Down-Regulation of SIX3 is Associated with Clinical Outcome in Lung Adenocarcinoma
Down-Regulation of SIX3 is Associated with Clinical Outcome in Lung Adenocarcinoma
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SIX3 的下调与肺腺癌的临床结果相关
DOI：
10.1371/journal.pone.0071816
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发表时间：
2013-08-16
期刊：
影响因子：
3.7
通讯作者：
He, Biao
中科院分区：
文献类型：
--
作者：
Mo, Min-Li;Okamoto, Junichi;He, Biao
背景：肺癌是一种常见的恶性肿瘤，是世界范围内癌症相关死亡的主要原因。SIX 3是高度保守的sine oculis基因家族的人类同源物，在脊椎动物胚胎发育期间是必需的，并且编码含有同源域的转录因子。关于SIX 3在人类肿瘤发生中的作用知之甚少。本研究旨在探讨SIX 3在肺腺癌中的表达、功能及其作为预后指标的意义。方法：采用实时荧光定量RT-PCR方法检测SIX 3 mRNA的表达，采用甲基化特异性定量PCR（MSP）方法检测SIX 3基因启动子区甲基化。进行MTS和集落形成测定以检查细胞增殖。伤口愈合试验用于评估细胞迁移，微阵列用于检查肺癌细胞中SIX 3调控的基因。采用Kaplan-Meier方法和多变量考克斯比例风险回归模型分析肺腺癌患者SIX 3表达水平与临床预后的关系。结果：与肺腺癌组织相比较，SIX 3在肺腺癌组织中表达下调，这种下调与SIX 3启动子甲基化有关。SIX 3在肺癌细胞系中也是甲基化沉默的。在缺乏内源性SIX 3的肺癌细胞中，SIX 3的恢复抑制细胞增殖和迁移，并下调参与增殖和转移的许多基因，如S100 P，TGFB 3，GINS 3和BAG 1。此外，SIX 3 mRNA表达与腺癌患者和细支气管肺泡癌（BAC）特征患者的总生存期（OS）和无进展生存期（PFS）显著改善相关。结论：SIX 3可能作为一种新的抑制剂在人类肺癌中发挥重要作用。SIX 3有可能成为肺腺癌患者的新的预后生物标志物。
Background: Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. SIX3 is a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encodes a homeo-domain containing transcription factor. Little is known about the role of SIX3 in human tumorigenesis. This study is to assess the expression/function of SIX3 and the significance of SIX3 as a prognostic biomarker in lung adenocarcinoma.Methods: Quantitative real-time RT-PCR was used to analyze SIX3 mRNA expression and quantitative methylation specific PCR (MSP) was used to examine promoter methylation. MTS and colony formation assays were performed to examine cell proliferation. Wound healing assays were used to assess cell migration, and microarrays were utilized to examine genes regulated by SIX3 in lung cancer cells. Association of SIX3 expression levels with clinical outcomes of patients with lung adenocarcinoma was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.Results: SIX3 was down-regulated in lung adenocarcinoma tissues compared to their matched adjacent normal tissues, and this down-regulation was associated with methylation of the SIX3 promoter. SIX3 was also methylation-silenced in lung cancer cell lines. Restoration of SIX3 in lung cancer cells lacking endogenous SIX3 suppressed cell proliferation and migration, and downregulated a number of genes involved in proliferation and metastasis such as S100P, TGFB3, GINS3 and BAG1. Moreover, SIX3 mRNA expression was associated with significantly improved overall survival (OS) and progression-free survival (PFS) in adenocarcinoma patients and patients with bronchioloalveolar carcinoma (BAC) features.Conclusions: SIX3 may play an important role as a novel suppressor in human lung cancer. SIX3 has potential as a novel prognostic biomarker for patients with lung adenocarcinomas.