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首页> 外文期刊>Cell cycle >p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells.
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p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells.

机译：p53依赖的正常胰腺上皮细胞生长，上皮-间质转化和干性的调节。

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Pancreatic acinar cells acquire in vitro a pancreatic progenitor phenotype associated with activation of p53, growth arrest and senescence. A similar program is also activated in chronic pancreatitis. To assess the mechanisms involved in this process, we cultured pancreatic acinar cells from wild-type, p53(-/-), p16(-/-) and p21(-/-) mice. Cultures from p53(-/-) mice, but not those from p16(-/-) or p21(-/-) mice, display an enhanced proliferation and can be expanded continuously for more than 20 passages. p53(-/-) cells also display features of stemness such as enhanced sphere formation, increased expression of pancreatic multipotent progenitor markers (Ptf1a, Pdx1, Cpa1, c-myc, Sox9 and Hnf1b), and of the stemness regulators Bmi1 and Klf4. Upon subculture, p53(-/-) cells undergo an epithelial-mesenchymal transition (EMT) and express high levels of vimentin and of the transcriptional regulators Snai1, Snai2, Twist, Zeb1 and Zeb2. Genetic lineage tracing unequivocally demonstrates the epithelial origin of the cells with mesenchymal phenotype. These cells express the endodermal markers Hhex, Pdx1, Sox9, Hnf1b, Foxa2, Gata6 and Sox17, and the stem cell markers c-myc, Bmi1 and Klf4. Cultures from p53(+/-) mice display intermediate levels of the transcription factors involved in EMT but do not surpass the growth arrest. Our findings support the notion that p53 controls both growth and epithelial cell differentiation in the pancreas. These observations have important implications regarding the mechanisms through which p53 inactivation in tumors may be associated with aggressive biological behavior.
机译：胰腺腺泡细胞在体外获得与p53激活，生长停滞和衰老相关的胰腺祖细胞表型。在慢性胰腺炎中也可以激活类似的程序。为了评估此过程涉及的机制，我们从野生型，p53（-/-），p16（-/-）和p21（-/-）小鼠中培养了胰腺腺泡细胞。来自p53（-/-）小鼠的培养物，而不是来自p16（-/-）或p21（-/-）小鼠的培养物，显示出增强的增殖能力，可以连续扩增20多次以上。 p53（-/-）细胞还显示干性的特征，例如增强的球体形成，胰腺多能祖细胞标记物（Ptf1a，Pdx1，Cpa1，c-myc，Sox9和Hnf1b）的表达以及干性调节因子Bmi1和Klf4。继代培养后，p53（-/-）细胞经历上皮-间质转化（EMT），并表达高水平的波形蛋白和转录调节因子Snai1，Snai2，Twist，Zeb1和Zeb2。遗传谱系追踪明确地证明了具有间充质表型的细胞的上皮起源。这些细胞表达内胚层标记物Hhex，Pdx1，Sox9，Hnf1b，Foxa2，Gata6和Sox17，以及干细胞标记物c-myc，Bmi1和Klf4。来自p53（+/-）小鼠的培养物显示参与EMT的转录因子处于中等水平，但没有超过生长停滞。我们的发现支持p53控制胰腺生长和上皮细胞分化的观点。这些观察结果对肿瘤中p53失活与侵略性生物学行为相关的机制具有重要意义。

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