应用非小细胞肺癌组织芯片检测P-gp、LRP、MRP和GST-π的表达及其临床意义
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摘要
目的探讨非小细胞肺癌(NSCLC)中P-糖蛋白(P-gp)、肺耐药相关蛋白(LRP)、多药耐药相关蛋白(MRP)和谷胱甘肽转移酶S(GST-π)的表达及新辅助化疗对其表达的影响和临床意义。方法应用组织芯片及图像定量分析技术，对92例NSCLC标本(其中52例未经化疗的直接手术标本，20例同时具备化疗前活检标本和化疗后手术标本)中P-gp、LRP、MRP和GST-π的表达进行检测。结果未经化疗NSCLC标本P-gp、LRP、MRP、GST-π表达的阳性率分别为65.22％、76.09％、81.52％、84.78％。未经化疗标本，P-gp、LRP和GST-π在腺癌中的表达水平均高于鳞癌(P＜0.05，P＜0.001，P＜0.001)，在低分化癌中表达水平低于高分化癌，且随分化程度的降低表达水平降低(均为P＜0.05)；MRP表达与组织学类型及分化程度无关(P＞0.05)；P-gp、LRP、MRP和GST-π表达水平均与患者年龄、肿瘤大小、临床分期及有无淋巴结转移无关(P＞0.05)。新辅助化疗后，P-gp、GST-π平均光密度与积分光密度在不同临床分期、组织学类型、分化程度、肿瘤大小、年龄以及淋巴结有无转移组中，均高于化疗前(P＜0.05或P＜0.001)；而上述各组中LRP、MRP平均光密度与积分光密度在新辅助化疗前、后均无显著性差异(P＞0.05)。结论(1)化疗前P-gp、LRP和GST-π在NSCLC的表达水平与组织学类型及分化程度有关；(2)同体新辅助化疗后NSCLC组织中P-gp、GST-π表达较化疗前明显增加，新辅助化疗可能通过诱导耐药蛋白的表达增加肺癌组织的获得性耐药性；(3)新辅助化疗的采用与否应视不同病人的具体情况而定，Ⅰ-Ⅱ期NSCLC采用新辅助化疗应慎重，以免影响术后化疗效果；(4)检测NSCLC新辅助化疗前、后耐药蛋白的定量表达，对术前及术后个性化化疗方案的选择和实施具有重要的指导意义。
Objective To investigate the expressions of P-glycoprotein (P-gp), lung resistance related protein (LRP), multidrug resistance-associated protein (MRP) and Glutathione S-transferase (GST-π) in samples from NSCLC patients before and after treated with neoadjuvant chemotherapy (NACT), and their quantitative changes, so that to evaluate the influence of NACT on drug resistance to chemotherapy of NSCLC. Methods 92 cases of NSCLC, including 52 excisional cases pre-chemotherapy and 20 paired samples before and after neoadjuvant chemotherapy were examined with tissue chip techniques and immunohistochemistry. The quantitations of P-gp, LRP, MRP and GST-πexpressions were assessed by computer image analysis system. Results The positive rates of P-gp, LRP, MRP, GST-πexpression were 65.22%, 76.09%, 81.52%, 84.78% respectively in untreated NSCLC. In untreated samples, P-gp, MRP and GST-πexpressions were higher in adenocarcinoma than in squamous cell carcinoma (P＜0.05, P＜0.001, P＜0.001 respectively). Their expressions were all higher in well differentiated group than in poorly differentiated group, and the expressions decreased with the differentiation grade decreasing (P＜0.05). The expression of MRP was not associated with the tissue type and differentiation grade(P＞0.05). All of them were not related to the age, size, clinical stage and lymph node metastasis (P＞0.05). In samples after treated with NACT, the expression of P-gp, GST-πdemonstrated by average optical density and integral optical density were significantly higher (P＜0.05, P＜0.001 respectively) compared with that of biopsy samples taken before NACT; The change in expression of P-gp, GST-πwas also showed difference in histopathological types, differentiation, ages, sizes, clinical stages as well as lymph node metastasis or not(P＜0.05 or P＜0.001). There was no significant difference between samples taken before and after NACT (P＞0.05) with the expression of LRP and MRP demonstrated by both of average optical density and integral optical density. Conclusions (1) This study implies that expressions of P-gp, LRP and GST-πare related to tissue type and differentiation grade before chemotherapy. Their expressions in adenocarcinoma are primarily stronger than those in squamous cell carcinoma. Meanwhile, their expressions were all higher in well differentiated group than in poorly differentiated group. (2) Expressions of P-gp and GST-πincrease noticeably after NACT. NACT may enhance acquired drug resistance of NSCLC through inducing the expression of drug resistance protein. (3) Since NACT may lead to the enhancement of acquired drug resistance inⅠ-Ⅱstage of NSCLC, this may dwindle the therapeutic effect of chemotherapy after surgery. So that acquired drug resistance must be considered with the application of NACT to NSCLC patient in clinic, especially to patient inⅠ-Ⅱstage of NSCLC. (4) Comparative examination of drug resistance proteins before and after NACT, combining with comprehensive consideration of chemical regimens of NACT is recommended during chemotherapy of NSCLC for both before and after surgery.
