雌激素、胰岛素对子宫内膜癌生长的协同及交叉作用
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摘要
子宫内膜癌(endometrial carcinoma, EC)是妇科三大恶性肿瘤之一,其发病原因及机制仍不明确。国内外研究数据显示EC发病率呈明显上升趋势。因此,对EC病因及发病机制的研究尤为重要。
子宫内膜癌的高危因素有肥胖、糖尿病、高血压、长期无孕激素对抗的雌激素刺激等。而肥胖、糖尿病、高血压的共同的病理生理基础是胰岛素抵抗及继发的高胰岛素血症。雌激素作为性激素,除调节正常的生长发育,维持女性性征外,还可作为生长因子,促进子宫内膜癌细胞的恶性转化和增殖。’胰岛素除参与物质代谢调节外,课题组前期研究表明胰岛素还可通过其下游的信号传导通路促进细胞的生长增殖、抑制其凋亡。而高雌激素、高胰岛素作为子宫内膜癌的发病高危因素,二者在子宫内膜癌增殖中是否具有协同及交叉作用,目前的研究鲜见报道。本研究将利用人子宫内膜癌细胞系探讨雌激素与胰岛素对子宫内膜癌细胞增殖的协同及交叉作用。
第一部分人子宫内膜癌细胞系雌激素受体α及胰岛素受体β表达情况
目的：探讨人子宫内膜癌细胞系雌激素受体α及胰岛素受体β表达情况。
方法：RT-PCR、Western blot方法检测人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1雌激素受体α(ER-α)及胰岛素受体β(INSR-β) mRNA、蛋白表达水平。
结果：人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1均存在ER-α及INSR-βmRNA、蛋白表达。其中以Ishikawa、ECC-1细胞系ER-α及INSR-βmRNA、蛋白表达相对较多,其它细胞系表达相对较少。
结论：人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1存在ER-α及INSR-β表达,具有雌激素及胰岛素信号通路下传的基础。
第二部分雌激素对子宫内膜癌细胞系的增殖作用
目的：探讨雌激素对子宫内膜癌细胞系Ishikawa的促增殖作用
方法：采用MTT法检测不同浓度17β-雌二醇(E2)对Ishikawa细胞系不同时间点的促增殖作用。实验分组：空白对照组,E2 10-10M处理组,E2 10-8M处理组,E2 10-6M处理组,E2 10-4M处理组,检测E2处理后24小时、48小时、72小时、96小时细胞增殖情况
结果：不同时间点E2对Ishikawa细胞的促增殖作用差异有统计学意义(F=25.117,P=0.000)。各浓度E2促细胞增殖作用两两比较,除0 mol/L与10-10mol／L促细胞增殖作用差异无统计学意义(P=0.227)之外,其余各浓度间的差异均有统计学意义(P<0.05)。72小时达最高峰,96小时增殖作用下降。结论：17β-雌二醇能够促进子宫内膜癌细胞增殖,具有浓度依赖性和时间依赖性。
第三部分雌激素、胰岛素促子宫内膜癌细胞增殖的协同及交叉作用
目的：探讨雌激素、胰岛素促子宫内膜癌细胞增殖的协同及交叉作用
方法：针对ER-α及INSR-β基因序列,设计并合成SiRNA,采用脂质体转染方法筛选有效沉默ER-α及INSR-β的序列。将血清饥饿的子宫内膜癌Ishikawa细胞分为不同处理组。①观察胰岛素(Ins)、E2对Ishikawa细胞增殖的协、同作用,分组情况：空白对照组,10-6M Ins处理组：10-8 E2处理组；10-6M Ins加10-8M E2处理组；②观察Ins、E2对Ishikawa细胞增殖的交叉作用,分组情况：ER-α干扰组；INSR-β干扰组；共转染组；阴性对照组,各组分别分为空白组,10-6M Ins处理组；10-8M E2处理组；10-6M Ins加10-8 M E2处理组。MTT法检测处理后24小时、48小时、72小时、96小时细胞增殖情况。
结果：SiRNA序列能有效降低ER-α及INSR-βmRNA及蛋白表达水平；Ins和E2共刺激组,Ishikawa细胞不同时间点促增殖作用高于单独刺激组(P<0.05)；ER-α干扰后,明显抑制了E2 48小时,72小时对Ishikawa细胞的增殖作用(P<0.05)；INSR-β干扰后,明显抑制了Ins 48小时,72小时对Ishikawa细胞的增殖作用；共转染后,明显抑制了E2和(或)Ins对Ishikawa细胞的增殖作用。
结论：雌激素及胰岛素对子宫内膜癌细胞的增殖存在协同及交叉作用。
综上所述,人子宫内膜癌细胞系存在ER-α及INSR-βmRNA及蛋白表达,具有雌激素及胰岛素信号传导通路下传的基础。雌激素能够促进子宫内膜癌细胞的增殖。雌激素与胰岛素在子宫内膜癌细胞增殖中存在协同及交叉作用。
Endometrial carcinoma is one of the three gynecological malignancies,and the carcinogenesis mechanism is not clear yet. It is reported that the incidence of endometrial carcinoma was significantly increased. Therefore, it is particularly important to study the etiology and pathogenesis about EC.
