X-linked FHL1 as a novel therapeutic target for head and neck squamous cell carcinoma.
X-linked FHL1 as a novel therapeutic target for head and neck squamous cell carcinoma.
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X连锁FHL1作为头颈鳞状细胞癌的新治疗靶点
DOI：
10.18632/oncotarget.7478
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Chen W
中科院分区：
文献类型：
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作者：
Cao W;Liu J;Xia R;Lin L;Wang X;Xiao M;Zhang C;Li J;Ji T;Chen W
鉴定X连锁的新型肿瘤抑制因子可以为改善某些癌症的预后预测和治疗策略提供新的见解。应用生物信息学和基因转录谱的Venn分析，我们发现X连锁的四个半LIM结构域蛋白1（FHL 1）基因在头颈部鳞状细胞癌（HNSCC）中表达下调。FHL 1功能进行了研究，并在体外和体内证实。通过甲基化特异性PCR、硫酸氢盐测序、5-Aza-dC处理和染色质免疫沉淀分析，分析HNSCC中FHL 1下调的机制。招募两个独立的HNSCC队列（训练队列n = 105，验证队列n = 101），通过实时PCR或免疫组织化学评价FHL 1表达的临床意义。FHL 1 mRNA和蛋白表达在HNSCC中常呈下降趋势。FHL 1的过度表达或缺失通过Cyclin D1、Cyclin E和p27的失调而抑制或促进细胞生长。在FHL 1启动子区，除DNA高甲基化外，EZH 2和H3 K27 Me 3均被大量占据。FHL 1 mRNA表达减少与分化差显著相关（p = 0.020）。多因素分析显示FHL 1 mRNA表达是总生存期的独立预后预测因子（p = 0.036; HR 0.520; Cl，0.283-0.958）和无病生存期（DFS）（p = 0.041; HR 0.527; Cl，0.284-0.975），这一点得到了另一个独立队列的验证（OS的p = 0.021; HR 0.404; Cl，0.187-0.871; DFS的p = 0.011; HR 0.407; Cl，0.203-0.815）。这些结果表明X连锁FHL 1的表观遗传沉默可能在HNSCC的辅助治疗干预中起重要作用，并且是HNSCC患者的独立预后因素。
To identify X-linked novel tumor suppressors could provide novel insights to improve prognostic prediction and therapeutic strategy for some cancers. Using bioinformatics and Venn analysis of gene transcriptional profiling, we identified downregulation of X-linked four-and-a-half LIM domains protein 1 (FHL1) gene in head and neck squamous cell carcinoma (HNSCC). FHL1 functions were investigated and confirmed in vitro and in vivo. FHL1 downregulated mechanisms were analyzed in HNSCCs by using methylation specific PCR, bisulfate-based sequencing, 5-Aza-dC treatment and chromatin immunoprecipitation assays. Two independent HNSCC cohorts (the training cohort n = 105 and the validation cohort n = 101) were enrolled to evaluate clinical implications of FHL1 expression by using real-time PCR or immunohistochemistry. FHL1 mRNA and protein expressions were frequently decreased in HNSCCs. FHL1 overexpression or depletion gave rise to suppress or promote cell growth through Cyclin D1, Cyclin E and p27 dysregulations. Abundant occupy of EZH2 or H3K27Me3 was observed in FHL1 promoter except for DNA hypermethylation. Reduced FHL1 mRNA expression was notably associated with poor differentiation (p = 0.020). Multivariate analysis demonstrated FHL1 mRNA expression was identified as independent prognostic predictors of overall survival (OS) (p = 0.036; HR 0.520; Cl, 0.283–0.958) and disease-free survival (DFS) (p = 0.041; HR 0.527; Cl, 0.284–0.975), which was validated by another independent cohort (p = 0.021; HR 0.404; Cl, 0.187–0.871 for OS; p = 0.011; HR 0.407; Cl, 0.203–0.815 for DFS). These results suggest epigenetic silencing of X-linked FHL1 may have an important role in adjuvant therapeutic intervention of HNSCCs and is an independent prognostic factor in patients with HNSCCs.