CCDC88A, a prognostic factor for human pancreatic cancers, promotes the motility and invasiveness of pancreatic cancer cells.
CCDC88A, a prognostic factor for human pancreatic cancers, promotes the motility and invasiveness of pancreatic cancer cells.
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DOI：
10.1186/s13046-016-0466-0
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发表时间：
2016-12-05
期刊：
影响因子：
--
通讯作者：
Saibara T
中科院分区：
文献类型：
--
作者：
Tanouchi A;Taniuchi K;Furihata M;Naganuma S;Dabanaka K;Kimura M;Watanabe R;Kohsaki T;Shimizu T;Saito M;Hanazaki K;Saibara T
含有88A的卷曲结构域(CCDC88A)被鉴定为能够与肌动蛋白细胞骨架结合的丝氨酸/苏氨酸激酶Akt的底物。本研究旨在探讨CCDC88A在胰腺导管腺癌细胞(PDAC)迁移和侵袭中的作用。采用免疫组织化学方法检测人PDAC组织中CCDC88A的高表达是否与预后不良有关。免疫沉淀、免疫印迹和免疫细胞化学方法检测CCDC88A在PDAC细胞内的分布及其与细胞内丝氨酸/苏氨酸激酶Akt和肌动蛋白细丝的关系。蛋白芯片分析确定CCDC88A相关的细胞内信号转导通路。免疫荧光分析和Matrigel侵袭实验检测CCDC88A对细胞突起形成和PDAC细胞侵袭的影响。CDC88A在PDAC组织中的表达与总生存期显著相关。CCDC88A与外周肌动蛋白结构共同定位于PDAC细胞突起。CCDC88A基因的敲除通过减少细胞突起而抑制PDAC细胞的迁移和侵袭。尽管CCDC88A以前被报道是Akt的结合伙伴和底物，但活性Akt的水平与CCDC88A向细胞突起的移位无关。依赖于CCDC88A的促进细胞迁移和侵袭的作用不受Akt信号的调节。CCDC88A基因敲除后，PDAC细胞中磷酸化的Src和ERK1/2减少，AMPK1磷酸化增加。AMPK1基因敲除可抑制PDAC细胞的迁移和侵袭能力。综合数据提示，CCDC88A可能是预测PDAC患者预后的有用标记物，CCDC88A可能通过涉及Src和ERK1/2的磷酸化和/或AMPK1的去磷酸化的信号通路促进PDAC细胞的迁移和侵袭。CCDC88A在细胞突起中聚集，促进膜突起的形成，增加PDAC细胞的迁移和侵袭能力。本文的在线版本(doi：10.1186/s13046-0160466-0)包含补充材料，授权用户可以使用。
Coiled-Coil Domain Containing 88A (CCDC88A) was identified as a substrate of the serine/threonine kinase Akt that is capable of binding to the actin cytoskeleton. The aim of this study was to investigate the potential role of CCDC88A in the migration and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. Immunohistochemistry was performed to determine whether high CCDC88A expression in human PDAC tissues is correlated with poor prognosis. Immunoprecipitation, immunoblotting and immunocytochemistry were performed to determine the intracellular distribution of CCDC88A, and its association with the serine/threonine kinase Akt and actin-filaments in PDAC cells. Phosphoprotein array analysis was performed to determine CCDC88A-associated intracellular signaling pathways. Finally, immunofluorescence analyses and Matrigel invasion assays were performed to examine the effects of CCDC88A on the formation of cell protrusions and PDAC cell invasion. Expression of CCDC88A in PDAC tissue was significantly correlated with overall survival. CCDC88A was co-localized with peripheral actin structures in cell protrusions of migrating PDAC cells. Knockdown of CCDC88A inhibited the migration and invasiveness of PDAC cells through a decrease in cell protrusions. Although CCDC88A has been previously reported to be a binding partner and substrate of Akt, the level of active Akt was not associated with the translocation of CCDC88A towards cell protrusions. CCDC88A-dependent promotion of cell migration and invasiveness was not modulated by Akt signaling. Knockdown of CCDC88A decreased phosphorylated Src and ERK1/2 and increased phosphorylated AMPK1 in PDAC cells. Knockdown of AMPK1 inhibited the migration and invasiveness of PDAC cells. The combined data suggest that CCDC88A may be a useful marker for predicting the outcome of patients with PDAC and that CCDC88A can promote PDAC cell migration and invasion through a signaling pathway that involves phosphorylation of Src and ERK1/2 and/or dephosphorylation of AMPK1. CCDC88A was accumulated in cell protrusions, contributed to the formation of membrane protrusions, and increased the migration and invasiveness of PDAC cells. The online version of this article (doi:10.1186/s13046-016-0466-0) contains supplementary material, which is available to authorized users.
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影响因子：
4.2
作者：
Farkas, A;Szatmári, E;Krizbai, IA
通讯作者：
Krizbai, IA
影响因子：
21.3
作者：
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影响因子：
4.8
作者：
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Saibara, Toshiji
影响因子：
78.5
作者：
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通讯作者：
Shaw, Reuben J.
影响因子：
5.7
作者：
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通讯作者：
Collins SP