卵泡刺激素对卵巢癌细胞Notch1/HEY表达的作用
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摘要
卵巢恶性肿瘤是女性生殖器常见的三大恶性肿瘤之一,其中卵巢恶性上皮性肿瘤占其85%～90%。虽然手术、化学药物治疗等传统治疗手段不断改进,但卵巢恶性上皮性肿瘤的治疗效果改善甚微,其5年生存率仍徘徊于30%～40%,病亡率居妇科恶性肿瘤之首。
临床研究发现卵巢恶性上皮性肿瘤好发于绝经后妇女,常伴有卵泡刺激素(FSH)和黄体生成素(LH)的升高;而多次妊娠、母乳喂养、口服避孕药的妇女发病风险较低,FSH和LH也较低。近20年来,很多研究结果表明FSH对卵巢癌的发生发展起重要作用。最近,越来越多研究结果表明Notch1与肿瘤发生及侵袭迁移有关,但对于其在卵巢癌细胞中和FSH之间的关系却报道甚少。本课题主要研究FSH与卵巢癌细胞中的Notch信号转导通路的关系,通过对不同浓度的FSH与Notch1通路关系的研究,分析FSH不同作用时间与Notch1信号转导通路关系,以及FSH对卵巢癌细胞Notch1信号转导通路下游靶基因表达的调控,探索影响卵巢癌发展的因素,为新的治疗药物和方法提供依据。
本课题共分两部分:①卵泡刺激素与卵巢癌细胞Notch1信号转导通路的关系,不同浓度和作用时间的卵泡刺激素对卵巢癌细胞Notch1信号转导通路的激活的影响;②卵泡刺激素对卵巢癌细胞Notch1信号转导通路下游靶基因表达的调控。
第一部分卵泡刺激素与卵巢癌细胞Notch1信号转导通路的关系
目的研究卵泡刺激素对卵巢癌细胞株SKOV-3和ES-2细胞中Notch1ICD(Notch 1 intracellualar domain)表达的影响。
方法(1)将FSH以浓度0及40mIU/ml分别作用于1×10~5个SKOV-3细胞和6×10~4~个ES-2细胞,其中FSH作用于SKOV-3细胞的适宜时间为48小时,ES-2细胞为24小时,用免疫组织化学的方法分别检测两种细胞中用或者没用FSH刺激后的N1ICD的表达,从而了解FSH与卵巢癌细胞N1ICD表达的关系。(2)将FSH以不同的时间(0、12、24、36、48、72h)和不同浓度(0、10、20、40、80mIU/ml)分别作用于2×10~6个SKOV-3细胞,将FSH以不同的时间(0、12、24、36、48h)和不同浓度(0、10、20、40、80mIU/ml)分别作用于1×10~6个ES-2细胞,用Western blot法分别检测N1ICD的表达,从而研究不同浓度及作用时间的FSH对N1ICD表达的影响。
结果(1)用FSH浓度处理后的卵巢癌细胞,相对于未用FSH处理的卵巢癌细胞,其核内可明显的检测到N1ICD的表达。(2)随着FSH作用时间增加,SKOV-2和ES-2细胞中的Notch1 ICD蛋白含量的表达较对照比较逐渐增强,呈时间效应关系。(3)随着FSH浓度的增加,SKOV-3和ES-2细胞中的Notch1 ICD蛋白含量的表达较对照比较逐渐增强,呈剂量效应关系。
结论FSH可促进N1ICD的表达。随着FSH浓度和作用时间的增加,卵巢癌细胞中N1ICD的表达也增加。
第二部分卵泡刺激素对卵巢癌细胞notch1信号转导通路下游靶基因表达的影响
目的研究不同浓度的卵泡刺激素对卵巢癌细胞株SKOV-3和ES-2细胞中Notch1信号传导通路下游靶基因HEY—1,HEY—2和HEY—L表达的影响。从而为进一步的相关研究奠定基础。
方法将FSH以不同浓度(0、10、20、40、80mIU/ml)分别作用于2×10~6个SKOV-3细胞和1×10~6个ES-2细胞,其中FSH作用于SKOV-3细胞的时间为48小时,ES-2细胞为24小时。用RT-PCR检测SKOV-3和ES-2细胞中HEY—1,HEY—2和HEY—L mRNA表达。
结果随着FSH浓度的增加,SKOV-3和ES—2细胞中HEY-1、HEY-2和HEY-LmRNA的表达较对照组比较有增加,但没有明显的剂量效应。
结论不同浓度FSH可使卵巢癌细胞中的Notch1信号通路下游靶基因HEY-1/HEY-2/HEY-L的表达有增加。
小结:FSH可能有促进N1ICD的表达的作用。随着FSH浓度和作用时间的增加,卵巢癌细胞中N1ICD的表达也增加。
不同浓度FSH作用后,SKOV-3和ES—2细胞中HEY-1、HEY-2和HEY-LmRNA的表达可增加。FSH可能通过Notch1通路调节Snail和E-Cadherin,可能会涉及到EMT的发生。
At present,ovarian cancer is one of the three gynecological malignancies. Ovarian cancer is the most common histopathological type accounting for 85%-90% of all ovarian malignancies.Despite continuous improvement in surgical modalities, chemotherapeutic and radiotherapy over the past several years,the 5-years survival rate for ovarian cancer with the most poor prognosis of all gynecological malignancies is about 30%-40%,which has not improve significantly.
