β2肾上腺素能受体在乳腺癌侵袭转移中的作用及其与趋化因子受体CXCR4的关系
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摘要
目的:探讨β2肾上腺素能受体(β2-AR)在乳腺癌侵袭转移中的作用及其与趋化因子受体CXCR4的关系。
方法:采用逆转录聚合酶链反应(RT-PCR)和免疫细胞化学(ICC)方法检测人正常乳腺上皮细胞及乳腺癌细胞β2-AR的表达;采用流式细胞术及活细胞计数剂CCK-8检测刺激β2-AR对乳腺癌细胞的细胞周期分布及生长的影响;采用Transwell细胞侵袭实验检测刺激β2-AR对乳腺癌细胞侵袭能力的影响。采用脂质体转染法将β2-AR基因转入人乳腺癌细胞MDA-MB-435;采用RT-PCR、ICC、流式细胞术等方法鉴定获得稳定高表达的细胞株MDA-MB-435_(β2-AR);采用Transwell细胞侵袭实验检测转染β2-AR基因对乳腺癌细胞侵袭能力的影响。采用免疫组织化学方法检测原发性乳腺癌及正常乳腺或乳腺良性疾病组织中β2-AR的表达;统计β2-AR表达与临床特征的关系;随访乳腺癌患者的复发转移情况。建立人乳腺癌细胞裸小鼠原位移植瘤模型;采用关笼制动及微渗透泵给药法刺激β2-AR;观察移植瘤的生长以及引流区淋巴结与肺的转移。采用基因芯片技术检测刺激β2-AR对MDA-MB-231细胞的趋化因子与受体家族成员的基因表达的影响;采用荧光实时定量PCR、免疫印迹法复核基因芯片的结果;采用Transwell细胞侵袭实验检测刺激β2-AR对MDA-MB-231细胞趋向特异性趋化因素的能力的影响。
结果:β2-AR在人正常乳腺上皮细胞HBL-100及乳腺癌细胞BT-549、HCC1937、BCaP-37中低表达;在乳腺癌细胞MDA-MB-435、MDA-MB-435HM、MCF-7、T47D中基本无表达;在乳腺癌细胞MDA-MB-231、MDA-MB-231HM、MDA-MB-468中高表达。刺激β2-AR可提高乳腺癌细胞MDA-MB-231分布于G_2/M期的比例,可促进MDA-MB-231细胞生长,这种作用可以被β2-AR阻滞剂所抑制。MDA-MB-231细胞可被β2-AR激动剂引导而产生侵袭运动,这种作用可以被β2-AR阻滞剂所抑制。稳定转染β2-AR基因可使MDA-MB-435细胞获得原本不具备的被β2-AR激动剂引导而定向侵袭的能力。在23例正常乳腺或乳腺良性疾病组织中β2-AR均呈弱阳性至中等阳性的表达,而90例女性原发性乳腺癌中,不表达者18例,弱阳性至中等阳性表达者53例,强阳性表达者19例,总阳性率80%;其中强阳性表达与腋淋巴结转移明显呈正相关(P=0.011),随访乳腺癌患者发现,强阳性表达组患者病情进展比例较高。动物预实验发现,关笼制动模拟精神压力法能促进β2-AR高表达的MDA-MB-231细胞裸小鼠移植瘤的生长,但其差异无统计学上的显著性意义。基因芯片技术、荧光实时定量PCR、免疫印迹法等观察到刺激β2-AR可在基因及蛋白水平下调MDA-MB-231细胞的趋化因子受体CXCR4的表达,并降低CXCR4特异性配体CXCL12对MDA-MB-231细胞的趋化作用。
结论:β2肾上腺素能受体(β2-AR)在乳腺癌的侵袭转移中可能具有重要作用;β2-AR对乳腺癌细胞的直接及间接作用似乎并不统一,提示了精神因素对恶性肿瘤转移作用的复杂性,值得进一步研究。
Objective:To investigate the role ofβ2 adrenergic receptor(β2-AR.) in breast cancer invasion and metastasis.To study the effect ofβ2-AR on chemokine receptor CXCR4.
