title: Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development.
abstract: Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects.
  
  
  CONCLUSIONS
  Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy.
authors.affiliation: State Key Laboratory for Liver Research, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Tim Hon Man
authors.initials: TH
authors.lastname: Chan
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Bo-jian
authors.initials: BJ
authors.lastname: Zheng
authors.forename: Vincent Kwok-Man
authors.initials: VK
authors.lastname: Poon
authors.forename: Pinzhu
authors.initials: P
authors.lastname: Huang
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yuan
authors.forename: Jian-dong
authors.initials: JD
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: George Sai-wah
authors.initials: GS
authors.lastname: Tsao
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D020090:Chromosome Segregation; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D015180:Electrophoresis, Gel, Two-Dimensional; D016195:G2 Phase; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D000090324:Tumor Protein, Translationally-Controlled 1; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; D016203:CDC2 Protein Kinase; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D004265:DNA Helicases; C543585:CHD1L protein, human