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Cluster of Differentiation 166 (CD166) Regulated by Phosphatidylinositide 3-Kinase (PI3K)/AKT Signaling to Exert Its Anti-apoptotic Role via Yes-associated Protein (YAP) in Liver Cancer
被引:48
作者:
Ma, Lifang
[1
]
Wang, Jiayi
[1
]
Lin, Jiafei
[2
]
Pan, Qiuhui
[3
]
Yu, Yongchun
[3
]
Sun, Fenyong
[1
]
机构:
[1] Tongji Univ, Dept Clin Lab Med, Shanghai Peoples Hosp 10, Shanghai 200072, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Dept Clin Lab Med, Ruijin Hosp, Shanghai 200025, Peoples R China
[3] Tongji Univ, Dept Cent Lab, Shanghai Peoples Hosp 10, Shanghai 200072, Peoples R China
关键词:
Akt PKB;
CREB;
Hepatocellular Carcinoma;
Membrane Proteins;
Signal Transduction;
INDEPENDENT PROGNOSTIC MARKER;
ORGAN SIZE CONTROL;
HIPPO PATHWAY;
HEPATOCELLULAR-CARCINOMA;
MUTUAL INTERACTION;
COLORECTAL-CANCER;
BREAST-CANCER;
CELLS;
EXPRESSION;
PHOSPHORYLATION;
D O I:
10.1074/jbc.M113.524819
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Background: CD166 is overexpressed and regarded as a valuable prognostic marker in tumors. Results: An autoregulatory feedback between PI3K/AKT and CD166 was revealed, and YAP was identified as a CD166 downstream effecter. Conclusion: CD166 is regulated by PI3K/AKT to exert its anti-apoptotic role via YAP. Significance: The relationship between CD166 and YAP provides new therapeutic insights into liver cancer. Cluster of differentiation 166 (CD166 or Alcam) is a cell surface molecule that can be greatly induced in liver cancer cells after serum deprivation, suggesting its role in influencing cell survival. However, whether and how CD166 acts as an anti-apoptotic regulator needs to be further investigated. Here, we report that gene silencing of CD166 promoted apoptosis via down-regulation of Bcl-2 in liver cancer cells. PI3K/AKT signaling was found to up-regulate CD166 expression independently of transcription. We also revealed that CD166 promoted both AKT expression and activity, thus providing a novel positive regulatory feedback between PI3K/AKT signaling and CD166. Moreover, Yes-associated protein (YAP) was identified as a CD166 downstream effecter, which can partly rescue CD166 knockdown-induced apoptosis and reduced in vivo cancer cell growth. Mechanically, CD166 modulated YAP expression and activity through at least two different ways, transcriptional regulation of YAP through cAMP-response element-binding protein and post-transcriptional control of YAP stability through inhibition to AMOT130. We also showed that CD9 enhanced CD166-mediated regulation of YAP via a mechanism involving facilitating CD166-CD166 homophilic interaction. Tissue microarray analysis revealed that CD166 and YAP were up-regulated and closely correlated in liver cancer samples, demonstrating the importance of their relationship. Taken together, this work summarizes a novel link between CD166 and YAP, explores the interplay among related important signaling pathways, and may lead to more effective therapeutic strategies for liver cancer.
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页码:6921 / 6933
页数:13
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