ER和MDM2及ERK1/2信号通与卵巢癌耐药关系的研究

目的:探讨ER、MDM2和ERK1/2信号通路在卵巢癌中的相关性及与卵巢癌耐药的关系。方法:采用免疫组织化学SP法检测40例卵巢癌标本中ER、MDM2及P-糖蛋白(P-gp)的表达水平;采用MTT比色分析法检测该40例标本对紫杉醇(PTX)、表柔比星(EADM)、顺铂(DDP)和卡铂(CBP)的药物敏感性;通过酶活性测定,检测ERK1/2酶活性。结果:PTX和EADM耐药者ERK1/2酶活性分别增高1.5倍,P值分别为0.015和0.004;ERK1/2酶活性与PTX和EADM的抑制率负相关,r分别为-0.531和-0.488,P<0.01;ER和MDM2不同表达水平间ERK1/2酶活性差异均有统计学意义,P值分别为0.001和0.034;P-gp阳性组ERK1/2酶活性是阴性组的1.4倍,P=0.022;P-gp阴性组PTX和EADM的抑制率分别是阳性组的1.5和2.0倍,P值分别为0.021和0.004;P-gp与MDM2的表达正相关,r=0.396,P<0.05;MDM2不同表达水平,PTX和EADM抑制率的差异有统计学意义,P值分别为0.024和0.039;ER与MDM2的表达正相关,r=0.671,P<0.01;DDP和CBP在本实验中差异无统计学意义。结论:ER、MDM2及ERK1/2激酶活性之间存在正相关性;ERK1/2激酶活性和MDM2的表达均与P-gp的表达正相关;卵巢癌PTX和EADM耐药的产生与ERK1/2酶活性的升高和P-gp及MDM2表达的增强有关。

Relationship between ER, MDM2 and ERK1/2 signal pathway and drug resistance in ovarian cancer

OBJECTIVE:To explore the relationship between the expressions of ER,MDM2 and the activation of ERK1/2 signal pathway and drug resistance in ovarian cancer,respectively.METHODS:SP immunohistochemistry was used to detect the expressions of ER,MDM2 and P-gp in 40 ovarian cancer specimens;MTT assay was used to investigate the susceptibilities of the 40 ovarian cancer tissues to PTX,EADM,DDP and CBP;and in the meanwhile the change of ERK1/2 activity was examed to measure its efficiency of phosphate transferase.RESULTS:Compared with the samples sensitive to PTX and EADM,ERK1/2 activity was 1.5-fold higher respectively for the samples resistant to PTX and EADM,and P were 0.015 and 0.004 respectively.ERK1/2 activity was inversely correlated with the inhibition rates of PTX and EADM.r were-0.531 and-0.488 respectively,P<0.01.To different levels of ER and MDM2,the differences of ERK1/2 activities were significant,Pwere 0.001 and 0.034 respectively.In the P-gp positive cases,the ERK1/2 activity was 1.4-fold higher than that in the P-gp negative cases(P=0.022),and in P-gp negative samples,the inhibition rates of PTX and EADM were 1.5 and 2.0-fold higher respectively than those of the P-gp positive samples(P were 0.021 and 0.004,respectively).P-gp was positively correlated with MDM2,r=0.396,P<0.05.To the different levels of MDM2 expression,the differences of inhibition rates of PTX and EADM were significant(P were 0.024 and 0.039 respectively).The expression of ER was positively correlated with the expression of MDM2,r=0.671,P<0.01.In this study,there were no significant consequences for DDP and CBP.CONCLUSION:ER,MDM2 and ERK1/2 activity are positively correlated with each other,ERK1/2 activity and MDM2 expression are both positively correlated with P-gp expression,the drug resistance of PTX and EADM is correlated with the enhancement of ERK1/2 activity and the expressions of P-gp and MDM2.