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.
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.
Department of Clinical Laboratory Medicine, 301 Middle Yanchang Rd., Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Lifang
L
Ma
Department of Clinical Laboratory Medicine, 301 Middle Yanchang Rd., Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: karajan2@163.com.
Jiayi
J
Wang
Department of Clinical Laboratory Medicine, Ruijin Hospital of Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
Jiafei
J
Lin
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Qiuhui
Q
Pan
Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
Yongchun
Y
Yu
Department of Clinical Laboratory Medicine, 301 Middle Yanchang Rd., Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: sunfenyong@126.com.
Fenyong
F
Sun
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis* / Q000235:genetics; D005326:Fetal Proteins / Q000096:biosynthesis* / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D020410:Activated-Leukocyte Cell Adhesion Molecule
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015816:Cell Adhesion Molecules, Neuronal; D005326:Fetal Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C088374:YAP1 protein, human
Akt PKB; CREB; Hepatocellular Carcinoma; Membrane Proteins; Signal Transduction