PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling.
PAD1 promotes epithelial-mesenchymal transition and metastasis in triple-negative breast cancer cells by regulating MEK1-ERK1/2-MMP2 signaling.
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PAD1通过调节MEK1-ERK1/2-MMP2信号促进三阴性乳腺癌细胞上皮间质转化和转移
DOI：
10.1016/j.canlet.2017.08.019
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发表时间：
2017-11-28
期刊：
影响因子：
9.7
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Qin H;Liu X;Li F;Miao L;Li T;Xu B;An X;Muth A;Thompson PR;Coonrod SA;Zhang X
肽精氨酸脱亚胺酶1 （PAD1）催化瓜氨酸化蛋白，其活性与表皮角化有关。然而，PAD1在包括乳腺癌在内的肿瘤发生中的作用尚未被探索。在这里，我们首次发现PAD1在人类三阴性乳腺癌（TNBC）中过表达。在培养细胞和异种移植小鼠模型中，PAD1缺失或抑制可降低细胞增殖，抑制上皮-间质转化，并阻止MDA-MB-231细胞转移。这些变化与MMP2/9表达的急剧下降相关。此外，PAD1沉默后，ERK1/2和P38 MAPK信号通路被激活。在PAD1敲除细胞中使用MEK1/2抑制剂可显著恢复MMP2的表达，而抑制P38的激活仅能略微提高MMP9的水平。随后，我们发现PAD1与MEK1相互作用并使其瓜氨酸化，从而破坏MEK1催化的ERK1/2磷酸化，从而导致MMP2过表达。总的来说，我们的数据表明，PAD1似乎通过调节TNBC中MEK1-ERK1/2-MMP2信号通路来促进肿瘤发生。这些结果也提出了PAD1可能作为TNBC肿瘤重要的新生物标志物的可能性，并表明PAD1特异性抑制剂可能用于治疗转移性乳腺癌。
Peptidylargininedeiminase 1 (PAD1) catalyzes protein for citrullination, and this activity has been linked to the epidermal cornification. However, a role for PAD1 in tumorigenesis, including breast cancers has not been previously explored. Here we first showed that PAD1 is overexpressed in human triple negative breast cancer (TNBC). In cultured cells and xenograft mouse models, PAD1 depletion or inhibition reduced cell proliferation, suppressed epithelial-mesenchymal transition, and prevented metastasis of MDA-MB-231 cells. These changes were correlated with a dramatic decrease in MMP2/9 expression. Furthermore, ERK1/2 and P38 MAPK signaling pathways are activated upon PAD1 silencing. Treatment with MEK1/2 inhibitor in PAD1 knockdown cells significantly recovered MMP2 expression, while inhibiting P38 activation only slightly elevated MMP9 levels. We then showed that PAD1 interacts with and citrullinates MEK1 thereby disrupting MEK1-catalyzed ERK1/2 phosphorylation, thus leading to the MMP2 overexpression. Collectively, our data indicate that PAD1 appears to promote tumorigenesis by regulating MEK1-ERK1/2-MMP2 signaling in TNBC. These results also raise the possibility that PAD1 may function as an important new biomarker for TNBC tumors and suggest that PAD1-specific inhibitors could potentially be utilized to treat metastatic breast cancer.
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影响因子：
3.8
作者：
Chang X;Han J;Pang L;Zhao Y;Yang Y;Shen Z
通讯作者：
Shen Z
影响因子：
3.5
作者：
Chavanas, S;Méchin, MC;Simon, M
通讯作者：
Simon, M
DOI：
10.1073/pnas.0407159102
发表时间：
2005-03-08
影响因子：
11.1
作者：
Lee, YH;Coonrod, SA;Stallcup, MR
通讯作者：
Stallcup, MR
影响因子：
5.7
作者：
Lin, Cheng-Wei;Shen, Shing-Chun;Chen, Yen-Chou
通讯作者：
Chen, Yen-Chou
影响因子：
5.3
作者：
Li, Pingxin;Yao, Hongjie;Wang, Yanming
通讯作者：
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