title: CD166 plays a pro-carcinogenic role in liver cancer cells via inhibition of FOXO proteins through AKT.
abstract: Cluster of differentiation 166 (CD166) is a cell surface membrane protein, which is regarded as a valuable prognostic marker in several types of epithelial tumors. We previously reported that CD166 exerts its pro-carcinogenic role by enhancing YAP function in liver cancer cells. However, YAP cannot completely rescue the increased anti‑carcinogenic effects by gene silencing of CD166, whose downstream effectors require further investigation. Here, we found that knockdown of CD166 inhibits phosphorylation of anti-carcinogenic FOXO proteins. Overexpression of CD166 led, not only to a faster protein degradation rate, but also a more accumulated ubiquitination of FOXO compared to the control. Moreover, overexpression of CD166 facilitated FOXO protein localization from the nuclear fraction to the cytosolic fraction, suggesting that CD166 modulates FOXO protein stability through alteration of their subcellular localization. In addition, simultaneous overexpression of CD166 partially reversed the evoked anti-carcinogenic effects by overexpression of FOXO both in vitro and in vivo. Furthermore, CD166 knockdown‑induced anti‑carcinogenic effects and dephosphorylation of FOXO proteins were rescued by overexpression of AKT. In liver cancer tissues, we also observed that higher expression levels of CD166, phospho-AKT, total AKT and phospho‑FOXO were correlated with lower expression levels of total FOXO, suggesting that the upregulation of CD166 leads to the activation of AKT, which in turn facilitates phosphorylation and degradation of FOXO. Taken together, our data demonstrate that AKT is an inter-mediator between the upstream regulator, CD166, and downstream effector, FOXO, in liver cancer cells. Disrupting the relationship between CD166 and the AKT/FOXO axis may serve as a novel therapeutic target for liver cancer patients.
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Xun
authors.initials: X
authors.lastname: Tang
authors.affiliation: School of Public Health, Shanghai Jiaotong University, Shanghai 200025, P.R. China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Qiao
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Quihui
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D051858:Forkhead Transcription Factors; D051057:Proto-Oncogene Proteins c-akt