Clinically,ovarian cancer is often found in postmenopausal women with high serum follicle stimulating hormone(FSH) and luteinizing hormone(LH) level.The risk for women who have many pregnancies,oral contraceptives,hormone replacement therapy is low,while their serum FSH and LH concentration is also low. In the past 20 years,previous studies have proven that FSH plays an important role in ovarian cancinogenesis.Recent studies showed that Notchl signaling pathway relates to the development of cancer,including carcinogenesis,invasion and migration.But little is known about the relationship between FSH and Notchl signaling pathway in ovarian cancer ceils.The result of our experiments suggests that FSH may effect Notchl signaling pathway activation in ovarian cancer cells.To better understand the relationship between different concentration of FSH and the activation of Notchl signaling pathway,different action time of FSH and the activation of Notchl signaling pathway,different concentration of FSH and the expression of Notchl signaling pathway's target gene,we could provide a new stratery for further studying the carcinogenesis of ovarian cancer.
These experiments were devided into 2 parts,as follows:①the relationship between FSH and Notchl signaling pathway of ovarian cancer cells;②The effect of different concentration of FSH on the expression of Notchl signaling pathway's target gene in ovarian cancer cells
SectionⅠ.The relationship between FSH and Notchl signaling pathway in ovarian cancer cells
Objective(1) To investigate whether FSH can effect the expression of Notchl ICD in ovarian cacer cell line SKOV-3 and ES-2 in vitro.(2) To investigate whether different concentration and different action time of FSH can effect the expression of Notchl ICD in ovarian cacer cell line SKOV-3 and ES-2 in vitro.
Methods(1) Cultured SKOV-3 and ES-2 all lines were treated by FSH with different concentration(0、40mIU/ml).SKOV-3 cultured were 48h,ES-2 were cultured 24 h.Cellular immunochemistry detects the expression of Notchl ICD in SKOV-3 and ES-2 which had been treated or not treated by FSH.(2) Cultured SKOV-3 were treated by FSH with different action time(0、12、24、36、48、72h) and different concentration(0、10、20、40、80mIU/ml).Cultured ES-2 were treated by different time(0、12、24、36、48h) and different concentration of FSH(0、10、20、40、80mIU/ml).Western blot was used to detect the expression of Notchl ICD in SKOV-3 and ES-2 which had been treated with different concentration and different action time.
Result Notchl ICD could be more obviously express in the nuclear of ovarian cancer cell lines SKOV-3 and ES-2 which had been treated by FSH than those which had not been treated by FSH.The expression of Notchl ICD protein in ovarian cancer cell lines SKOV-3 and ES-2 increased with the increased concentration and time of FSH.
