肺癌组织多药耐药因子表达与临床病理的相关性研究

Study on the relationship among multidrug resistance factor expression of lung cancer tissues and clinicopathological characteristics in patients with lung cancer

背景与目的多药耐药是肺癌化疗失败的主要原因,也是化疗不能提高肺癌生存率的最大障碍。肺癌耐药机制复杂,其形成与多种耐药基因有关,联合检测多种耐药基因表达具有重要临床意义。本研究旨在探讨肺癌组织中五种多药耐药因子的表达、共表达及与患者临床病理特征的相关性。方法采用微波EnVision免疫组化法联合检测72例肺癌患者癌组织中肺耐药蛋白(LRP)、P-糖蛋白(P-gp)、谷胱甘肽-S转移酶π(GST-π)、拓扑异构酶Ⅱ(TopoⅡ)及多药耐药相关蛋白(MRP)的表达水平。结果LRP、P-gp、GST-π、TopoⅡ、MRP在肺癌组织中的阳性表达率分别为79.2%、86.1%、54.2%、29.2%、30.6%。不同性别的LRP、TopoⅡ表达明显不同(χ2=11.460、4.877,P=0.001、0.027)。非小细胞肺癌与小细胞肺癌的LRP、GST-π、TopoⅡ表达明显不同(χ2=15.104、14.076、9.409,P=0.001、0.001、0.009)。不同细胞分化程度的GST-π表达明显不同(χ2=8.933,P=0.011)。不同T分期的TopoⅡ表达明显不同(χ2=3.963,P=0.049)。Spearman等级相关分析显示LRP、TopoⅡ表达与性别相关(r=0.464、-0.205,P=0.000、0.027);LRP、GST-π、TopoⅡ表达与病理类型相关,非小细胞肺癌LRP、GST-π表达高于小细胞肺癌(r=-0.390、-0.262,P=0.000、0.018),腺癌LRP表达高于鳞癌(r=0.604,P=0.000),鳞癌GST-π、TopoⅡ表达高于腺癌(r=-0.257、-0.264,P=0.015、0.012);GST-π表达仅与分化程度呈负相关,低分化或未分化者GST-π表达率低于中高分化者(r=-0.232,P=0.012);TopoⅡ表达与T分期呈正相关(r=0.200,P=0.031),GST-π表达与T分期近似负相关(r=-0.182,P=0.050)。耐药因子共表达的Spearman等级相关分析显示LRP与P-gp、LRP与MRP、P-gp与GST-π、P-gp与MRP、GST-π与MRP呈正相关(r=0.283、0.234、0.453、0.204、0.323,P=0.002、0.011、0.000、0.027、0.000),共表达率分别为70.8%、27.8%、52.8%、29.2%、23.6%;LRP与TopoⅡ呈负相关(r=-0.183,P=0.048),共表达率为19.4%。结论肺癌组织表达多种耐药因子,各耐药因子间共表达具有明显相关性。多数耐药因子与T、N、M分期及临床分期无关,部分与性别、病理类型、分化程度相关。肺癌耐药由多种耐药基因共同参与,联合检测多项耐药因子有重要的临床意义。

Background and objective Multidrug resistance （MDR） is not only the main reason of the failure of chemotherapy, but also the largest obstacle of the increase of survival rate in lung cancer. MDR of lung cancer is a complex procedure involved in multiple genes and mutiple pathways. Combined examination of resistance-related genes in lung cancer tissues has an important clinical significance. The aim of this study is to explore the relationship among the expression, coexpression of five multidrug resistance factors of lung cancer tissues and clinicopathological characteristics in patients with lung cancer. Methods Immunohistochemical staining （EnVision method） was used to evaluated the expression of lung resistance protein （LRP）, P-glycoprotein （P-gp）, glutathione S-transferaseπ （GST-π）, topoisomerase Ⅱ （Topo Ⅱ ）, and multidrug-resistance-associated protein （MRP） in cancer tissues from 72 patients with lung cancer. Results The positive rate of LRP, P-gp, GST-π, Topoi Ⅱ and MRP was 79.2%, 86.1%, 54.2%, 29.2% and 30.6% respectively. There was a significant difference of the expression of LRP and TopoⅡ in different sex （X^2 =11. 460 and 4. 877, P=0. 001 and 0.027）, of the expression of LRP, GST-n and Topo Ⅱ in NSCLC and SCLC （X^2 = 15. 104, 14.076 and 9. 409, P=0. 001, 0. 001 and 0. 009）, of the expression of GST-π in various grade of cell differentiation （X^2 =8. 933,P=0. 011）, of the expression of Topo Ⅱ in various T staging （X^2 =3. 963,P=0. 049）. Spearman analysis of rank relativity showed that there was a better relativity between the expression of LRP, Topo Ⅱ and sex （r=0. 464 and -0. 205, P=0. 000 and 0.027）, between the expression of LRP, GST-π, Topo Ⅱ and histology. The expression of LRP and GST-π was significantly higher in NSCLC than in SCLC （r=-0. 390 and -0. 262, P=0. 000 and 0. 018）, the expression of LRP was significantly higher in adenocarcinoma than in squamous cell carcinoma （r =0. 604, P= 0. 000）. The expression of GST-π and Topo Ⅱ was significantly higher in squamous cell carcinoma than in adenocarcinoma （r = -0. 257 and -0. 264, P=0. 015 and 0.012）. There was a reverse relativity between the expression of GST-π and cell differentiation （r = -0. 232, P = 0.012）. There was a positive relativity between the expression of Topo Ⅱ and T staging （r =0. 200, P= 0. 031） and a reverse relativity between the expression of GST-π and T staging （r = -0. 182, P=0. 050）. Spearman analysis of rank relativity of five multidrug resistance factors＇ coexpression showed that there was a positive relativity beween LRP and P-gp, LRP and MRP, P-gp and GST-π, P-gp and MRP, GST-π and MRP （r =0. 283, 0.234, 0.453, 0. 204 and 0. 323, P=0.002, 0.011, 0. 000, 0. 027 and 0.000）, the coexpression rate was 70. 8%, 27.8%, 52, 8%, 29.2%, 23.6% respectively. There was a reverse relativity between LRP and Topo Ⅱ （r = - 0. 183, P- 0. 048）, and the coexpression rate was 19.4 %. Conclusion The expression of partial multidrug resistance factors is relative significantly to sex, histology and cell differentiation, but not to T, N, M stage and clinical stage. The higher coexpression rate and positive relativity indicate MDR in lung cancer is affected by various multidrug resistance factors. It is important to detect coalescently various multidrug resistance factors.