Objective To investigate the expressions of P-glycoprotein (P-gp), lung resistance related protein (LRP), multidrug resistance-associated protein (MRP) and Glutathione S-transferase (GST-π) in samples from NSCLC patients before and after treated with neoadjuvant chemotherapy (NACT), and their quantitative changes, so that to evaluate the influence of NACT on drug resistance to chemotherapy of NSCLC. Methods 92 cases of NSCLC, including 52 excisional cases pre-chemotherapy and 20 paired samples before and after neoadjuvant chemotherapy were examined with tissue chip techniques and immunohistochemistry. The quantitations of P-gp, LRP, MRP and GST-πexpressions were assessed by computer image analysis system. Results The positive rates of P-gp, LRP, MRP, GST-πexpression were 65.22%, 76.09%, 81.52%, 84.78% respectively in untreated NSCLC. In untreated samples, P-gp, MRP and GST-πexpressions were higher in adenocarcinoma than in squamous cell carcinoma (P＜0.05, P＜0.001, P＜0.001 respectively). Their expressions were all higher in well differentiated group than in poorly differentiated group, and the expressions decreased with the differentiation grade decreasing (P＜0.05). The expression of MRP was not associated with the tissue type and differentiation grade(P＞0.05). All of them were not related to the age, size, clinical stage and lymph node metastasis (P＞0.05). In samples after treated with NACT, the expression of P-gp, GST-πdemonstrated by average optical density and integral optical density were significantly higher (P＜0.05, P＜0.001 respectively) compared with that of biopsy samples taken before NACT; The change in expression of P-gp, GST-πwas also showed difference in histopathological types, differentiation, ages, sizes, clinical stages as well as lymph node metastasis or not(P＜0.05 or P＜0.001). There was no significant difference between samples taken before and after NACT (P＞0.05) with the expression of LRP and MRP demonstrated by both of average optical density and integral optical density. Conclusions (1) This study implies that expressions of P-gp, LRP and GST-πare related to tissue type and differentiation grade before chemotherapy. Their expressions in adenocarcinoma are primarily stronger than those in squamous cell carcinoma. Meanwhile, their expressions were all higher in well differentiated group than in poorly differentiated group. (2) Expressions of P-gp and GST-πincrease noticeably after NACT. NACT may enhance acquired drug resistance of NSCLC through inducing the expression of drug resistance protein. (3) Since NACT may lead to the enhancement of acquired drug resistance inⅠ-Ⅱstage of NSCLC, this may dwindle the therapeutic effect of chemotherapy after surgery. So that acquired drug resistance must be considered with the application of NACT to NSCLC patient in clinic, especially to patient inⅠ-Ⅱstage of NSCLC. (4) Comparative examination of drug resistance proteins before and after NACT, combining with comprehensive consideration of chemical regimens of NACT is recommended during chemotherapy of NSCLC for both before and after surgery.
引文
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