Conclusion FSH may has effection on expression of Notchl ICD in ovarian cancer cells,and FSH may enhance the activation.The expression level of Notchl ICD had positive correlation with the increased concentration and time of FSH in ovarian cancer cells.
SectionⅡ.The effection of FSH on the expression of Notchl signaling pathway's target gene in ovarian cancer cells
Objective To investigate whether different concentration of FSH could impact the express of Notchl signaling pathway's target gene HEY in ovarian cacer cells
Methods SKOV-3 and ES-2 were treated by FSH with different concentration(0、 10、20、40、80mIU/ml).SKOV-3 were cultured 48h,ES-2 cultured were 24 h.RT-PCR was used to detect the expression of HEY—1,HEY—2 and HEY—L mRNA in SKOV-3 and ES-2,which had been treated with different concentration.
Result FSH could increase the mRNA expressions of HEY—1,HEY—2 and HEY—L in ovarian cancer cell lines SKOV-3 and ES-2,but there is no obvious dose effect between them.
Conclusion FSH may increase the level of the expression of Notchl signaling pathway's target gene HEY—1,HEY—2 and HEY—L in ovarian cancer cells without dose dependent.
临床研究发现卵巢恶性上皮性肿瘤好发于绝经后妇女,常伴有卵泡刺激素(FSH)和黄体生成素(LH)的升高;而多次妊娠、母乳喂养、口服避孕药的妇女发病风险较低,FSH和LH也较低。近20年来,很多研究结果表明FSH对卵巢癌的发生发展起重要作用。最近,越来越多研究结果表明Notch1与肿瘤发生及侵袭迁移有关,但对于其在卵巢癌细胞中和FSH之间的关系却报道甚少。本课题主要研究FSH与卵巢癌细胞中的Notch信号转导通路的关系,通过对不同浓度的FSH与Notch1通路关系的研究,分析FSH不同作用时间与Notch1信号转导通路关系,以及FSH对卵巢癌细胞Notch1信号转导通路下游靶基因表达的调控,探索影响卵巢癌发展的因素,为新的治疗药物和方法提供依据。
本课题共分两部分:①卵泡刺激素与卵巢癌细胞Notch1信号转导通路的关系,不同浓度和作用时间的卵泡刺激素对卵巢癌细胞Notch1信号转导通路的激活的影响;②卵泡刺激素对卵巢癌细胞Notch1信号转导通路下游靶基因表达的调控。
第一部分卵泡刺激素与卵巢癌细胞Notch1信号转导通路的关系
目的研究卵泡刺激素对卵巢癌细胞株SKOV-3和ES-2细胞中Notch1ICD(Notch 1 intracellualar domain)表达的影响。
方法(1)将FSH以浓度0及40mIU/ml分别作用于1×10~5个SKOV-3细胞和6×10~4~个ES-2细胞,其中FSH作用于SKOV-3细胞的适宜时间为48小时,ES-2细胞为24小时,用免疫组织化学的方法分别检测两种细胞中用或者没用FSH刺激后的N1ICD的表达,从而了解FSH与卵巢癌细胞N1ICD表达的关系。(2)将FSH以不同的时间(0、12、24、36、48、72h)和不同浓度(0、10、20、40、80mIU/ml)分别作用于2×10~6个SKOV-3细胞,将FSH以不同的时间(0、12、24、36、48h)和不同浓度(0、10、20、40、80mIU/ml)分别作用于1×10~6个ES-2细胞,用Western blot法分别检测N1ICD的表达,从而研究不同浓度及作用时间的FSH对N1ICD表达的影响。
结果(1)用FSH浓度处理后的卵巢癌细胞,相对于未用FSH处理的卵巢癌细胞,其核内可明显的检测到N1ICD的表达。(2)随着FSH作用时间增加,SKOV-2和ES-2细胞中的Notch1 ICD蛋白含量的表达较对照比较逐渐增强,呈时间效应关系。(3)随着FSH浓度的增加,SKOV-3和ES-2细胞中的Notch1 ICD蛋白含量的表达较对照比较逐渐增强,呈剂量效应关系。
结论FSH可促进N1ICD的表达。随着FSH浓度和作用时间的增加,卵巢癌细胞中N1ICD的表达也增加。
第二部分卵泡刺激素对卵巢癌细胞notch1信号转导通路下游靶基因表达的影响
目的研究不同浓度的卵泡刺激素对卵巢癌细胞株SKOV-3和ES-2细胞中Notch1信号传导通路下游靶基因HEY—1,HEY—2和HEY—L表达的影响。从而为进一步的相关研究奠定基础。
方法将FSH以不同浓度(0、10、20、40、80mIU/ml)分别作用于2×10~6个SKOV-3细胞和1×10~6个ES-2细胞,其中FSH作用于SKOV-3细胞的时间为48小时,ES-2细胞为24小时。用RT-PCR检测SKOV-3和ES-2细胞中HEY—1,HEY—2和HEY—L mRNA表达。
