Background

Sal-like protein 4 (SALL4), an embryonic stem cell factor, has been reported to play an essential role in embryogenesis and oncogenesis. As yet, however, the expression and role of this transcription factor in head and neck squamous cell carcinoma (HNSCC) has not been established.

Methods

We assessed SALL4 mRNA expression in a well-characterised dataset of 230 HNSCC samples (test cohort 110 cases and validation cohort 120 cases). We also transfected HNSCC cells (FaDu and UM-SCC-6) with SALL4 siRNA and assessed its effects on proliferation and expression of specific epigenetic factors in order to uncover the role of SALL4 in HNSCC.

Results

Overexpression of SALL4 was detected in tumour samples of both cohorts. HNSCC cells treated with SALL4 siRNA showed a reduction in growth and a decrease in DNA methyltransferase 3 alpha (DNMT3A) expression. In the patient cohorts, SALL4 overexpression was found to significantly correlate with disease recurrence (p < 0.001) and SALL4 methylation status (p = 0.002). We also found that DNMT3A was significantly upregulated upon SALL4 upregulation (p < 0.001). High expression levels of SALL4 correlated with decreases in disease-free survival (DFS) rates (log-rank test, p < 0.001). Multivariate analysis revealed that SALL4 expression served as an independent prognostic factor for DFS (hazard ratio: 2.566, 95% confidence interval: 1.598–4.121; p < 0.001).

Conclusions

Our findings indicate that SALL4 upregulation correlates with HNSCC tumour aggressiveness and an adverse patient outcome. Our findings also indicate that DNMT3A may synergistically contribute to the regulatory effects of SALL4. Our findings provide insight into SALL4-mediated HNSCC development via epigenetic modulation.

中文翻译：

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Sal-like蛋白4在头颈癌中的过表达：表观遗传效应和临床相关性。

背景

Sal-like蛋白4（SALL4）是一种胚胎干细胞因子，据报道在胚胎发生和肿瘤发生中起重要作用。然而，迄今为止，尚未确定该转录因子在头颈鳞状细胞癌（HNSCC）中的表达和作用。

方法

我们在特征明确的230个HNSCC样本数据集中评估了SALL4 mRNA表达（测试队列110例，验证队列120例）。我们还用SALL4 siRNA转染了HNSCC细胞（FaDu和UM-SCC-6），并评估了其对增殖和特定表观遗传因子表达的影响，以揭示SALL4在HNSCC中的作用。

结果

在两个队列的肿瘤样品中均检测到SALL4的过表达。用SALL4 siRNA处理的HNSCC细胞显示出生长减少和DNA甲基转移酶3α（DNMT3A）表达减少。在患者队列中，发现SALL4过表达与疾病复发（p  <0.001）和SALL4甲基化状态（p  = 0.002）显着相关。我们还发现DNMT3A在SALL4上调后显着上调（p  <0.001）。SALL4的高表达水平与无病生存率（DFS）降低相关（对数秩检验，p <0.001）。多变量分析显示，SALL4表达是DFS的独立预后因素（危险比：2.566，95％置信区间：1.598-4.121；p  <0.001）。

结论

我们的研究结果表明SALL4上调与HNSCC肿瘤的侵袭性和不良的患者预后相关。我们的发现还表明DNMT3A可能协同作用于SALL4的调节作用。我们的发现为通过表观遗传调控SALL4介导的HNSCC发育提供了见识。