Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
PLoS One. 2013 Sep 2;8(9):e72846. doi: 10.1371/journal.pone.0072846. eCollection 2013.
Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the biggest obstacle in curing HCC is its high metastasis potential. Alteration of p53 is the most frequent genetic change found in HCC. Although the biological function of p53 in tumor initiation and progression has been well characterized, whether or not p53 is implicated in metastasis of HCC is largely unknown. In this study, we analyzed the potential functions of p53 in epithelial-mesenchymal transition (EMT) and metastasis of HCC cells. Both insulin- and TGF-β1-induced changes of critical EMT markers were greatly enhanced by p53 knockdown in HCC cells. The insulin- and TGF-β1-stimulated migration of HCC cells were enhanced by p53 knockdown. Furthermore, in vivo metastasis of HCC cells using different mouse models was robustly enhanced by p53 knockdown. In addition, we found that p53 regulation on EMT and metastasis involves β-catenin signaling. The nuclear accumulation and transcriptional activity of β-catenin was modulated by p53. The enhanced EMT phenotype, cell migration and tumor metastasis of HCC cells by p53 knockdown were abrogated by inhibiting β-catenin signal pathway. In conclusion, this study reveals that p53 plays a pivotal role in EMT and metastasis of HCC cells via its regulation on β-catenin signaling.
肝细胞癌 (HCC) 是最恶性的肿瘤之一，治愈 HCC 的最大障碍是其高转移潜能。p53 的改变是 HCC 中发现的最常见的遗传变化。尽管 p53 在肿瘤起始和进展中的生物学功能已经得到很好的描述，但 p53 是否参与 HCC 的转移在很大程度上尚不清楚。在这项研究中，我们分析了 p53 在肝癌细胞上皮-间充质转化 (EMT) 和转移中的潜在功能。胰岛素和 TGF-β1 诱导的关键 EMT 标志物的变化在 HCC 细胞中被 p53 敲低大大增强。胰岛素和 TGF-β1 刺激的 HCC 细胞迁移也被 p53 敲低增强。此外，使用不同的小鼠模型，p53 敲低显著增强了 HCC 细胞的体内转移。此外，我们发现 p53 对 EMT 和转移的调节涉及 β-连环蛋白信号。β-连环蛋白的核积累和转录活性受 p53 调节。p53 敲低通过抑制 β-连环蛋白信号通路，使 HCC 细胞的 EMT 表型、细胞迁移和肿瘤转移增强。总之，这项研究揭示了 p53 通过其对 β-连环蛋白信号的调节，在 HCC 细胞的 EMT 和转移中发挥关键作用。
