Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Shizuoka, 431-3192, Japan.
Department of Molecular Oncology, Chiba University, Chiba, Japan.
Cell Oncol (Dordr). 2020 Aug;43(4):631-641. doi: 10.1007/s13402-020-00509-5. Epub 2020 Apr 2.
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.
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.
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).
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.
SALL4 是一种胚胎干细胞因子，已有研究报道其在胚胎发生和肿瘤发生中发挥重要作用。然而，目前尚未确定该转录因子在头颈部鳞状细胞癌（HNSCC）中的表达和作用。
我们评估了 230 例 HNSCC 样本（测试队列 110 例，验证队列 120 例）中 SALL4 mRNA 的表达情况。我们还通过 SALL4 siRNA 转染 HNSCC 细胞（FaDu 和 UM-SCC-6），并评估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。
两个队列的肿瘤样本均检测到 SALL4 过表达。用 SALL4 siRNA 处理的 HNSCC 细胞显示生长减少和 DNA 甲基转移酶 3α（DNMT3A）表达降低。在患者队列中，SALL4 过表达与疾病复发（p<0.001）和 SALL4 甲基化状态（p=0.002）显著相关。我们还发现，SALL4 上调会显著上调 DNMT3A（p<0.001）。SALL4 高表达与无病生存率（DFS）降低相关（对数秩检验，p<0.001）。多因素分析显示，SALL4 表达是 DFS 的独立预后因素（风险比：2.566，95%置信区间：1.598-4.121；p<0.001）。
我们的研究结果表明，SALL4 的上调与 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 可能与 SALL4 的调节作用协同作用。我们的研究结果为 SALL4 通过表观遗传调控促进 HNSCC 发生发展提供了新的见解。
