Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
Oncol Rep. 2019 Apr;41(4):2540-2548. doi: 10.3892/or.2019.6988. Epub 2019 Jan 30.
Maternal embryonic leucine zipper kinase (MELK) has been reported to serve critical roles in the maintenance of stemness of cancer cells, although its mechanism remains unclear. Since SRY‑box 2 (SOX2) was demonstrated to be involved in self‑renewal and tumorigenicity of head and neck squamous cell carcinoma (HNSCC) and is aberrantly expressed in HNSCC tumors, the association between MELK and SOX2 was examined. Firstly, MELK inhibition was performed by small interfering RNA or MELK inhibitor OTS167, and it was determined that MELK inhibition by these approaches could decrease the SOX2 expression in HNSCC cells and OTS167 could suppress the SOX2 expression in a dose‑dependent manner. The present results indicated that MELK inhibition may target cancer stem cells (CSCs) through downregulation of the SOX2 gene. To further confirm the transcriptional regulation of SOX2, the transcription factors (TFs) were screened for SOX2 using a promoter‑binding TF assay followed by reverse transcription‑quantitative polymerase chain reaction and a decrease of the majority of the SOX2 TFs following MELK knockdown was observed. The present results provide evidence that MELK serves a key role in CSCs through the regulation of SOX2 and further indicates that MELK inhibition may also be promising for clinical applications in the treatment of HNSCC.
母系胚胎亮氨酸拉链激酶 (MELK) 已被报道在维持癌细胞的干性中发挥关键作用，尽管其机制尚不清楚。由于性别决定区 Y 框 2 (SOX2) 被证明参与头颈部鳞状细胞癌 (HNSCC) 的自我更新和致瘤性，并且在 HNSCC 肿瘤中异常表达，因此研究了 MELK 和 SOX2 之间的关联。首先，通过小干扰 RNA 或 MELK 抑制剂 OTS167 进行 MELK 抑制，并确定这些方法的 MELK 抑制可降低 HNSCC 细胞中的 SOX2 表达，并且 OTS167 可以以剂量依赖性方式抑制 SOX2 的表达。本研究结果表明，MELK 抑制可能通过下调 SOX2 基因来靶向癌症干细胞 (CSC)。为了进一步证实 SOX2 的转录调控，使用启动子结合 TF 测定法筛选了 SOX2 的转录因子 (TF)，随后进行逆转录-定量聚合酶链反应，并且观察到大多数 SOX2 TF 在 MELK 敲低后减少。本研究结果提供了证据表明，MELK 通过调节 SOX2 在 CSC 中发挥关键作用，并进一步表明 MELK 抑制也可能在 HNSCC 的治疗中具有临床应用前景。
