Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance
Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance
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DOI：
10.1016/j.lungcan.2004.07.043
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发表时间：
2005-02-01
期刊：
影响因子：
5.3
通讯作者：
Haura, E
中科院分区：
文献类型：
--
作者：
Bepler, G;Zheng, Z;Haura, E
RRM1 是确定肿瘤表型的关键基因。它编码核糖核苷酸还原酶的调节亚基，是吉西他滨的分子靶标。此外，RRM1 诱导 PTEN 表达并抑制细胞迁移、侵袭和转移形成。在肺癌切除患者中，RRM1 水平升高与长生存期高度相关。相比之下，如果 RRM1 表达较高，则接受吉西他滨和顺铂治疗的晚期疾病患者的生存期很差，这可能是因为化疗疗效下降。我们分析了 RRM1 启动子的多态性，以开发一种实用且廉价的 RRM1 表达检测方法。发现了两个单核苷酸多态性：RR37和RR524。这些多态性影响体外启动子活性，并且在不同群体中具有不同的频率。启动子等位基因型与患者的总体生存率（P = 0.06）和无病生存率（P = 0.03）高度相关。具有最高预测活性的等位基因型与最佳患者结果相关。然而，我们没有发现等位基因型和肿瘤 RRM1 表达之间的关联。这可能是由于所描述的启动子多态性对整体体内基因表达影响有限的结果。我们得出的结论是，使用 RR37 和 RR524 来决定化疗的临床研究还为时过早，需要对 RRM1 启动子进行进一步的功能研究，以充分阐明控制 RRM1 表达的因素。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
RRM1 is a gene crucial for determination of the tumor phenotype. It encodes the regulatory subunit of ribonucleotide reductase, and it is a molecular target of gemcitabine. In addition, RRM1 induces PTEN expression and inhibits cell migration, invasion, and metastasis formation. In patients with resected lung cancers, increased Levels of RRM1 are highly associated with long survival. In contrast, patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if RRM1 expression is high presumably because of decreased efficacy of chemotherapy. We analyzed the RRM1 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for RRM1 expression. Two single nucleotide polymorphisms, RR37 and RR524, were discovered. These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations. Promoter allelotypes were highly associated with overall (P = 0.06) and disease-free (P = 0.03) patient survival. The allelotype with the highest predicted activity was associated with the best patient outcome. However, we did not find an association between allelotype and tumoral RRM1 expression. This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression.We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the RRM1 promoter are required to fully elucidate factors controlling RRM1 expression. (C) 2004 Elsevier Ireland Ltd. All rights reserved.