TGF-β1对乳腺癌细胞及乳腺癌干细胞特征作用的研究
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摘要
研究目的：
研究TGF-β1对乳腺癌细胞中乳腺癌干细胞标记物表达、对乳腺癌干细胞富集、自我更新、转移侵袭、化疗耐药等相关基因蛋白表达的影响及对乳腺癌细胞周期、侵袭及诱导耐药等方面的作用；盐霉素对乳腺癌干细胞的作用及其逆转表阿霉素及多西紫杉醇耐药的作用。
研究方法：
取用MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株乳腺癌细胞株,运用流式细胞仪法检测各株细胞中ALDH1阳性细胞群比例及细胞周期,实时定量逆转录PCR(Q-RT-PCR), Western blot法检测p21的表达；同法比较TGF-β1作用四株细胞后ALDH1阳性细胞群、细胞周期、p21基因及蛋白水平表达差异；乳腺细胞球培养法富集乳腺癌干细胞,流式细胞仪检测TGF-β1在富集乳腺癌干细胞中的作用,Q-RT-PCR、Western blot法检测各处理因素的乳腺癌细胞侵袭转移、化疗耐药、周期调控、细胞转化相关因子SATB1、MMP1、P21、Vimentin、E-cadherin基因及蛋白水平表达差异；Transwell侵袭小室法检测各处理因素前后乳腺癌细胞侵袭能力变化；CCK-8法检测各处理因素前后乳腺癌细胞对化疗药物表阿霉素、多西紫杉醇、盐霉素药物敏感性差异；将盐霉素与表阿霉素、多西紫杉醇两药或三药联合作用各处理因素乳腺癌细胞,CCK-8法检测细胞生长抑制率,检测盐霉素在逆转表阿霉素及多西紫杉醇耐药方面的作用。
实验结果：
流式细胞仪检测显示MCF7、MCF7/ADM、MDA-MB-23、SKBR3四株细胞中ALDH1阳性细胞群比例分别为1.49%、8.38%、1.53%、4.23%,以MCF7/ADM细胞株中ALDH1阳性细胞群含量最高。加入TGF-β1培养后MCF7、MCF7/ADM、SKBR3三株细胞株(ALDH1不宜做为MDA-MB-231乳腺癌干细胞标记物)中ALDH1阳性乳腺癌干细胞侧群比例平均分别为3.83%、10.06%、6.32%。加入TGF-β1培养后MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株细胞中p21 mRNA的表达分别较未加入TGF-β1培养细胞显著上调,分别上调2倍、1.7倍、1.5倍和1.2倍(n=3,p<0.05)。加入TGF-β1培养后MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株细胞表现出G1期阻滞(n=3,p<0.05)。TGF-β1上调p21、SATB1、MMP1、Vimentin的表达,下调E-cadherin的表达；TGF-β1使细胞出现进一步的G0/G1期阻阻滞(p<0.001)。TGF-β1可使细胞具有更强的克隆形成能力,细胞球形成率显著升高(p<0.001)；TGF-β1可增强细胞侵袭能力(p<0.05)。表阿霉素(EPI)、多西紫杉(DOX)对MCF7的IC50值分别为：0.4ug/ml、0.2ug/ml;对MCF7/ADM的IC50值分别为：20ug/ml、0.6ug/ml;对SC细胞的IC50值分别为：50ug/ml、lug/ml;对SC-T细胞的IC50值分别为：120ug/ml、10ug/ml。SC及SC-T细胞对EPI、DOX体现出显著耐药性。盐霉素(SAL)对MCF7/ADM、SC、SC-T三组细胞的IC50值分别为：3±0.2ug/ml、8±0.5ug/ml、9±0.2umol/ml。EPI、DOX及SAL三种药物单独作用于MCF7/ADM、SC、SC-T细胞时,乳腺癌干细胞体现出明显的药物抵抗性,在TGF-β1、作用后药物抵抗更为明显,p<0.01；在两药联用方面,DOX和SAL联用的方式显著优于其他组合,p<0.01。EPI、DOX、SAL三药联用时,三组细胞生长抑制率无明显差异,p>0.1。
实验结论：
1.TGF-β1可以增加乳腺癌细胞的肿瘤干细胞池,提高细胞周期调控因子p21的表达,使细胞出现G0/G1期阻滞。
2.TGF-β1可以上调自我更新和侵袭能力相关的p21、MMP、SATB1、Vimentin基因水平和蛋白水平的表达。
3.TGF-β1可以有效富集乳腺癌干细胞。促进乳腺癌干细胞标记物ALDH1的表达,增强细胞自我更新、侵袭能力,诱导乳腺癌细胞化疗耐药。
4.针对乳腺癌干细胞杀伤的药物盐霉素可以增加乳腺癌细胞对表阿霉素及多西紫杉醇的敏感性,逆转表阿霉素和多西紫杉醇的耐药,三药联合使用时在中等剂量即可有效杀伤乳腺癌细胞及乳腺癌干细胞。
Objective:To detect the enrichment of breast cancer stem cells induced by TGF-β1, and the effect on the metastasis, invasion, cell cycle regulation, drug resistance of breast cancer stem cells; To detect the killing effect of salinomycin on breast cancer stem cells and the effect of reversing epirubicin and docetacel resistance.