The risk factors of Endometrial carcinoma include obesity, diabetes, hypertension, long-term estrogen stimulating without progesterone.The common pathophysiological basis of these factors is insulin resistance and hyperinsulinemia. As a hormone, estrogen not only regulates the normal body growth and maintain female characteristic, but also can be used as a growth factor that promotes endometrial proliferation and the malignant transformation. Insulin can also regulate the growth and differentiation of cells through its downstream signaling pathways. As endometrial cancer risk factors, high estrogen and high insulin promote the malignant transformation of endometrial cells and they induce proliferation of endometrial carcinoma together. But how do the estrogen, insulin and their signal transduction interact in endometrial carcinoma? This study will use endometrial cancer cell line to discuss the synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
SectionⅠThe expression of estrogen receptorαand insulin receptorβin endometrial carcinoma cell lines
Objective:To investigate the expression of ER-a and INSR-βin endometrial carcinoma cell lines.
Methods:The expression of ER-a and INSR-βin endometrial carcinoma cell lines were detected by RT-PCR and Western blot.These cell lines include AN3CA, Ishikawa, HEC1-A, HEC1B,KLE, ECC-1.
Results:The six endometrial carcinoma cell lines were all existing the expression of ER-αand INSR-β.The expression of ER-a and INSR-βin Ishikawa and ECC-1 cell lines was more than others.
Conclusion:The six endometrial carcinoma cell lines were all existing the expression of ER-a and INSR-P, and had the basis of estrogen and insulin signaling pathways.
SectionⅡMitogenic effects induced by 17βEstrodial in endometrial carcinoma cell line
Objective:To explore mitogenic effects induced by 17-βEstrodial in endometrial carcinoma cell line.
Methods:The mitogenic effects of different concentration of 17-βestradiol in endometrial carcinoma cell line were detected by MTT at different time. Experimental group:control, and 10-10 M 17-βestradiol,10-8 M 17-βestradiol,10-6 M 17-βestradiol, 10-4 M 17-βestradiol.
Results:The effects of 17-βestradiol on Ishikawa cell at different time have statistically significant (F=25.117, P=0.000). Besides the concentrations of 0 M and 10-10M, the effects of various concentrations of 17-βestradiol have statistically significant (P<0.05). At the time of 72 hours, the effects reached the peak and then dereased.
Conclusion:17-βestradiol could promote endometrial cell proliferation and dependent on the concentration and stimulating time.
SectionⅢsynergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line
Objective:To investigate synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line
Methods:The SiRNA of ER-αand INSR-βwere designed and synthetized.Screen effective sequence of ER-αand INSR-β. No-Serum hunger Ishikawa cells were divided into different groups.①To investigate the synergitic effects of insulin and 17-βestradiol, gouped:control,10-6M insulin treatment group,10-8M 17βestradiol treatment group,10-6M insulin plus 10-8M 17βestradiol treatment group;②To investigate the crosstalk effects of insulin and 17-βestradiol:ER-a interference groups, INSR-βinterference groups,co-transfection group, negative control.Each group was divided into control,17-βestradiol treatment group, insulin treatment group,17-βestradiol plus insulin treatment groups. the effects of cell proliferation were detected by MTT at different time.
Results:The mitogenic effect of insulin plus 17βestradiol group were much more than insulin or 17-βestradiol group.After silencing ER-α, the effect of 17-βestrodiol was inhibited obviously.After silencing INSR-P, the effect 17-βestrodiol and insulin was inhibited obviously. After co-transfection, the effect of 17-βestrodiol and/or insulin were inhibited obviously.
