S100B Mediates Stemness of Ovarian Cancer Stem-Like Cells Through Inhibiting p53
S100B Mediates Stemness of Ovarian Cancer Stem-Like Cells Through Inhibiting p53
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S100B 通过抑制 p53 介导卵巢癌干细胞样细胞的干细胞性
DOI：
10.1002/stem.2472
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发表时间：
2017-02-01
期刊：
影响因子：
5.2
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
--
作者：
Yang, Tao;Cheng, Jianan;Zhu, Bo
S100 B是S100蛋白家族的成员之一，参与多种癌症的进展。卵巢癌是由参与肿瘤发生、转移、化疗耐药性和复发的癌症干细胞样细胞（CSLC）驱动的。然后，我们假设S100 B可能通过调节卵巢CSLCs的干性（CSLCs的一个关键特征）发挥促肿瘤作用。首先，我们观察到S100B在卵巢癌标本中的高表达，与正常卵巢相比。S100B的上调与更晚期的肿瘤阶段、更差的分化和更差的存活相关。此外，升高的S100 B表达与干细胞标志物（包括CD133、Nanog和Oct4）的表达增加相关。然后，我们发现S100 B优先在来自卵巢癌细胞系和患者原发肿瘤的CD133（+）卵巢CSLCs中表达。更重要的是，我们发现，S100 B基因敲低抑制卵巢CSLCs的体外自我更新和体内致瘤性，并降低其干细胞标志物的表达。S100B异位表达赋予非CSLCs干细胞性，这已经通过体外和体内实验证明。从机制上讲，我们证明了S100 B介导的对CSLCs干性的影响的潜在机制不依赖于其与晚期糖基化终产物（AGEs）受体的结合，但可能是通过细胞内调节，通过抑制p53表达和磷酸化。总之，我们的研究结果阐明了S100 B在维持卵巢CSLCs干性中的重要性，这可能为卵巢癌提供一个有前途的治疗靶点。
S100B is one of the members of the S100 protein family and is involved in the progression of a variety of cancers. Ovarian cancer is driven by cancer stem-like cells (CSLCs) that are involved in tumorigenesis, metastasis, chemo-resistance and relapse. We then hypothesized that S100B might exert pro-tumor effects by regulating ovarian CSLCs stemness, a key characteristic of CSLCs. First, we observed the high expression of S100B in ovarian cancer specimens when compared to that in normal ovary. The S100B upregulation associated with more advanced tumor stages, poorer differentiation and poorer survival. In addition, elevated S100B expression correlated with increased expression of stem cell markers including CD133, Nanog and Oct4. Then, we found that S100B was preferentially expressed in CD133(+) ovarian CSLCs derived from both ovarian cancer cell lines and primary tumors of patients. More importantly, we revealed that S100B knockdown suppressed the in vitro self-renewal and in vivo tumorigenicity of ovarian CSLCs and decreased their expression of stem cell markers. S100B ectopic expression endowed non-CSLCs with stemness, which has been demonstrated with both in vitro and in vivo experiments. Mechanically, we demonstrated that the underlying mechanism of S100B-mediated effects on CSLCs stemness was not dependent on its binding with a receptor for advanced glycation end products (RAGE), but might be through intracellular regulation, through the inhibition of p53 expression and phosphorylation. In conclusion, our results elucidate the importance of S100B in maintenance of ovarian CSLCs stemness, which might provide a promising therapeutic target for ovarian cancer.