Methods:The expression ofβ2-AR in human breast cancer cell lines was determined using reverse transcription-polymerase chain reaction(RT-PCR) and immunocytochemistry (ICC).The cell cycle and cell proliferation of breast cancer cells MDA-MB-231 cultured withβ2-AR agonists were observed using flow cytometry and alive cell count agents CCK-8 respectively.The invasion capability of MDA-MB-231 cells induced byβ2-AR agonists was detected using transwell invasion assay.After stable transfection with the vector containing human entire coding sequence ofβ2-AR,the transfected cells MDA-MB-435_(β2-AR) were identified by RT-PCR and ICC,and the cell cycle and cell proliferation were observed using flow cytometry and growth curve.The effect ofβ2-AR-transfection on cell invasion was defined by transwell.The expression ofβ2-AR in 90 female primary breast cancer samples and 23 normal or benign breast diseases tissues was determined using immunohistochemistry(IHC),and then analyzed their relationship with clinical feature, furthermore,followed up the breast cancer patients.Human breast cancer cells(MDA-MB -231,MDA-MB-435) were injected orthotopically into BALB/c female nude mice,and then stimulatedβ2-AR by immobilizing the mice in cages or administratingβ2-AR agents carried within mini osmotic pumps.The effect ofβ2-AR on chemokine receptor CXCR4 was investigated using functional gene microarray,Real-time PCR,Western Blot and transwell.
Results:.Although absent in breast cancer cell lines MDA-MB-435,MDA-MB -435HM,MCF-7 and T47D,β2-AR was present in normal human breast epithelial cell HBL-100 and breast cancer cell lines BT-549,HCC1937 and BCaP-37.Furthermore,β2-AR was highly expressed in MDA-MB-231,MDA-MB-231HM and MDA-MB-468 cells.β2-AR agonists not only enhanced the G_2/M proportion and cell proliferation of MDA-MB-231 cells,but also induced MDA-MB-231 cells invasion.β2-AR-overexpression can enable MDA-MB-435 cells to be attracted byβ2-AR agonists.In contrast to the non-enhanced expression in all the 23 normal or benign breast diseases tissues,β2-AR was intensely expressed in 21%(19/90) primary breast cancer samples.Strong expression is very positively correlated with lymph node metastasis(P=0.011 ).However,there still were 20%samples withoutβ2-AR presence.β2-AR agonists can down regulate the expression and function of chemokine receptor CXCR4 viaβ2-AR.
Conclusions:β2 adrenergic receptor may play an important role in breast cancer metastasis.
方法:采用逆转录聚合酶链反应(RT-PCR)和免疫细胞化学(ICC)方法检测人正常乳腺上皮细胞及乳腺癌细胞β2-AR的表达;采用流式细胞术及活细胞计数剂CCK-8检测刺激β2-AR对乳腺癌细胞的细胞周期分布及生长的影响;采用Transwell细胞侵袭实验检测刺激β2-AR对乳腺癌细胞侵袭能力的影响。采用脂质体转染法将β2-AR基因转入人乳腺癌细胞MDA-MB-435;采用RT-PCR、ICC、流式细胞术等方法鉴定获得稳定高表达的细胞株MDA-MB-435_(β2-AR);采用Transwell细胞侵袭实验检测转染β2-AR基因对乳腺癌细胞侵袭能力的影响。采用免疫组织化学方法检测原发性乳腺癌及正常乳腺或乳腺良性疾病组织中β2-AR的表达;统计β2-AR表达与临床特征的关系;随访乳腺癌患者的复发转移情况。建立人乳腺癌细胞裸小鼠原位移植瘤模型;采用关笼制动及微渗透泵给药法刺激β2-AR;观察移植瘤的生长以及引流区淋巴结与肺的转移。采用基因芯片技术检测刺激β2-AR对MDA-MB-231细胞的趋化因子与受体家族成员的基因表达的影响;采用荧光实时定量PCR、免疫印迹法复核基因芯片的结果;采用Transwell细胞侵袭实验检测刺激β2-AR对MDA-MB-231细胞趋向特异性趋化因素的能力的影响。
结果:β2-AR在人正常乳腺上皮细胞HBL-100及乳腺癌细胞BT-549、HCC1937、BCaP-37中低表达;在乳腺癌细胞MDA-MB-435、MDA-MB-435HM、MCF-7、T47D中基本无表达;在乳腺癌细胞MDA-MB-231、MDA-MB-231HM、MDA-MB-468中高表达。刺激β2-AR可提高乳腺癌细胞MDA-MB-231分布于G_2/M期的比例,可促进MDA-MB-231细胞生长,这种作用可以被β2-AR阻滞剂所抑制。MDA-MB-231细胞可被β2-AR激动剂引导而产生侵袭运动,这种作用可以被β2-AR阻滞剂所抑制。稳定转染β2-AR基因可使MDA-MB-435细胞获得原本不具备的被β2-AR激动剂引导而定向侵袭的能力。在23例正常乳腺或乳腺良性疾病组织中β2-AR均呈弱阳性至中等阳性的表达,而90例女性原发性乳腺癌中,不表达者18例,弱阳性至中等阳性表达者53例,强阳性表达者19例,总阳性率80%;其中强阳性表达与腋淋巴结转移明显呈正相关(P=0.011),随访乳腺癌患者发现,强阳性表达组患者病情进展比例较高。动物预实验发现,关笼制动模拟精神压力法能促进β2-AR高表达的MDA-MB-231细胞裸小鼠移植瘤的生长,但其差异无统计学上的显著性意义。基因芯片技术、荧光实时定量PCR、免疫印迹法等观察到刺激β2-AR可在基因及蛋白水平下调MDA-MB-231细胞的趋化因子受体CXCR4的表达,并降低CXCR4特异性配体CXCL12对MDA-MB-231细胞的趋化作用。
结论:β2肾上腺素能受体(β2-AR)在乳腺癌的侵袭转移中可能具有重要作用;β2-AR对乳腺癌细胞的直接及间接作用似乎并不统一,提示了精神因素对恶性肿瘤转移作用的复杂性,值得进一步研究。
Objective:To investigate the role ofβ2 adrenergic receptor(β2-AR.) in breast cancer invasion and metastasis.To study the effect ofβ2-AR on chemokine receptor CXCR4.