结果随着FSH浓度的增加,SKOV-3和ES—2细胞中HEY-1、HEY-2和HEY-LmRNA的表达较对照组比较有增加,但没有明显的剂量效应。
结论不同浓度FSH可使卵巢癌细胞中的Notch1信号通路下游靶基因HEY-1/HEY-2/HEY-L的表达有增加。
小结:FSH可能有促进N1ICD的表达的作用。随着FSH浓度和作用时间的增加,卵巢癌细胞中N1ICD的表达也增加。
不同浓度FSH作用后,SKOV-3和ES—2细胞中HEY-1、HEY-2和HEY-LmRNA的表达可增加。FSH可能通过Notch1通路调节Snail和E-Cadherin,可能会涉及到EMT的发生。
At present,ovarian cancer is one of the three gynecological malignancies. Ovarian cancer is the most common histopathological type accounting for 85%-90% of all ovarian malignancies.Despite continuous improvement in surgical modalities, chemotherapeutic and radiotherapy over the past several years,the 5-years survival rate for ovarian cancer with the most poor prognosis of all gynecological malignancies is about 30%-40%,which has not improve significantly.
Clinically,ovarian cancer is often found in postmenopausal women with high serum follicle stimulating hormone(FSH) and luteinizing hormone(LH) level.The risk for women who have many pregnancies,oral contraceptives,hormone replacement therapy is low,while their serum FSH and LH concentration is also low. In the past 20 years,previous studies have proven that FSH plays an important role in ovarian cancinogenesis.Recent studies showed that Notchl signaling pathway relates to the development of cancer,including carcinogenesis,invasion and migration.But little is known about the relationship between FSH and Notchl signaling pathway in ovarian cancer ceils.The result of our experiments suggests that FSH may effect Notchl signaling pathway activation in ovarian cancer cells.To better understand the relationship between different concentration of FSH and the activation of Notchl signaling pathway,different action time of FSH and the activation of Notchl signaling pathway,different concentration of FSH and the expression of Notchl signaling pathway's target gene,we could provide a new stratery for further studying the carcinogenesis of ovarian cancer.
These experiments were devided into 2 parts,as follows:①the relationship between FSH and Notchl signaling pathway of ovarian cancer cells;②The effect of different concentration of FSH on the expression of Notchl signaling pathway's target gene in ovarian cancer cells
SectionⅠ.The relationship between FSH and Notchl signaling pathway in ovarian cancer cells
Objective(1) To investigate whether FSH can effect the expression of Notchl ICD in ovarian cacer cell line SKOV-3 and ES-2 in vitro.(2) To investigate whether different concentration and different action time of FSH can effect the expression of Notchl ICD in ovarian cacer cell line SKOV-3 and ES-2 in vitro.
