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Abstract
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.
Highlights
Despite decades of continuous efforts and significant progress in understanding the molecular mechanisms of malignant tumorigenic cells,[1] it remains unresolved what these tumorigenic cells are and what controls the growth and proliferation of these tumor cells
Using microarrays to screen for potential factors, we have identified nuclear protein 1 (Nupr1) that is markedly reduced in the tumor-repopulating cell. *Po 0.05 (TRC) in 3D soft fibrin matrices when compared with melanoma cells on two dimensional (2D) rigid plastic
To determine the impact of matrix rigidity on Nupr[1], we compared its expression in cells that are cultured on 2D rigid plastic with that in cells in 3D soft fibrin matrices
Summary
Despite decades of continuous efforts and significant progress in understanding the molecular mechanisms of malignant tumorigenic cells,[1] it remains unresolved what these tumorigenic cells are and what controls the growth and proliferation of these tumor cells. We mechanically selected tumorigenic tumor-repopulating cells (TRCs) independent of surface stem cell markers, a small sub-population of cancer cells, by culturing single cancer cells from cancer cell lines or primary tumors in three-dimensional (3D) soft fibrin matrices.[2] These TRCs exhibit highly tumorigenic and proliferative capacity and they efficiently repopulate tumors at distant organs in wild-type syngeneic and non-syngeneic mice.[2] The soft fibrin matrices promote TRC growth by facilitating Sox[2] expression.[3] the melanoma cells can significantly increase their proliferation when Sox[2] expression is only modestly increased,[3] suggesting that other factors that are regulated by matrix softness may contribute to TRC proliferation independent of Sox[2]. Using microarrays to screen for potential factors, we have identified nuclear protein 1 (Nupr1) that is markedly reduced in the TRCs in 3D soft fibrin matrices when compared with melanoma cells on 2D rigid plastic
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