The novel tumor-suppressor Mel-18 in prostate cancer: Its functional polymorphism, expression and clinical significance
The novel tumor-suppressor Mel-18 in prostate cancer: Its functional polymorphism, expression and clinical significance
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DOI：
10.1002/ijc.24721
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发表时间：
2009-12-15
影响因子：
6.4
通讯作者：
Habuchi, Tomonori
中科院分区：
文献类型：
--
作者：
Wang, Wei;Yuasa, Takeshi;Habuchi, Tomonori
Mel-18 是多梳蛋白 (PcG) 蛋白的成员，PcG 蛋白是染色质调节因子，在发育和肿瘤发生中发挥重要作用。本研究旨在探讨 Mel-18 对前列腺癌患者的临床和预后意义。本研究共招募了 539 名日本本土受试者，其中包括 393 名前列腺癌患者和 146 名对照者。使用 PCR-RFLP 方法和使用 GENESCAN 软件的自动测序仪对 Mel-18 基因分型进行分析。免疫组织化学显示，Mel-18 表达在大级别和高级别前列腺癌中减少。此外，Mel-18 表达阳性的患者比 Mel-18 表达阴性的患者具有显着更长的 PSA 无复发生存期 (p = 0.038)。 Mel-18 1805A/G SNP 位于 3' 非翻译区，预计会改变 mRNA 的二级结构。通过等位基因特异性定量RT-PCR，1805A等位基因的Mel-18 mRNA表达明显高于1805G等位基因的表达。在多变量分析中，纯合 G 等位基因基因型和 Mel-18 阴性表达是预测根治性前列腺切除术后 PSA 高复发的独立危险因素，HR 分别为 2.757 (p = 0.022) 和 2.271 (p = 0.045)。此外，G 等位基因也是癌症特异性生存率较差的独立预测因子，D2 期前列腺癌患者的 HR 为 4.658 (p = 0.019)。这是第一项提供重要证据的研究，证明 Mel-18 是一种肿瘤抑制因子和可能的治疗靶点，也是前列腺癌患者预后不良的诊断标志物。 (C)2009年UICC
Mel-18 is a member of the polycomb group (PcG) proteins, which are chromatin regulatory factors and play important roles in development and oncogenesis. This study was designed to investigate the clinical and prognostic significance of Mel-18 in patients with prostate cancer. A total of 539 native Japanese subjects consisting of 393 prostate cancer patients and 146 controls were enrolled in this study. Mel-18 genotyping was analyzed using a PCR-RFLP method and an automated sequencer using the GENESCAN software. Immunohistochemistry revealed that Mel-18 expression was diminished in big grade and high stage prostate cancers. Moreover, patients wit positive Mel-18 expression had significantly longer PSA recurrence-free survival than patients negative for Mel-18 expression (p = 0.038). A Mel-18 1805A/G SNP was located in the 3' untranslated region and was predicted to alter the secondary structure of the mRNA. Mel-18 mRNA expression of the 1805A allele was clearly higher than expression of the 1805G allele by allele specific quantitative RT-PCR. In multivariate analysis, a homozygous G allele genotype and negative Mel-18 expression were independent risk factors predicting high PSA recurrence after radical prostatectomy, with HRs of 2.757 (p = 0.022) and 2.271 (p = 0.045), respectively. Moreover, the G allele was also an independent predictor of poor cancer-specific survival with an HR of 4.658 (p = 0.019) for patients with stage D2 prostate cancer. This is the first study to provide important evidence demonstrating that Mel-18 is a tumor suppressor and possible therapeutic target, as well as a diagnostic marker for poor prognosis in prostate cancer patients. (C) 2009 UICC