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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma
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Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma

机译：叉头盒C1的过表达促进肿瘤转移并指示肝细胞癌的预后不良

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摘要

Recurrence and metastasis remain the most common causes of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Thus, it is critical to discover the mechanisms underlying HCC metastasis. Forkhead box C1 (FoxC1), a member of the Fox family of transcription factors, induces epithelial-mesenchymal transition (EMT) and promotes epithelial cell migration. However, the role of FoxC1 in the progression of HCC remains unknown. Here, we report that FoxC1 plays a critical role in HCC metastasis. FoxC1 expression was markedly higher in HCC tissues than in adjacent noncancerous tissues. HCC patients with positive FoxC1 expression had shorter overall survival times and higher recurrence rates than those with negative FoxC1 expression. FoxC1 expression was an independent, significant risk factor for recurrence and survival after curative resection. FoxC1 overexpression induced changes characteristic of EMT and an increase in HCC cell invasion and lung metastasis. However, FoxC1 knockdown inhibited these processes. FoxC1 transactivated Snai1 expression by directly binding to the Snai1 promoter, thereby leading to the inhibition of E-cadherin transcription. Knockdown of Snai1 expression significantly attenuated FoxC1-enhanced invasion and lung metastasis. FoxC1 expression was positively correlated with Snai1 expression, but inversely correlated with E-cadherin expression in human HCC tissues. Additionally, a complementary DNA microarray, serial deletion, site-directed mutagenesis, and a chromatin immunoprecipitation assay confirmed that neural precursor cell expressed, developmentally down-regulated 9 (NEDD9), which promotes the metastasis of HCC cells, is a direct transcriptional target of FoxC1 and is involved in FoxC1-mediated HCC invasion and metastasis. Conclusions: FoxC1 may promote HCC metastasis through the induction of EMT and the up-regulation of NEDD9 expression. Thus, FoxC1 may be a candidate prognostic biomarker and a target for new therapies.
机译：复发和转移仍然是根治性切除术后肝细胞癌（HCC）致死结果的最常见原因。因此，至关重要的是发现肝癌转移的潜在机制。叉头盒C1（FoxC1）是Fox转录因子家族的成员，它诱导上皮-间质转化（EMT）并促进上皮细胞迁移。但是，FoxC1在肝癌进展中的作用仍然未知。在这里，我们报道FoxC1在肝癌转移中起关键作用。在肝癌组织中，FoxC1的表达明显高于邻近的非癌组织。 FoxC1表达阳性的HCC患者比FoxC1表达阴性的患者具有更短的总生存时间和更高的复发率。 FoxC1表达是根治性切除术后复发和生存的独立，重要的危险因素。 FoxC1的过表达诱导EMT的特征改变以及HCC细胞侵袭和肺转移的增加。但是，FoxC1组合式抑制了这些过程。 FoxC1通过直接与Snai1启动子结合来激活Snai1表达，从而抑制E-钙粘蛋白的转录。击倒Snai1表达大大减弱了FoxC1增强的侵袭和肺转移。 FoxC1表达与Snai1表达呈正相关，但与人HCC组织中E-cadherin表达呈负相关。此外，互补的DNA芯片，序列缺失，定点诱变和染色质免疫沉淀测定证实，神经前体细胞表达的，发育下调的9（NEDD9）是促进HCC细胞转移的一种直接转录靶标。 FoxC1，并参与FoxC1介导的HCC侵袭和转移。结论：FoxC1可能通过诱导EMT和上调NEDD9表达来促进肝癌的转移。因此，FoxC1可能是候选的预后生物标志物和新疗法的目标。

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