CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation
CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation
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CAPS1通过Snail介导的上皮间质转化促进结直肠癌转移
DOI：
10.1038/s41388-019-0740-7
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发表时间：
2019-06-06
期刊：
影响因子：
8
通讯作者：
Chen, She
中科院分区：
文献类型：
--
作者：
Zhao, Guang-Xi;Xu, Ying-Ying;Chen, She
结直肠癌（Colorectal cancer， CRC）是一种常见的消化道肿瘤，主要因转移而导致死亡率高。Ca2+依赖性分泌激活蛋白1 （CAPS1）最初被确定为重建Ca2+依赖性分泌的可溶性因子。在这项研究中，我们发现了CAPS1在结直肠癌转移中的新作用。CAPS1在结直肠癌组织中经常上调。CAPS1表达升高与结直肠癌患者转移频繁、预后不良相关。过表达CAPS1可促进CRC细胞在体外的迁移和侵袭，以及体内的肝转移，但不影响细胞增殖。CAPS1诱导上皮-间质转化（epithelial - mesenchymal transition， EMT），包括上皮标志物E-cadherin和ZO-1表达降低，上皮标志物N-cadherin和Snail表达升高。Snailknockdown逆转caps1诱导的EMT、细胞迁移和侵袭。这一结果表明，在结直肠癌中，caps1介导的EMT过程和转移需要Snail。此外，CAPS1可以与Septin2和p85 （PI3K的亚基）结合。PI3K/Akt抑制剂LY294002和wortmanin可以消除caps1诱导的Akt/GSK3β活性升高，以及蜗牛蛋白水平升高。综上所述，CAPS1通过PI3K/Akt/GSK3β/Snail信号通路介导的EMT过程促进结直肠癌转移。
Colorectal cancer (CRC) is a common gastrointestinal cancer with high mortality rate mostly due to metastasis. Ca2+-dependent activator protein for secretion 1 (CAPS1) was originally identified as a soluble factor that reconstitutes Ca2+-dependent secretion. In this study, we discovered a novel role of CAPS1 in CRC metastasis. CAPS1 is frequently up-regulated in CRC tissues. Increased CAPS1 expression is associated with frequent metastasis and poor prognosis of CRC patients. Overexpression of CAPS1 promotes CRC cell migration and invasion in vitro, as well as liver metastasis in vivo, without affecting cell proliferation. CAPS1 induces epithelial–mesenchymal transition (EMT), including decreased E-cadherin and ZO-1, epithelial marker expression, and increased N-cadherin and Snail, mesenchymal marker expression.Snailknockdown reversed CAPS1-induced EMT, cell migration and invasion. This result indicates that Snail is required for CAPS1-mediated EMT process and metastasis in CRC. Furthermore, CAPS1 can bind with Septin2 and p85 (subunit of PI3K). LY294002 and wortmanin, PI3K/Akt inhibitors, can abolish CAPS1-induced increase of Akt/GSK3β activity, as well as increase of Snail protein level. Taken together, CAPS1 promotes colorectal cancer metastasis through PI3K/Akt/GSK3β/Snail signal pathway-mediated EMT process.