Methods(1) Cultured SKOV-3 and ES-2 all lines were treated by FSH with different concentration(0、40mIU/ml).SKOV-3 cultured were 48h,ES-2 were cultured 24 h.Cellular immunochemistry detects the expression of Notchl ICD in SKOV-3 and ES-2 which had been treated or not treated by FSH.(2) Cultured SKOV-3 were treated by FSH with different action time(0、12、24、36、48、72h) and different concentration(0、10、20、40、80mIU/ml).Cultured ES-2 were treated by different time(0、12、24、36、48h) and different concentration of FSH(0、10、20、40、80mIU/ml).Western blot was used to detect the expression of Notchl ICD in SKOV-3 and ES-2 which had been treated with different concentration and different action time.
Result Notchl ICD could be more obviously express in the nuclear of ovarian cancer cell lines SKOV-3 and ES-2 which had been treated by FSH than those which had not been treated by FSH.The expression of Notchl ICD protein in ovarian cancer cell lines SKOV-3 and ES-2 increased with the increased concentration and time of FSH.
Conclusion FSH may has effection on expression of Notchl ICD in ovarian cancer cells,and FSH may enhance the activation.The expression level of Notchl ICD had positive correlation with the increased concentration and time of FSH in ovarian cancer cells.
SectionⅡ.The effection of FSH on the expression of Notchl signaling pathway's target gene in ovarian cancer cells
Objective To investigate whether different concentration of FSH could impact the express of Notchl signaling pathway's target gene HEY in ovarian cacer cells
Methods SKOV-3 and ES-2 were treated by FSH with different concentration(0、 10、20、40、80mIU/ml).SKOV-3 were cultured 48h,ES-2 cultured were 24 h.RT-PCR was used to detect the expression of HEY—1,HEY—2 and HEY—L mRNA in SKOV-3 and ES-2,which had been treated with different concentration.
Result FSH could increase the mRNA expressions of HEY—1,HEY—2 and HEY—L in ovarian cancer cell lines SKOV-3 and ES-2,but there is no obvious dose effect between them.
Conclusion FSH may increase the level of the expression of Notchl signaling pathway's target gene HEY—1,HEY—2 and HEY—L in ovarian cancer cells without dose dependent.
引文
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[45]Jundt F,Schulze Proebsting KS,Anagnostopoulos I,et al.Jagged12induced Notch signaling drives proliferationof multiple myeloma cells[J].
[46]Timmerman LA,Grego-Bessa J,Raya A,Bertran E,Perez-Pomares JM,Diez J,Aranda S,Palomo S,McCormick F,Izpisua-Belmonte JC,de la Pompa JL.Notch promotes epithelial-mesenchymal transition during cardiac development and oneogenic transformation[J].Genes Dev.2004,18(1):99-115.
[47]王承芳,王晓炜,张朋,孙媛,孔庆友,刘佳,李宏.Notch-1和Notch-2在卵巢肿瘤中的表达及意义[J].中国实用妇科与产科杂志.2006,22(6):421-423.
[48]王明义,刘玉,辛晓燕.Notch1信号蛋白在卵巢肿瘤中的表达及其临床意义[J].世界肿瘤杂志.2007,6(1):11-13.
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[52]Schiffenbauer YS,Meir G,Maoz M,Even-Ram SC,Bar-Shavit R,Neeman M 2002 Gonadotropin stimulation of MLS human epithelial ovarian carcinoma cells augments cell adhesion mediated by CD44 and by[alpha](v)-integrin.[J]Gynecol Oncol 84:296-302
[53]Yan H,Keqin H,Xianrong Z et al.Activation of the PI3K/AKT pathway mediates FSH-stimu-lated VEGF expression in ovarian serous cystadenocarci-noma[J].Cell Research (2008):1-12.
[54]Wang Z,Banerjee S,Li Y,Rahman KM,Zhang Y,Sarkar FH.Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB,vascular endothelial growth factor,and matrix metalloproteinase-9 in pancreatic cancer cells[J].Cancer Res.2006,66(5):2778-84.
[55]Bailey JM,Singh PK,Hollingsworth MA.Cancer metastasis facilitated by developmental pathways:Sonic hedgehog,Notch,and bone morphogenic proteins[J].J Cell Biochem.2007;102(4):829-39.
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