Iizuka N, Hirose K, Noma T, Hazama S, Tangoku A, Hayashi H, Abe T, Yamamoto K, Oka M
Department of Bioregulatory Function, Yamaguchi University School of Medicine, Ube, Japan.
Br J Cancer. 1999 Oct;81(3):469-75. doi: 10.1038/sj.bjc.6690717.
Recently, nm23-H1, an anti-metastasis gene, has been reported to correlate with sensitivity to chemotherapeutic agents including cisplatin in human breast and ovarian carcinoma cells. The aim of this study was to evaluate a role for nm23-H1 in responsiveness to cisplatin-based chemotherapy in patients with oesophageal squamous cell carcinoma (OSCC). The expression of nm23-H1 protein was examined immunohistochemically in 32 eligible patients with OSCC who underwent adjuvant chemotherapy with cisplatin, etoposide, and 5-fluorouracil after tumour resection. Fifteen (46.9%) of 32 patients were positive for nm23-H1 staining and 17 (53.1%) were negative. Both disease-free survival and overall survival rates of nm23-H1-negative patients were significantly shorter than in nm23-H1-positive patients (P < 0.01 for both). There was no significant difference in clinicopathologic characteristics between nm23-H1-positive and nm23-H1-negative groups. Multivariate analysis also showed that nm23-H1 expression was the most significant factor for overall survival of OSCC patients included in this study (P = 0.0007). To further study the role of nm23-H1, a human OSCC cell line (YES-2) was transfected with a plasmid containing a fragment of the nm23-H1 cDNA in an antisense orientation. Reduced expression of nm23-H1 protein in the antisense-transfected (AS) clones was found by Western blot analysis as compared to wild-type YES-2 and YES-2/Neo (clone transfected with the neomycin resistance gene alone). MTT (3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H tetrazolium bromide) assay showed that reduced expression of the nm23-H1 protein in AS clones was consistent with the degree of increased resistance to cisplatin but not etoposide or 5-fluorouracil. These data support the conclusion that reduced expression of nm23-H1 may be associated with resistance to cisplatin, suggesting the value of nm23-H1 expression as a prognostic marker for OSCC patients who are to undergo cisplatin-based chemotherapy.
最近，据报道，抗转移基因nm23-H1与人乳腺癌和卵巢癌细胞对包括顺铂在内的化疗药物的敏感性相关。本研究的目的是评估nm23-H1在食管鳞状细胞癌（OSCC）患者对基于顺铂的化疗反应中的作用。对32例符合条件的OSCC患者进行免疫组织化学检测nm23-H1蛋白的表达，这些患者在肿瘤切除后接受了顺铂、依托泊苷和5-氟尿嘧啶的辅助化疗。32例患者中，15例（46.9%）nm23-H1染色阳性，17例（53.1%）阴性。nm23-H1阴性患者的无病生存期和总生存率均显著短于nm23-H1阳性患者（两者P均<0.01）。nm23-H1阳性组和nm23-H1阴性组之间的临床病理特征无显著差异。多因素分析还显示，nm23-H1表达是本研究中OSCC患者总生存的最显著因素（P = 0.0007）。为了进一步研究nm23-H1的作用，用人OSCC细胞系（YES-2）转染含有反义方向nm23-H1 cDNA片段的质粒。与野生型YES-2和YES-2/Neo（仅转染新霉素抗性基因的克隆）相比，通过蛋白质印迹分析发现反义转染（AS）克隆中nm23-H1蛋白表达降低。MTT（3-(4,5-二甲基-2-噻唑)-2,5-二苯基-2H溴化四唑）试验表明AS克隆中nm23-H1蛋白表达降低与对顺铂耐药性增加程度一致，但与对依托泊苷或5-氟尿嘧啶的耐药性无关。这些数据支持以下结论：nm23-H1表达降低可能与对顺铂耐药有关，提示nm23-H1表达作为接受基于顺铂化疗的OSCC患者预后标志物的价值。