Conclusion:There are synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
Above all, endometrial carcinoma cell line were existing the expression of ER-αand INSR-β, and have the basis of estrogen and insulin signaling pathways. Estrogen can promote endometrial proliferation. There are synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
子宫内膜癌的高危因素有肥胖、糖尿病、高血压、长期无孕激素对抗的雌激素刺激等。而肥胖、糖尿病、高血压的共同的病理生理基础是胰岛素抵抗及继发的高胰岛素血症。雌激素作为性激素,除调节正常的生长发育,维持女性性征外,还可作为生长因子,促进子宫内膜癌细胞的恶性转化和增殖。’胰岛素除参与物质代谢调节外,课题组前期研究表明胰岛素还可通过其下游的信号传导通路促进细胞的生长增殖、抑制其凋亡。而高雌激素、高胰岛素作为子宫内膜癌的发病高危因素,二者在子宫内膜癌增殖中是否具有协同及交叉作用,目前的研究鲜见报道。本研究将利用人子宫内膜癌细胞系探讨雌激素与胰岛素对子宫内膜癌细胞增殖的协同及交叉作用。
第一部分人子宫内膜癌细胞系雌激素受体α及胰岛素受体β表达情况
目的：探讨人子宫内膜癌细胞系雌激素受体α及胰岛素受体β表达情况。
方法：RT-PCR、Western blot方法检测人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1雌激素受体α(ER-α)及胰岛素受体β(INSR-β) mRNA、蛋白表达水平。
结果：人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1均存在ER-α及INSR-βmRNA、蛋白表达。其中以Ishikawa、ECC-1细胞系ER-α及INSR-βmRNA、蛋白表达相对较多,其它细胞系表达相对较少。
结论：人子宫内膜癌细胞系Ishikawa、AN3CA、HEC1-A、HEC1-B、KLE、ECC-1存在ER-α及INSR-β表达,具有雌激素及胰岛素信号通路下传的基础。
第二部分雌激素对子宫内膜癌细胞系的增殖作用
目的：探讨雌激素对子宫内膜癌细胞系Ishikawa的促增殖作用
方法：采用MTT法检测不同浓度17β-雌二醇(E2)对Ishikawa细胞系不同时间点的促增殖作用。实验分组：空白对照组,E2 10-10M处理组,E2 10-8M处理组,E2 10-6M处理组,E2 10-4M处理组,检测E2处理后24小时、48小时、72小时、96小时细胞增殖情况
结果：不同时间点E2对Ishikawa细胞的促增殖作用差异有统计学意义(F=25.117,P=0.000)。各浓度E2促细胞增殖作用两两比较,除0 mol/L与10-10mol／L促细胞增殖作用差异无统计学意义(P=0.227)之外,其余各浓度间的差异均有统计学意义(P<0.05)。72小时达最高峰,96小时增殖作用下降。结论：17β-雌二醇能够促进子宫内膜癌细胞增殖,具有浓度依赖性和时间依赖性。
第三部分雌激素、胰岛素促子宫内膜癌细胞增殖的协同及交叉作用
目的：探讨雌激素、胰岛素促子宫内膜癌细胞增殖的协同及交叉作用
方法：针对ER-α及INSR-β基因序列,设计并合成SiRNA,采用脂质体转染方法筛选有效沉默ER-α及INSR-β的序列。将血清饥饿的子宫内膜癌Ishikawa细胞分为不同处理组。①观察胰岛素(Ins)、E2对Ishikawa细胞增殖的协、同作用,分组情况：空白对照组,10-6M Ins处理组：10-8 E2处理组；10-6M Ins加10-8M E2处理组；②观察Ins、E2对Ishikawa细胞增殖的交叉作用,分组情况：ER-α干扰组；INSR-β干扰组；共转染组；阴性对照组,各组分别分为空白组,10-6M Ins处理组；10-8M E2处理组；10-6M Ins加10-8 M E2处理组。MTT法检测处理后24小时、48小时、72小时、96小时细胞增殖情况。
结果：SiRNA序列能有效降低ER-α及INSR-βmRNA及蛋白表达水平；Ins和E2共刺激组,Ishikawa细胞不同时间点促增殖作用高于单独刺激组(P<0.05)；ER-α干扰后,明显抑制了E2 48小时,72小时对Ishikawa细胞的增殖作用(P<0.05)；INSR-β干扰后,明显抑制了Ins 48小时,72小时对Ishikawa细胞的增殖作用；共转染后,明显抑制了E2和(或)Ins对Ishikawa细胞的增殖作用。
结论：雌激素及胰岛素对子宫内膜癌细胞的增殖存在协同及交叉作用。
综上所述,人子宫内膜癌细胞系存在ER-α及INSR-βmRNA及蛋白表达,具有雌激素及胰岛素信号传导通路下传的基础。雌激素能够促进子宫内膜癌细胞的增殖。雌激素与胰岛素在子宫内膜癌细胞增殖中存在协同及交叉作用。
Endometrial carcinoma is one of the three gynecological malignancies,and the carcinogenesis mechanism is not clear yet. It is reported that the incidence of endometrial carcinoma was significantly increased. Therefore, it is particularly important to study the etiology and pathogenesis about EC.
