Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices.
Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices.
复制标题
DOI：
10.1038/oncsis.2016.29
复制
发表时间：
2016-04-18
期刊：
影响因子：
6.2
通讯作者：
Wang N
中科院分区：
文献类型：
--
作者：
Jia Q;Zhou W;Yao W;Yang F;Zhang S;Singh R;Chen J;Chen JJ;Zhang Y;Wei F;Zhang Y;Jia H;Wang N
尽管几十年来在理解恶性致瘤细胞的分子机制方面取得了重大进展，但这些致瘤细胞是什么以及控制这些恶性细胞生长的因素仍然难以捉摸。最近，我们通过在软纤维蛋白基质中培养单个癌细胞，机械地选择并培养了高度恶性和致瘤的肿瘤再生细胞（TRC），这是癌细胞的一个小亚群。然而，目前尚不清楚除了 Sox2 之外还有什么调节 TRC 的生长。在这里，我们发现核蛋白 1 (Nupr1) 是一种独立于 Sox2 的蛋白，在软纤维蛋白基质中培养的黑色素瘤、卵巢癌和乳腺癌的 TRC 中下调。 Nupr1 的表达依赖于在 Nupr1 启动子位点富集的 YAP 的核转位； YAP 受 Cdc42 介导的 F-肌动蛋白和 Lats1 相互作用控制。 Nupr1 调节肿瘤抑制因子 p53，并对独立于 Sox2 的 Nestin 和 Tert 进行负调节，促进 TRC 生长。在培养物和免疫活性小鼠中，沉默 Nupr1 会增加 TRC 生长，而 Nupr1 过表达会抑制 TRC 生长。我们的结果表明，Nupr1 是高致瘤性 TRC 生长的抑制剂，可能在癌症进展中发挥关键作用。
Despite decades of significant progress in understanding the molecular mechanisms of malignant tumorigenic cells, it remains elusive what these tumorigenic cells are and what controls the growth of these malignant cells. Recently, we have mechanically selected and grown highly malignant and tumorigenic tumor-repopulating cells (TRCs), a small sub-population of cancer cells, by culturing single cancer cells in soft fibrin matrices. However, it is unclear what regulates TRC growth besides Sox2. Here we show that nuclear protein 1 (Nupr1), a protein independent of Sox2, is downregulated in TRCs of melanoma, ovarian cancer and breast cancer cultured in soft fibrin matrices. Nupr1 expression depends on nuclear translocation of YAP that is enriched at the Nupr1 promoter sites; YAP is controlled by Cdc42-mediated F-actin and Lats1 interactions. Nupr1 regulates tumor-suppressor p53 and negatively regulates Nestin and Tert that are independent of Sox2 and promote TRC growth. Silencing Nupr1 increases TRC growth and Nupr1 overexpression inhibits TRC growth in culture and in immune-competent mice. Our results suggest that Nupr1 is a suppressor of growth of highly tumorigenic TRCs and may have a critical role in cancer progression.