EIF4EBP1 overexpression is associated with poor survival and disease progression in patients with hepatocellular carcinoma

PLoS One. 2015 Feb 6;10(2):e0117493. doi: 10.1371/journal.pone.0117493. eCollection 2015.

Abstract

Objective: EIF4EBP1 acts as a crucial effector in mTOR signaling pathway. Studies have suggested that EIF4EBP1 plays a critical role in carcinogenesis. However, the clinical significance and biological role of EIF4EBP1 in hepatocellular carcinoma (HCC) have not been elucidated. Therefore, we aimed to investigate the clinical significance of EIF4EBP1 in HCC.

Methods: Total 128 cases of HCCs were included in this study. EIF4EBP1 expression in HCC tissues was detected by qRT-PCR, Western blot and immunohistochemistry, respectively. Then the relationships between EIF4EBP1 expression and clinical features as well as survival were analyzed.

Results: The expression level of EIF4EBP1 mRNA is significantly higher in 60% (24/40) of fresh HCC tissues than that in the matched adjacent nontumor liver (NCL) tissues (P = 0.044). Similarly, EIF4EBP1 protein is notably upregulated in 8 HCC tissues (randomly selected from the 40 HCCs) measured by Western blot and is significantly increased in another 88 paraffin-embedded HCCs (53%, 47/88) by immunohistochemistry compared with the matched NCLs (P < 0.001). EIF4EBP1 protein expression in HCC tissues is significantly correlated with serum AFP (P = 0.003) and marginally significantly associated with pathological grade (P = 0.085), tumor number (P = 0.084), tumor embolus (P = 0.084) and capsulation (P = 0.073). Patients with higher EIF4EBP1 protein expression have a much worse 5-year overall survival (40.3% vs 73.6%) and 5-year disease-free survival (33.0% vs 49.0%) than those with low expression. Furthermore, Cox regression analysis shows that EIF4EBP1 protein is an independent prognostic factor for overall survival (HR, 2.285; 95% CI, 1.154-4.527; P = 0.018) and disease-free survival (HR, 1.901; 95% CI, 1.067-3.386; P = 0.029) in HCC patients.

Conclusions: Our results demonstrate for the first time that EIF4EBP1 mRNA and protein are markedly up-regulated in HCC tissues, and the protein overexpression is significantly associated with poor survival and progression, which provide a potential new prognostic marker and therapeutic target for HCC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adolescent
  • Adult
  • Aged
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / physiopathology*
  • Cell Cycle Proteins
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Humans
  • Liver / metabolism
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / mortality
  • Liver Neoplasms / physiopathology*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Up-Regulation
  • Young Adult
  • alpha-Fetoproteins / analysis

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Phosphoproteins
  • RNA, Messenger
  • alpha-Fetoproteins

Grants and funding

This work was supported by a grant (No: 81171891) from the National Natural Science Foundation of China (http://www.nsfc.gov.cn/) and partly supported by the Research Fund of National Key Laboratory of Oncology in South China (http://skl.sysucc.org.cn/). The grants were awarded to HYW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.