Oshika Y, Nakamura M, Tokunaga T, Fukushima Y, Abe Y, Ozeki Y, Yamazaki H, Tamaoki N, Ueyama Y
Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Mod Pathol. 1998 Nov;11(11):1059-63.
Multidrug resistance-associated protein (MRP) is one of the major factors for non-P-glycoprotein (PGp)-mediated multidrug resistance. We reported previously that overexpression of the MRP gene was related to the prognosis of non-small cell lung cancer (NSCLC). It is unclear how MRP expression is regulated in NSCLC. In this study, we examined MRP and mutant p53 expression in 107 NSCLCs by immunohistochemical procedures. Forty-seven (43.9%) of these 107 NSCLCs were positive for MRP in the cytoplasm. Mutant p53-positive NSCLC showed a significant correlation with MRP overexpression (P=.011). Coexpression of MRP and p53 in the same cells of NSCLC was confirmed by double-staining procedures. Twenty-six patients with MRP-positive tumors who underwent postoperative chemotherapy with MRP-related anticancer drugs (vindesine and etoposide) had significantly poorer prognoses than did those with MRP-negative tumors (P=.017). This correlation between MRP expression and prognosis was also seen in Stage III patients (P=.022) and in patients with squamous cell carcinoma (P=.062). NSCLC patients with coexpression of MRP and p53 showed poorer prognoses than did those without MRP and p53 (P=.014). These results suggested that MRP overexpression affected by mutant p53 had a significant effect on prognosis through atypical non-PGp-mediated multidrug resistance in NSCLC.
多药耐药相关蛋白（MRP）是非P-糖蛋白（PGp）介导的多药耐药的主要因素之一。我们之前报道过MRP基因的过表达与非小细胞肺癌（NSCLC）的预后相关。目前尚不清楚NSCLC中MRP的表达是如何调控的。在本研究中，我们通过免疫组化方法检测了107例NSCLC中MRP和突变型p53的表达。这107例NSCLC中有47例（43.9%）细胞质中MRP呈阳性。突变型p53阳性的NSCLC与MRP过表达显著相关（P = 0.011）。通过双重染色法证实了NSCLC同一细胞中MRP和p53的共表达。26例MRP阳性肿瘤患者接受了与MRP相关的抗癌药物（长春地辛和依托泊苷）术后化疗，其预后明显比MRP阴性肿瘤患者差（P = 0.017）。MRP表达与预后之间的这种相关性在Ⅲ期患者（P = 0.022）和鳞状细胞癌患者（P = 0.062）中也可见。MRP和p53共表达的NSCLC患者的预后比无MRP和p53表达的患者差（P = 0.014）。这些结果表明，受突变型p53影响的MRP过表达通过非典型的非PGp介导的多药耐药对NSCLC的预后有显著影响。
