FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition.
FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition.
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DOI：
10.18632/oncotarget.13786
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发表时间：
2017-01-03
期刊：
影响因子：
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通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Dong T;Zhang Y;Chen Y;Liu P;An T;Zhang J;Yang H;Zhu W;Yang X
上皮间质转化（EMT）程序对于上皮细胞癌进展和纤维化疾病至关重要。 FOXO1 影响广泛的生理和病理过程。然而，FOXO1 抑制 EMT 的机制尚不完全清楚。在这项研究中，我们证明FOXO1过表达在体外抑制细胞运动和侵袭性，并在体内抑制肺转移。此外，我们发现FOXO1可以逆转EMT程序。在肝细胞癌 (HCC) 细胞系中，通过 siRNA 沉默 FOXO1 可增强间质标记物的表达并降低上皮标记物的表达。与这些发现一致的是，FOXO1 过度表达产生了相反的效果。此外，我们发现 HCC 细胞中 FOXO1 水平与 EMT 诱导剂（包括 Snail、Slug、ZEB1、ZEB2 和 Twist1）的水平呈负相关。免疫共沉淀和免疫组织化学测定揭示了 FOXO1 和 ZEB2 之间的相互作用。双荧光素酶报告基因测定和 ChIP 测定进一步证明 FOXO1 与 ZEB2 启动子结合。总之，这些发现表明 FOXO1 过度表达或 ZEB2 抑制可能是治疗 HCC 的潜在治疗策略。
The epithelial-to-mesenchymal transition (EMT) program is critical for epithelial cell cancer progression and fibrotic diseases. FOXO1 influences a broad range of physiological and pathological processes. However, the mechanism by which FOXO1 inhibits EMT is not fully understood. In this study, we demonstrated that FOXO1 overexpression inhibited cell motility and invasiveness in vitro and inhibited lung metastasis in vivo. In addition, we found that FOXO1 couldreverse the EMT program. FOXO1 silencing by siRNA in hepatocellular carcinoma (HCC) cell lines enhanced the expression of mesenchymal markers and decreased the expression of the epithelial markers. Consistent with these findings, FOXO1 overexpression exerted opposite effects. Furthermore, we found that FOXO1 levels were inversely correlated with the levels of EMT inducers, including Snail, Slug, ZEB1, ZEB2 and Twist1 in HCC cells. Co-immunoprecipitation and immunohistochemistry assays revealed that an interaction between FOXO1 and ZEB2. A dual-luciferase reporter assay and a ChIP assay further demonstrated that FOXO1 binds to the ZEB2 promoter. Together, these findings suggest that FOXO1 overexpression or ZEB2 inhibition might be potential therapeutic strategies for treating HCC.