p38-regulated FOXC1 stability is required for colorectal cancer metastasis
p38-regulated FOXC1 stability is required for colorectal cancer metastasis
复制标题
p38 调节的 FOXC1 稳定性是结直肠癌转移所必需的
DOI：
10.1002/path.5362
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发表时间：
2020
影响因子：
7.3
通讯作者：
Zhang Honghe
中科院分区：
文献类型：
--
作者：
Zhang Yi;Liao Yan;Chen Chaoyi;Sun Wenjie;Sun Xiaohui;Liu Yuan;Xu Enping;Lai Maode;Zhang Honghe
叉头盒C1（FOXC 1）异常表达促进多种人类恶性肿瘤的肿瘤转移然而，FOXC 1在大肠癌转移中的上游调控方式和下游分子机制尚不清楚。在本文中，我们描述了一个系统的分析FOXC 1的表达和预后的CRC进行我们的临床数据和公共数据库，这表明FOXC 1上调CRC样本中与预后不良显着相关。FOXC 1敲低抑制迁移和侵袭，而FOXC 1过表达在体外和体内引起相反的表型。MMP 10、SOX 4和SOX 13是FOXC 1促进结直肠癌转移的靶基因，MMP 10是FOXC 1的直接靶基因和介导基因。有趣的是，FOXC 1的Ser 241和Ser 272被确定为与p38和磷酸化相互作用的关键位点，这是维持FOXC 1蛋白稳定性的关键。此外，FOXC 1被蛋白磷酸酶2A去磷酸化，并被p38磷酸化，这通过抑制泛素化来维持FOXC 1蛋白的稳定性。p38的表达与FOXC 1和MMP 10的表达相关，间接表明FOXC 1受p38 MAPK的调节。因此，FOXC 1被强烈认为是CRC中的促转移基因，通过转录激活MMP 10、SOX 4和SOX 13; p38与FOXC 1的Ser 241和ser 272位点相互作用并磷酸化，通过抑制泛素化和降解来维持其稳定性。总之，p38介导的FOXC 1蛋白的稳定性有助于CRC的转移效应。© 2019大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
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 phenotypein vitroandin vivo. Furthermore,MMP10,SOX4andSOX13were verified as the target genes of FOXC1 for promoting CRC metastasis.MMP10was 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 activatingMMP10,SOX4andSOX13; 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.