title: CD166 positively regulates MCAM via inhibition to ubiquitin E3 ligases Smurf1 and βTrCP through PI3K/AKT and c-Raf/MEK/ERK signaling in Bel-7402 hepatocellular carcinoma cells.
abstract: Both Cluster of Differentiation 166 (CD166) and Melanoma Cell Adhesion Molecule (MCAM) play critical roles in maintaining transformative phenotype of Hepatocellular Carcinoma (HCC) cells. However, the relationship between these two membrane proteins remains unknown. Here, we found that CD166 has a positive impact on the expression of MCAM, while MCAM has no feedback on CD166. Tissue microarray analysis (TMA) also showed a positive correlation between CD166 and MCAM. Depletion of CD166-induced anti-carcinogenic phenotype could be reversed by overexpression of MCAM, suggesting MCAM is functional important in the CD166-induced liver tumorigenesis. Furthermore, we found CD166 regulates MCAM mainly through protecting MCAM from ubiquitin-mediated protein degradation. Mechanically, CD166 down-regulated two ubiquitin E3 ligases, βTrCP and Smurf1, which play critical roles in the destability of MCAM protein. In addition, overexpression of βTrCP and Smurf1-reduced transformative phenotype could be partially reversed by MCAM, providing evidence that MCAM is a target of βTrCP and Smurf1. Moreover, we identified c-Raf/MEK/ERK signaling acts as a downstream effecter of CD166/PI3K/AKT axis to stimulate ubiquitination and destability of βTrCP and Smurf1. Taken together, we establish a model that CD166 regulates MCAM through a signaling flow from activation of PI3K/AKT and c-Raf/MEK/ERK signaling to the inhibition of potential MCAM ubiquitin E3 ligases, βTrCP and Smurf1, blockage of this signaling cascade may be useful in the treatment of CD166 and MCAM-dependent HCC.
authors.affiliation: Department of Clinical laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Xianzhen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai 200071, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: School of Public Health, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Clinical laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Laboratory Centre, Shanghai Municipal Hospital of Traditional Chinese Medicine affiliated to Shanghai TCM University, Shanghai 200071, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Clinical laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China. Electronic address: sunfenyong@126.com.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Clinical laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China; Translation Medicine of High Institute, Tongji University, Shanghai 200092, China. Electronic address: karajan2@163.com.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*; D020410:Activated-Leukocyte Cell Adhesion Molecule
chemical_list: D015703:Antigens, CD; D051929:CD146 Antigen; D015816:Cell Adhesion Molecules, Neuronal; D048049:Extracellular Signal-Regulated MAP Kinases; D005326:Fetal Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D044767:Ubiquitin-Protein Ligases; D044844:beta-Transducin Repeat-Containing Proteins; C105613:ALCAM protein, human; D020410:Activated-Leukocyte Cell Adhesion Molecule; C471644:BTRC protein, human; C497902:MCAM protein, human; C498342:SMURF1 protein, human
keywords: Apoptosis; Membrane protein; Signaling transduction; Tumorigenesis; Ubiquitination