Methods:The expression ofβ2-AR in human breast cancer cell lines was determined using reverse transcription-polymerase chain reaction(RT-PCR) and immunocytochemistry (ICC).The cell cycle and cell proliferation of breast cancer cells MDA-MB-231 cultured withβ2-AR agonists were observed using flow cytometry and alive cell count agents CCK-8 respectively.The invasion capability of MDA-MB-231 cells induced byβ2-AR agonists was detected using transwell invasion assay.After stable transfection with the vector containing human entire coding sequence ofβ2-AR,the transfected cells MDA-MB-435_(β2-AR) were identified by RT-PCR and ICC,and the cell cycle and cell proliferation were observed using flow cytometry and growth curve.The effect ofβ2-AR-transfection on cell invasion was defined by transwell.The expression ofβ2-AR in 90 female primary breast cancer samples and 23 normal or benign breast diseases tissues was determined using immunohistochemistry(IHC),and then analyzed their relationship with clinical feature, furthermore,followed up the breast cancer patients.Human breast cancer cells(MDA-MB -231,MDA-MB-435) were injected orthotopically into BALB/c female nude mice,and then stimulatedβ2-AR by immobilizing the mice in cages or administratingβ2-AR agents carried within mini osmotic pumps.The effect ofβ2-AR on chemokine receptor CXCR4 was investigated using functional gene microarray,Real-time PCR,Western Blot and transwell.
Results:.Although absent in breast cancer cell lines MDA-MB-435,MDA-MB -435HM,MCF-7 and T47D,β2-AR was present in normal human breast epithelial cell HBL-100 and breast cancer cell lines BT-549,HCC1937 and BCaP-37.Furthermore,β2-AR was highly expressed in MDA-MB-231,MDA-MB-231HM and MDA-MB-468 cells.β2-AR agonists not only enhanced the G_2/M proportion and cell proliferation of MDA-MB-231 cells,but also induced MDA-MB-231 cells invasion.β2-AR-overexpression can enable MDA-MB-435 cells to be attracted byβ2-AR agonists.In contrast to the non-enhanced expression in all the 23 normal or benign breast diseases tissues,β2-AR was intensely expressed in 21%(19/90) primary breast cancer samples.Strong expression is very positively correlated with lymph node metastasis(P=0.011 ).However,there still were 20%samples withoutβ2-AR presence.β2-AR agonists can down regulate the expression and function of chemokine receptor CXCR4 viaβ2-AR.
Conclusions:β2 adrenergic receptor may play an important role in breast cancer metastasis.
引文
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2.Thaker PH,et al.Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.Nat Med 12,939-944(2006).
3.Askari MD,et al.The tobacco-specific carcinogen,4-(methylnitrosarnino)-1-(3-pyridyl)-l-butanone stimulates proliferation of immortalized human pancreatic duct epithelia through beta-adrenergic transactivation of EGF receptors.J Cancer Res Clin Oncol 131,639-648(2005).
4.Lutgendorf SK,et al.Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines.Clin Cancer Res 9,4514-4521(2003).
5.Schuller HM,et al.Neurotransmitter receptor-mediated signaling pathways as modulators of carcinogenesis.Prog Exp Tumor Res 39,45-63(2007).
6.Wu WK,et al.4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors.Cancer Res 65,5272-5277(2005).
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