50 nmol/mL) was able to specifically block p-p38 activation. So U0126 and SB202190 was utilized to assess the role of p-ERK and p-p38 in rH-OSM induced growth of SKOV3 cells. STAT3 also was silenced by RNAi to assess the role of p-STAT3 in rH-OSM induced growth of SKOV3 cells.
Result The study showed that rH-OSM promoted the proliferation of SKOV3 ovarian cancer cells. Western blot analysis showed that p-STAT3, phosphorylated-extracellular regulated protein kinase 1/2(p-ERK1/2), p-p38 protein levels were increased in the cell lines treated with rH-OSM. Proliferation in SKOV3 cells induced by rH-OSM was suppressed by inhibitors of p-p38 or p-ERK 1/2. Western blot analysis showed that p-STAT3 protein was decreased in SKOV3 cells treated by inhibitors of p-p38 prior to treatment with rH-OSM. Also, p-STAT3 was not increased in the cells treated by inhibitors of ERK1/2 prior to treatment with rH-OSM. Cell proliferation showed a moderate increase in sh-STAT3+rh-OSM control group compared with sh-STAT3 group. And after cells treated with rh-OSM, p-ERK1/2 and p-p38 protein expression was similarly affected in sh-STAT3+rh-OSM group compared with SKOV3 cells with STAT3.
Conclusion These data demonstrate that rH-OSM promotes the proliferation of SKOV3 ovarian cancer cells and the growth-promoting activity of rH-OSM can be mediated through different signaling pathways. ERK1/2 and p38 proteins regulate STAT3 expression in SKOV3 cells, while STAT3 may be pivotal to the proliferation of SKOV3 cells in vitro.
引文
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