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 2733 to 21,027) 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 5 0.037) and overall survival time of HCC patients (P 5 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;55:491-505) H epatocellular carcinoma (HCC) is the sixth most common human cancer in the world, with extremely poor prognosis and a <3% 5-year survival rate for untreated cancer.1 The ultimate cause of HCC is perhaps better understood than other types of human cancers, which is chronic liver disease (eventually leading to cirrhosis), particularly chronic hepatitis B and C and alcoholic liver disease. Other risk factors, such as tobacco smoking, nonalcoholic steatohepatitis, and inherited metabolic diseases, have also been proposed to cause HCC, albeit at a lower frequency.2 In addition, HCC is predominantly male

A Novel Regulatory Mechanism of Pim-3 Kinase Stability and Its Involvement in Pancreatic Cancer Progression

“…TCTP was overexpressed in many human cancer tissues including liver (42), colorectal (43), prostate (44), breast (45), and lung cancer (46). Similarly, TCTP was detected in pancreatic cancer cell lines, and malignant duct epithelial cells and some normal acinar cells but not normal pancreatic duct epithelial cells adjacent to tumor foci.…”

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Promotion of mitosis. A very specific role of TCTP in cancer promotion was described by Chan et al in 2012, who studied the chromodomain helicase/ ATPase DNA-binding protein 1-like gene (CHD1L), which is a specific oncogene in human hepatocellular carcinoma (HCC) (Chan et al 2012b). They found that CHD1L acts as a transcriptional activator of TCTP and that the resulting overexpression of TCTP contributed to the mitotic defects of tumour cells.…”

“…For example, TCTP promoted cell cycle progression in pancreatic cancer cells through stabilisation of the protein kinase Pim-3 . In hepatocellular carcinoma (HCC), the oncogene CHD1L was found to drive the overexpression of TCTP, resulting in an increased number of mitotic defects (Chan et al 2012b). TCTP in turn promoted the degradation of Cdc25C during mitosis, leading to a faster mitotic exit and miss-segregation of chromosomes and consequently to chromosomal instability.…”

“…The ubiquitin-proteasome-dependent degradation of Cdc25C is an important step in mitotic progression. It was shown that in hepatocellular cancer (HCC) this step is promoted by overexpression of TCTP, leading to a faster mitotic exit and consequently to chromosome miss-segregation (Chan et al 2012b). On the other hand, TCTP itself has been found to be subject to proteasomal degradation after the first embryonic mitosis in Xenopus laevis (Kubiak et al 2008).…”

“…The activity of the cyclin-dependent kinase 1 (Cdk1) is normally maintained by Cdc25C and is required for an orderly mitotic exit. The sudden drop of Cdk1 activity caused by TCTP overexpression resulted in a faster mitotic exit and chromosome miss-segregation, which in turn led to chromosomal instability (Chan et al 2012b). The observation that TCTP is involved in regulating the degradation of Cdc25C through the ubiquitinproteasome pathway is consistent with other studies reporting a role of TCTP in regulating the ubiquitin-proteasome-dependent degradation of specific proteins (see Sect.…”