QKI impairs self-renewal and tumorigenicity of oral cancer cells via repression of SOX2
QKI impairs self-renewal and tumorigenicity of oral cancer cells via repression of SOX2
复制标题
DOI：
10.4161/cbt.29502
复制
发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Lei, Xiaoying
中科院分区：
文献类型：
--
作者：
Lu, Wei;Feng, Feixue;Lei, Xiaoying
肿瘤干细胞（cancer stem cells，CSCs）可能参与肿瘤的发生、远处转移和化疗耐药。Quaking（QKI）是一种RNA结合蛋白，具有肿瘤抑制作用。在这里，我们发现在许多人口腔癌样本中观察到QKI水平降低。此外，与口腔癌细胞系中的非CSC相比，检测到CSC中QKI表达的进一步降低。在口腔癌细胞中过表达QKI显著减少CSC球体形成和干细胞相关基因。在裸鼠移植瘤模型中，QKI显著降低肿瘤的起始率、肿瘤的大小和肺转移率。相反，敲除QKI增强了上述效应。在CSC靶基因中，QKI对SOX 2的表达有负性影响，其作用机制可能是通过与SOX 2的3UTR特异性结合，以顺式元件依赖的方式直接调控SOX 2的表达。S0X2的缺失甚至完全逆转了QKI敲减细胞系中的球体形成能力。总之，这些数据表明，SOX 2是口腔癌中重要的CSC调节剂。QKI是一种新型CSC抑制剂，通过部分抑制SOX 2而损害多种口服CSC特性。因此，QKI的表达降低可能为口腔癌提供一种新的诊断标志物。
Cancer stem cells (CSCs) may contribute to tumor initiation, distant metastasis and chemo-resistance. One of RNA-binding proteins, Quaking (QKI), was reported to be a tumor suppressor. Here we showed that reduced QKI levels were observed in many human oral cancer samples. Moreover further reduction of QKI expression in CSCs was detected compared with non-CSCs in oral cancer cell lines. Overexpressing QKI in oral cancer cells significantly reduced CSC sphere formation and stem cell-associated genes. In tumor implanting nude mice model, QKI significantly impeded tumor initiation rates, tumor sizes and lung metastasis rates. As a contrast, knocking down QKI enhanced the above effects. Among the putative CSC target genes, SOX2 expression was negatively affected by QKI, mechanism study revealed that QKI may directly regulate SOX2 expression via specific binding with its 3UTR in a cis element-dependent way. Loss of SOX2 even completely reversed the sphere forming ability in QKI knockdown cell line. Taken together, these data demonstrated that SOX2 is an important CSC regulator in oral cancer. QKI is a novel CSC inhibitor and impaired multiple oral CSC properties via partial repression of SOX2. Therefore, reduced expression of QKI may provide a novel diagnostic marker for oral cancer.