Aberrant expression of forkhead box C1 (FOXC1) promotes tumor metastasis in multiple human malignant tumors. However, the upstream modulating mode and downstream molecular mechanism of FOXC1 in metastasis of colorectal cancer (CRC) remain unclear. Herein we describe a systematic analysis of FOXC1 expression and prognosis in CRC performed on our clinical data and public databases, which indicated that FOXC1 upregulation in CRC samples was significantly associated with poor prognosis. FOXC1 knockdown inhibited migration and invasion, whereas FOXC1 overexpression caused the opposite phenotype in vitro and in vivo. Furthermore, MMP10, SOX4 and SOX13 were verified as the target genes of FOXC1 for promoting CRC metastasis. MMP10 was demonstrated as the direct target and mediator of FOXC1. Interestingly, Ser241 and Ser272 of FOXC1 were identified as the key sites to interact with p38 and phosphorylation, which were critically required for maintaining the stability of FOXC1 protein. Moreover, FOXC1 was dephosphorylated by protein phosphatase 2A and phosphorylated by p38, which maintained FOXC1 protein stability through inhibiting ubiquitination. Expression of p38 was correlated with FOXC1 and MMP10 expression, indirectly indicating that FOXC1 was regulated by p38 MAPK. Therefore, FOXC1 is strongly suggested as a pro-metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13; p38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. In conclusion, the protein stability of FOXC1 mediated by p38 contributes to the metastatic effect in CRC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

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大肠癌转移需要p38调节的FOXC1稳定性。

前叉箱C1（FOXC1）的异常表达促进了多种人类恶性肿瘤的肿瘤转移。然而，FOXC1在结直肠癌（CRC）转移中的上游调节模式和下游分子机制仍不清楚。在这里，我们描述了对我们的临床数据和公共数据库进行的FOXC1在CRC中的表达和预后的系统分析，这表明CRC样品中FOXC1的上调与不良预后显着相关。FOXC1组合式抑制迁移和入侵，而FOXC1的过表达在体内和体外引起相反的表型。此外，还证实了MMP10，SOX4和SOX13是FOXC1促进CRC转移的靶基因。MMP10被证明是FOXC1的直接靶标和介体。有趣的是，FOXC1的Ser241和Ser272被确定为与p38和磷酸化相互作用的关键位点，这对于维持FOXC1蛋白的稳定性至关重要。此外，FOXC1被蛋白磷酸酶2A磷酸去磷酸化，并被p38磷酸化，从而通过抑制泛素化作用来维持FOXC1蛋白的稳定性。p38的表达与FOXC1和MMP10的表达相关，间接表明FOXC1受p38 MAPK调控。因此，强烈建议通过转录激活MMP10，SOX4和SOX13将FOXC1作为CRC中的促转移基因。p38与FOXC1的Ser241和ser272位点相互作用并使其磷酸化，从而通过抑制泛素化和降解来维持其稳定性。总之，p38介导的FOXC1的蛋白质稳定性有助于CRC的转移作用。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版