PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness.
PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness.
复制标题
DOI：
10.1038/ncomms10633
复制
发表时间：
2016-02-04
影响因子：
16.6
通讯作者：
Park JI
中科院分区：
文献类型：
--
作者：
Wang X;Jung YS;Jun S;Lee S;Wang W;Schneider A;Sun Oh Y;Lin SH;Park BJ;Chen J;Keyomarsi K;Park JI
癌症干细胞（CSC）导致肿瘤异质性、治疗耐药性和转移。然而，癌细胞干性的调节机制仍然难以捉摸。在这里，我们将 PCNA 相关因子 (PAF) 确定为控制癌细胞干性的关键分子。 PAF 在乳腺癌细胞中高表达，但在乳腺上皮细胞 (MEC) 中不表达。在 MEC 中，PAF 的异位表达诱导不依赖贴壁的细胞生长和乳腺 CSC 标志物表达。在小鼠模型中，条件性 PAF 表达会诱导乳腺导管增生。此外，PAF 表达赋予 MEC 自我更新能力，并通过 Wnt 信号传导产生细胞异质性。相反，内源性 PAF 的消融会导致乳腺癌细胞干性的丧失。进一步的癌症药物再利用方法表明，NVP-AUY922 下调 PAF 并降低乳腺癌细胞干性。我们的结果揭示了 PAF-Wnt 信号轴在调节细胞可塑性方面的意想不到的作用，这是维持乳腺癌细胞干性所必需的。 干细胞存在于许多肿瘤类型中，并且被认为对治疗后细胞的存活负有部分责任。在这里，作者表明 PCNA 相关因子 PAF 有助于乳腺癌细胞的干细胞性，并且 PAF 的药理学靶向可减少乳腺球的形成。
Cancer stem cells (CSCs) contribute to tumour heterogeneity, therapy resistance and metastasis. However, the regulatory mechanisms of cancer cell stemness remain elusive. Here we identify PCNA-associated factor (PAF) as a key molecule that controls cancer cell stemness. PAF is highly expressed in breast cancer cells but not in mammary epithelial cells (MECs). In MECs, ectopic expression of PAF induces anchorage-independent cell growth and breast CSC marker expression. In mouse models, conditional PAF expression induces mammary ductal hyperplasia. Moreover, PAF expression endows MECs with a self-renewing capacity and cell heterogeneity generation via Wnt signalling. Conversely, ablation of endogenous PAF induces the loss of breast cancer cell stemness. Further cancer drug repurposing approaches reveal that NVP-AUY922 downregulates PAF and decreases breast cancer cell stemness. Our results unveil an unsuspected role of the PAF-Wnt signalling axis in modulating cell plasticity, which is required for the maintenance of breast cancer cell stemness. Stem cells are found in many tumour types and are thought to be partially responsible for cell survival following therapy. Here, the authors show that PCNA-associated factor, PAF, contributes to stemness in breast cancer cells and pharmacological targeting of PAF reduces mammosphere formation.