Methods:The breast cancer stem cells from MCF7/ADM were enriched by mammosphere method cultured with or without TGF-β1 (lOng/ml) which labeled with SC and SC-T respectively. MCF7, MCF7/ADM, MDA-MB-231, SKBR3 cultured with or without TGF-β1 (10ng/ml) were labeled with ALDEFLOUR kit, the proportion of ALDH1 positive cells in four cell lines and SC, SC-T cells were detected with flow cytometry (n=3); Expression of p21, MMP1, SATB1, Vimentin, E-cadherin protein were detected with Q-RT-PCR and Western blot; The cell cycle of the six cells were detected with flow cytometry; The invasion ability of MCF7/ADM、SC and SC-T cells were detected with Transwell. The cell self-renewal ability of the three cells were detected with mammosphere formation method. The cell cycle of the three cells were detected with flow cytometry (n=3); The drug sensitivity of the three cells were detected with cell counting kit 8 (CCK8) method. The growth inhibition of salinomycin combined with epirubicin and/or docetaxel were detected with CCK8 method (n=3).
Results:The proportion of ALDH1 positive cells in MCF7, MCF7/ADM, MDA-MB-231, SKBR3 were 1.49%,8.38%,1.53%,4.23%; The proportion of ALDH1 positive cells in MCF7, MCF7/ADM, SKBR3 which were cultured with TGF-β1 were 3.83%,10.06%, 6.32% respectively (n=3), which were obviously higher than the cell cultured without TGF-β1 (n=3, p＜0.05)); Compared with cells cultured without TGF-β1, there is G1 phase cell cycle arrest when MCF7, MCF7/ADM, MDA-MB-231, SKBR3 cells cultured with TGF-β1 (n=3, p＜0.05). The expression of p21 in the cell lines were significant higher than the cells cultured without with TGF-β1 (n=3,P＜0.05). TGF-β1 up-regulated the expression of p21, SATB1, MMP1, while down-regulated the expression of E-cadherin. TGF-β1 enhanced the mammosphere formation ability (p＜0.001), invasion ability of breast cancer stem cells (p＜0.05) and G1 phase arrest (p＜0.001). The IC50 value of epirubicin (EPI) and docetaxel (DOX) in MCF7 were 0.4ug/ml,0.2ug/ml respectively (n=3); the IC50 value of EPI and DOX in MCF7/ADM cell were 20ug/ml,0.6ug/ml respectively (n=3); while the IC50 value of EPI and DOX in SC cell were 50ug/ml, lug/ml respectively (n=3); the IC50 value of EPI and DOX in SC-T cell were 120ug/ml, 10ug/ml respectively (n=3). The IC50 value of salinomycin (SAL) in MCF7/ADM, SC, SC-T cells were 3±0.2ug/ml,8±0.5ug/ml, 9±0.2umol/ml respectively; The growth inhibition on SC and SC-T cells were lower than MCF7/ADM, with EPI, DOX and SAL respectively. Combined with two of EPI, DOX and SAL, the better growth inhibition effect was arised when DOX combined with SAL, p＜0.01; Combined with all three drugs, the growth inhibition were more than 70% on MCF7/ADM, SC and SC-T cells, p＞0.1.
Conclusion:
1. TGF-β1 could increase the proportion of breast cancer stem cells, and could up-regulate the expression of p21 mRNA and help the cells arrest in G0/G1 phase as well.
2. TGF-β1 could up-regulate the expression of p21、MMP、SATB1、Vimentin, while down-regulate the expression of E-cadherin.
3. TGF-β1 could enhance the enrichment of breast cancer stem cells. TGF-β1 could boost self-renewal and invasion ability of breast cancer stem cell, and induce the chemotherapy resistance, promote the expression of breast cancer stem cell marker.
4. Salinomycin could kill breast cancer stem cells effectively. Salinomycin sensitizes breast cancer cells and breast cancer stem cells to the effect of epirubicin and docetaxel.
