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Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
- Source :
- Hepatology (Baltimore, Md.). 55(2)
- Publication Year :
- 2011
-
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. Conclusion: 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. (HEPATOLOGY 2012)
- Subjects :
- G2 Phase
Carcinoma, Hepatocellular
Biology
CHD1L
Malignant transformation
Chromosome instability
Chromosome Segregation
Translationally-controlled tumor protein
CDC2 Protein Kinase
Biomarkers, Tumor
Humans
cdc25 Phosphatases
Electrophoresis, Gel, Two-Dimensional
Mitosis
Cyclin-dependent kinase 1
Hepatology
Liver Neoplasms
DNA Helicases
Tumor Protein, Translationally-Controlled 1
Hep G2 Cells
HCCS
Up-Regulation
DNA-Binding Proteins
Cell Transformation, Neoplastic
Mitotic exit
Cancer research
Disease Progression
Cell Division
Subjects
Details
- ISSN :
- 15273350
- Volume :
- 55
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Hepatology (Baltimore, Md.)
- Accession number :
- edsair.doi.dedup.....2910426c6bc72f9f8285f3a26434e453