Identification of LZAP as a new candidate tumor suppressor in hepatocellular carcinoma.

State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
PLoS ONE (Impact Factor: 3.53). 10/2011; 6(10):e26608. DOI: 10.1371/journal.pone.0026608
Source: PubMed

ABSTRACT LZAP was isolated as a binding protein of the Cdk5 activator p35. LZAP has been highly conserved during evolution and has been shown to function as a tumor suppressor in various cancers. This study aimed to investigate LZAP expression and its prognostic value in hepatocellular carcinoma (HCC). Meanwhile, the function of LZAP in hepatocarcinogenesis was further investigated in cell culture models and mouse models.
Real-time quantitative PCR, western blot and immunohistochemistry were used to explore LZAP expression in HCC cell lines and primary HCC clinical specimens. The functions of LZAP in the proliferation, colony formation, cell cycle, migration, invasion and apoptosis of HCC cell lines were also analyzed by infecting cells with an adenovirus containing full-length LZAP. The effect of LZAP on tumorigenicity in nude mice was also investigated.
LZAP expression was significantly decreased in the tumor tissues and HCC cell lines. Clinicopathological analysis showed that LZAP expression was significantly correlated with tumor size, histopathological classification and serum α-fetoprotein (AFP). The Kaplan-Meier survival curves revealed that decreasing LZAP expression was associated with poor prognosis in HCC patients. LZAP expression was an independent prognostic marker of overall HCC patient survival in a multivariate analysis. The re-introduction of LZAP expression in the HepG2 and sk-Hep1 HCC cell lines significantly inhibited proliferation and colony formation in the HCC cells and induced G1 phase arrest and apoptosis of the HCC cells in vitro. Restoring LZAP expression in the HCC cell lines also inhibited migration and invasion. In addition, experiments with a mouse model revealed that LZAP overexpression could suppress HCC tumorigenicity in vivo.
Our data suggest that LZAP may play an important role in HCC progression and could be a potential molecular therapy target for HCC.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tripartite motif-containing 3 (TRIM3) is a member of the tripartite motif (TRIM) protein family and is reported to be involved in the pathogenesis of various cancers. The role of TRIM3 in hepatocellular carcinoma (HCC) is unknown; thus, the goal of this study was to explore the expression level and prognostic value of TRIM3 in HCC. The expression level of TRIM3 in HCC surgically resected tumors and corresponding nontumorous samples was detected by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. The correlation between TRIM3 expression level and the clinicopathological features and prognosis of HCC patients was also analyzed. We observed that TRIM3 expression was remarkably decreased in tumor tissue samples from HCC patients, relative to matched nontumorous tissue samples, at the mRNA (p = 0.018) and protein level (p = 0.02). Similarly, immunohistochemical analysis showed that 53.4 % of samples had low TRIM3 protein expression. Clinicopathological analysis revealed that low TRIM3 expression was significantly correlated with tumor size (p = 0.034), histological grade (p < 0.001), serum AFP (p = 0.025), and TNM stage (p = 0.021). Furthermore, Kaplan-Meier survival analysis revealed that low TRIM3 expression was associated with poor survival in HCC patients. Finally, our multivariate Cox regression analysis showed that TRIM3 expression was an independent prognostic factor for overall survival of HCC patients. In conclusion, this study suggests that TRIM3 may play a significant role in HCC progression and acts as a valuable prognostic marker and potential therapeutic target for HCC.
    Medical Oncology 08/2014; 31(8):102. DOI:10.1007/s12032-014-0102-9 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GTP binding protein overexpressed in skeletal muscle (Gem) is a Ras-related protein whose expression is induced in several cell types upon activation by extracellular stimuli. To investigate the potential roles of Gem in hepatocellular carcinoma (HCC), expression of Gem was examined in human HCC samples. Western blot analysis showed that compared with primary human hepatocytes and adjacent noncancerous tissue, significant down-regulation of Gem was found in HCC cells and tumor tissues. In addition, immunohistochemical analysis of Gem expression was investigated in 108 specimens of HCC tissues. Clinicopathological data were collected to analyze the association with Gem expression. Expression of Gem was significantly negatively correlated with histological grade (P = 0.001), tumor size (P = 0.020), and vascular invasion (P = 0.005), and Gem was also negatively correlated with proliferation marker Ki-67 (P < 0.01). More importantly, the Kaplan-Meier survival curves analysis revealed that low expression of Gem was associated with poor prognosis in HCC patients. Univariate analysis showed that Gem expression was associated with poor prognosis (P = 0.006). Multivariate analysis indicated that Gem expression was an independent prognostic marker for HCC (P = 0.007). Finally, serum starvation and release experiments showed that Gem expression was negatively related with cell proliferation. In the conclusion, our results suggested that down regulation of Gem expression was involved in the pathogenesis of hepatocellular carcinoma, and it might be a favorable independent prognostic parameter for HCC.
    Pathology - Research and Practice 11/2014; 210(11). DOI:10.1016/j.prp.2014.07.001 · 1.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Telomerase is a large ribonucleoprotein complex that contains a catalytic telomerase reverse transcriptase (TERT) and an RNA template. Telomerase activity is tightly controlled by TERT expression, which is regulated at both the transcriptional and post-translational levels. However, the detailed molecular mechanisms of telomerase regulation and function are not fully understood. To identify cofactors that contribute to telomerase regulation, we employed a yeast two-hybrid system to screen for hTERT-interacting proteins, using the hTERT T-motif as bait. We identify C53 as a novel hTERT interaction partner. We show that C53 interacts with hTERT both in vivo and in vitro. C53 depletion increases telomerase activity, and C53 overexpression inhibits telomerase activity in MCF7 cells. In addition, the C53 leucine zipper domain (amino acids 301–400) is required for interaction with hTERT. Deleting the leucine zipper domain eliminates C53 interaction with hTERT and abrogates its inhibitory effect on telomerase activity. Taken together, our results demonstrate that C53 is a novel hTERT-associated protein that negatively regulates telomerase activity.
    Chinese Science Bulletin 07/2014; 59(19):2324-2330. DOI:10.1007/s11434-014-0184-y · 1.37 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014