研究TGF-β1对乳腺癌细胞中乳腺癌干细胞标记物表达、对乳腺癌干细胞富集、自我更新、转移侵袭、化疗耐药等相关基因蛋白表达的影响及对乳腺癌细胞周期、侵袭及诱导耐药等方面的作用；盐霉素对乳腺癌干细胞的作用及其逆转表阿霉素及多西紫杉醇耐药的作用。
研究方法：
取用MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株乳腺癌细胞株,运用流式细胞仪法检测各株细胞中ALDH1阳性细胞群比例及细胞周期,实时定量逆转录PCR(Q-RT-PCR), Western blot法检测p21的表达；同法比较TGF-β1作用四株细胞后ALDH1阳性细胞群、细胞周期、p21基因及蛋白水平表达差异；乳腺细胞球培养法富集乳腺癌干细胞,流式细胞仪检测TGF-β1在富集乳腺癌干细胞中的作用,Q-RT-PCR、Western blot法检测各处理因素的乳腺癌细胞侵袭转移、化疗耐药、周期调控、细胞转化相关因子SATB1、MMP1、P21、Vimentin、E-cadherin基因及蛋白水平表达差异；Transwell侵袭小室法检测各处理因素前后乳腺癌细胞侵袭能力变化；CCK-8法检测各处理因素前后乳腺癌细胞对化疗药物表阿霉素、多西紫杉醇、盐霉素药物敏感性差异；将盐霉素与表阿霉素、多西紫杉醇两药或三药联合作用各处理因素乳腺癌细胞,CCK-8法检测细胞生长抑制率,检测盐霉素在逆转表阿霉素及多西紫杉醇耐药方面的作用。
实验结果：
流式细胞仪检测显示MCF7、MCF7/ADM、MDA-MB-23、SKBR3四株细胞中ALDH1阳性细胞群比例分别为1.49%、8.38%、1.53%、4.23%,以MCF7/ADM细胞株中ALDH1阳性细胞群含量最高。加入TGF-β1培养后MCF7、MCF7/ADM、SKBR3三株细胞株(ALDH1不宜做为MDA-MB-231乳腺癌干细胞标记物)中ALDH1阳性乳腺癌干细胞侧群比例平均分别为3.83%、10.06%、6.32%。加入TGF-β1培养后MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株细胞中p21 mRNA的表达分别较未加入TGF-β1培养细胞显著上调,分别上调2倍、1.7倍、1.5倍和1.2倍(n=3,p<0.05)。加入TGF-β1培养后MCF7、MCF7/ADM、MDA-MB-231、SKBR3四株细胞表现出G1期阻滞(n=3,p<0.05)。TGF-β1上调p21、SATB1、MMP1、Vimentin的表达,下调E-cadherin的表达；TGF-β1使细胞出现进一步的G0/G1期阻阻滞(p<0.001)。TGF-β1可使细胞具有更强的克隆形成能力,细胞球形成率显著升高(p<0.001)；TGF-β1可增强细胞侵袭能力(p<0.05)。表阿霉素(EPI)、多西紫杉(DOX)对MCF7的IC50值分别为：0.4ug/ml、0.2ug/ml;对MCF7/ADM的IC50值分别为：20ug/ml、0.6ug/ml;对SC细胞的IC50值分别为：50ug/ml、lug/ml;对SC-T细胞的IC50值分别为：120ug/ml、10ug/ml。SC及SC-T细胞对EPI、DOX体现出显著耐药性。盐霉素(SAL)对MCF7/ADM、SC、SC-T三组细胞的IC50值分别为：3±0.2ug/ml、8±0.5ug/ml、9±0.2umol/ml。EPI、DOX及SAL三种药物单独作用于MCF7/ADM、SC、SC-T细胞时,乳腺癌干细胞体现出明显的药物抵抗性,在TGF-β1、作用后药物抵抗更为明显,p<0.01；在两药联用方面,DOX和SAL联用的方式显著优于其他组合,p<0.01。EPI、DOX、SAL三药联用时,三组细胞生长抑制率无明显差异,p>0.1。
实验结论：
1.TGF-β1可以增加乳腺癌细胞的肿瘤干细胞池,提高细胞周期调控因子p21的表达,使细胞出现G0/G1期阻滞。
2.TGF-β1可以上调自我更新和侵袭能力相关的p21、MMP、SATB1、Vimentin基因水平和蛋白水平的表达。
3.TGF-β1可以有效富集乳腺癌干细胞。促进乳腺癌干细胞标记物ALDH1的表达,增强细胞自我更新、侵袭能力,诱导乳腺癌细胞化疗耐药。
4.针对乳腺癌干细胞杀伤的药物盐霉素可以增加乳腺癌细胞对表阿霉素及多西紫杉醇的敏感性,逆转表阿霉素和多西紫杉醇的耐药,三药联合使用时在中等剂量即可有效杀伤乳腺癌细胞及乳腺癌干细胞。
Objective:To detect the enrichment of breast cancer stem cells induced by TGF-β1, and the effect on the metastasis, invasion, cell cycle regulation, drug resistance of breast cancer stem cells; To detect the killing effect of salinomycin on breast cancer stem cells and the effect of reversing epirubicin and docetacel resistance.
