Overexpression of Sal-like protein 4 in head and neck cancer: epigenetic effects and clinical correlations
Overexpression of Sal-like protein 4 in head and neck cancer: epigenetic effects and clinical correlations
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DOI：
10.1007/s13402-020-00509-5
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发表时间：
2020-04-02
影响因子：
6.6
通讯作者：
Mineta, Hiroyuki
中科院分区：
文献类型：
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作者：
Misawa, Kiyoshi;Misawa, Yuki;Mineta, Hiroyuki
研究背景SAL样蛋白4(SALL4)是一种胚胎干细胞因子，在胚胎发育和肿瘤发生中起重要作用。然而，该转录因子在头颈部鳞状细胞癌(HNSCC)中的表达和作用尚未确定。方法我们在230例HNSCC样本(测试队列110例，验证队列120例)中评估SALL4mRNA的表达。我们还将SALL4 siRNA导入HNSCC细胞(FaDu和UM-SCC-6)，检测其对HNSCC细胞增殖和特异性表观遗传因子表达的影响，以揭示SALL4在HNSCC中的作用。结果SALL4在两组肿瘤标本中均有过表达。经SALL4 siRNA处理的HNSCC细胞生长受阻，DNA甲基转移酶3α(DNMT3A)表达降低。在患者队列中，发现SALL4过表达与疾病复发显著相关(p<；0.001)和SALL4甲基化状态(p=0.002)。我们还发现，当SALL4上调时，DNMT3A显著上调(p<；0.001)。SALL4的高表达水平与无病生存率的下降相关(对数等级检验，p<；0.001)。多因素分析显示，SALL4表达是DFS的独立预后因素(危险比：2.566，95%可信区间：1.598-4.121；p<；0.001)。结论我们的研究结果表明SALL4上调与HNSCC肿瘤侵袭性和不良患者预后相关。我们的研究结果还表明，DNMT3A可能协同作用于SALL4的调控效应。我们的发现为SALL4通过表观遗传调控介导的HNSCC的发展提供了洞察力。
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.