The risk factors of Endometrial carcinoma include obesity, diabetes, hypertension, long-term estrogen stimulating without progesterone.The common pathophysiological basis of these factors is insulin resistance and hyperinsulinemia. As a hormone, estrogen not only regulates the normal body growth and maintain female characteristic, but also can be used as a growth factor that promotes endometrial proliferation and the malignant transformation. Insulin can also regulate the growth and differentiation of cells through its downstream signaling pathways. As endometrial cancer risk factors, high estrogen and high insulin promote the malignant transformation of endometrial cells and they induce proliferation of endometrial carcinoma together. But how do the estrogen, insulin and their signal transduction interact in endometrial carcinoma? This study will use endometrial cancer cell line to discuss the synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
SectionⅠThe expression of estrogen receptorαand insulin receptorβin endometrial carcinoma cell lines
Objective:To investigate the expression of ER-a and INSR-βin endometrial carcinoma cell lines.
Methods:The expression of ER-a and INSR-βin endometrial carcinoma cell lines were detected by RT-PCR and Western blot.These cell lines include AN3CA, Ishikawa, HEC1-A, HEC1B,KLE, ECC-1.
Results:The six endometrial carcinoma cell lines were all existing the expression of ER-αand INSR-β.The expression of ER-a and INSR-βin Ishikawa and ECC-1 cell lines was more than others.
Conclusion:The six endometrial carcinoma cell lines were all existing the expression of ER-a and INSR-P, and had the basis of estrogen and insulin signaling pathways.
SectionⅡMitogenic effects induced by 17βEstrodial in endometrial carcinoma cell line
Objective:To explore mitogenic effects induced by 17-βEstrodial in endometrial carcinoma cell line.
Methods:The mitogenic effects of different concentration of 17-βestradiol in endometrial carcinoma cell line were detected by MTT at different time. Experimental group:control, and 10-10 M 17-βestradiol,10-8 M 17-βestradiol,10-6 M 17-βestradiol, 10-4 M 17-βestradiol.
Results:The effects of 17-βestradiol on Ishikawa cell at different time have statistically significant (F=25.117, P=0.000). Besides the concentrations of 0 M and 10-10M, the effects of various concentrations of 17-βestradiol have statistically significant (P<0.05). At the time of 72 hours, the effects reached the peak and then dereased.
Conclusion:17-βestradiol could promote endometrial cell proliferation and dependent on the concentration and stimulating time.
SectionⅢsynergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line
Objective:To investigate synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line
Methods:The SiRNA of ER-αand INSR-βwere designed and synthetized.Screen effective sequence of ER-αand INSR-β. No-Serum hunger Ishikawa cells were divided into different groups.①To investigate the synergitic effects of insulin and 17-βestradiol, gouped:control,10-6M insulin treatment group,10-8M 17βestradiol treatment group,10-6M insulin plus 10-8M 17βestradiol treatment group;②To investigate the crosstalk effects of insulin and 17-βestradiol:ER-a interference groups, INSR-βinterference groups,co-transfection group, negative control.Each group was divided into control,17-βestradiol treatment group, insulin treatment group,17-βestradiol plus insulin treatment groups. the effects of cell proliferation were detected by MTT at different time.
Results:The mitogenic effect of insulin plus 17βestradiol group were much more than insulin or 17-βestradiol group.After silencing ER-α, the effect of 17-βestrodiol was inhibited obviously.After silencing INSR-P, the effect 17-βestrodiol and insulin was inhibited obviously. After co-transfection, the effect of 17-βestrodiol and/or insulin were inhibited obviously.
Conclusion:There are synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
Above all, endometrial carcinoma cell line were existing the expression of ER-αand INSR-β, and have the basis of estrogen and insulin signaling pathways. Estrogen can promote endometrial proliferation. There are synergy and crosstalk between estrogen and insulin on the growth of endometrial carcinoma cell line.
引文
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