Methods:The breast cancer stem cells from MCF7/ADM were enriched by mammosphere method cultured with or without TGF-β1 (lOng/ml) which labeled with SC and SC-T respectively. MCF7, MCF7/ADM, MDA-MB-231, SKBR3 cultured with or without TGF-β1 (10ng/ml) were labeled with ALDEFLOUR kit, the proportion of ALDH1 positive cells in four cell lines and SC, SC-T cells were detected with flow cytometry (n=3); Expression of p21, MMP1, SATB1, Vimentin, E-cadherin protein were detected with Q-RT-PCR and Western blot; The cell cycle of the six cells were detected with flow cytometry; The invasion ability of MCF7/ADM、SC and SC-T cells were detected with Transwell. The cell self-renewal ability of the three cells were detected with mammosphere formation method. The cell cycle of the three cells were detected with flow cytometry (n=3); The drug sensitivity of the three cells were detected with cell counting kit 8 (CCK8) method. The growth inhibition of salinomycin combined with epirubicin and/or docetaxel were detected with CCK8 method (n=3).
Results:The proportion of ALDH1 positive cells in MCF7, MCF7/ADM, MDA-MB-231, SKBR3 were 1.49%,8.38%,1.53%,4.23%; The proportion of ALDH1 positive cells in MCF7, MCF7/ADM, SKBR3 which were cultured with TGF-β1 were 3.83%,10.06%, 6.32% respectively (n=3), which were obviously higher than the cell cultured without TGF-β1 (n=3, p＜0.05)); Compared with cells cultured without TGF-β1, there is G1 phase cell cycle arrest when MCF7, MCF7/ADM, MDA-MB-231, SKBR3 cells cultured with TGF-β1 (n=3, p＜0.05). The expression of p21 in the cell lines were significant higher than the cells cultured without with TGF-β1 (n=3,P＜0.05). TGF-β1 up-regulated the expression of p21, SATB1, MMP1, while down-regulated the expression of E-cadherin. TGF-β1 enhanced the mammosphere formation ability (p＜0.001), invasion ability of breast cancer stem cells (p＜0.05) and G1 phase arrest (p＜0.001). The IC50 value of epirubicin (EPI) and docetaxel (DOX) in MCF7 were 0.4ug/ml,0.2ug/ml respectively (n=3); the IC50 value of EPI and DOX in MCF7/ADM cell were 20ug/ml,0.6ug/ml respectively (n=3); while the IC50 value of EPI and DOX in SC cell were 50ug/ml, lug/ml respectively (n=3); the IC50 value of EPI and DOX in SC-T cell were 120ug/ml, 10ug/ml respectively (n=3). The IC50 value of salinomycin (SAL) in MCF7/ADM, SC, SC-T cells were 3±0.2ug/ml,8±0.5ug/ml, 9±0.2umol/ml respectively; The growth inhibition on SC and SC-T cells were lower than MCF7/ADM, with EPI, DOX and SAL respectively. Combined with two of EPI, DOX and SAL, the better growth inhibition effect was arised when DOX combined with SAL, p＜0.01; Combined with all three drugs, the growth inhibition were more than 70% on MCF7/ADM, SC and SC-T cells, p＞0.1.
Conclusion:
1. TGF-β1 could increase the proportion of breast cancer stem cells, and could up-regulate the expression of p21 mRNA and help the cells arrest in G0/G1 phase as well.
2. TGF-β1 could up-regulate the expression of p21、MMP、SATB1、Vimentin, while down-regulate the expression of E-cadherin.
3. TGF-β1 could enhance the enrichment of breast cancer stem cells. TGF-β1 could boost self-renewal and invasion ability of breast cancer stem cell, and induce the chemotherapy resistance, promote the expression of breast cancer stem cell marker.
4. Salinomycin could kill breast cancer stem cells effectively. Salinomycin sensitizes breast cancer cells and breast cancer stem cells to the effect of epirubicin and docetaxel.
引文
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