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Annals of Surgical Oncology

, Volume 20, Issue 12, pp 4041–4054 | Cite as

The E2F Transcription Factor 1 Transactives Stathmin 1 in Hepatocellular Carcinoma

  • Yi-Ling Chen
  • Yih-Huei Uen
  • Chien-Feng Li
  • Kuo-Chan Horng
  • Lih-Ren Chen
  • Wen-Ren Wu
  • Hong-Yu Tseng
  • Hsuan-Ying Huang
  • Li-Ching Wu
  • Yow-Ling Shiue
Translational Research and Biomarkers

Abstract

Background

Through data mining the Stanford Microarray Database, the stathmin 1 (STMN1) transcript was found to be frequently upregulated in the hepatocellular carcinoma (HCC) with low alpha-fetoprotein level. The molecular mechanism of STMN1 upregulation in HCCs remained unclear.

Methods

Quantitative RT-PCR, immunoblotting, immunohistochemistry, and transfection of expression or small hairpin RNA interference plasmids, chromatin immunoprecipitation (ChIP), and quantitative ChIP assays were performed in HCC specimens or 2 distinct HCC-derived cell lines. Dual luciferase assay and site-directed mutagenesis were applied to analyze the activities of STMN1 proximal promoter region.

Results

STMN1 mRNA and proteins were significantly associated with several clinicopathological features. High STMN1 or E2F1 immunoexpression was predictive of poor overall survival (OS) rate (P < .01). In HCC-derived cell lines, E2F1 was elevated before STMN1 mRNA during the cell cycle. Exogenous expression of E2F1 or both transcription factor DP-1 (TFDP1) and E2F1 genes induced E2F1 and STMN1 mRNA (P < .01). Knockdown of the E2F1 gene suppressed E2F1 and STMN1 mRNA and E2F1 and STMN1 protein levels (P < .05). The promoter activity of STMN1 gene increased with overexpression of both E2F1 and TFDP1 genes (P < .05); however, it decreased when mutations were introduced in the E2F1-binding sites (P < .05).

Conclusions

Upregulation of E2F1 and STMN1 proteins associate with worse outcomes in patients with HCC. E2F1 significantly correlates with STMN1 protein level in HCC lesions and in vitro transactivation assays, suggesting that STMN1 gene is transactivated by the E2F1 protein.

Keywords

E2F1 Gene E2F1 Protein Stanford Microarray Database Normal Peripheral Blood Lymphocyte E2F1 mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

The first 2 authors contributed equally. The authors thank Dr. Shu-Chun Teng (College of Medicine, National Taiwan University) for valuable discussions. This work was supported by the National Science Council, Taiwan (98-2311-B-110-001-MY3 to YL Shiue) and Chi-Mei Foundation Medical Center (CMFHR9658 to YH Uen).

Supplementary material

10434_2012_2519_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 27 kb)
10434_2012_2519_MOESM2_ESM.pdf (460 kb)
Supplementary material 2 (PDF 460 kb)

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Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Yi-Ling Chen
    • 1
  • Yih-Huei Uen
    • 2
    • 3
  • Chien-Feng Li
    • 1
    • 4
    • 5
  • Kuo-Chan Horng
    • 1
  • Lih-Ren Chen
    • 6
    • 7
  • Wen-Ren Wu
    • 1
  • Hong-Yu Tseng
    • 8
  • Hsuan-Ying Huang
    • 9
  • Li-Ching Wu
    • 4
  • Yow-Ling Shiue
    • 1
    • 10
  1. 1.Institute of Biomedical ScienceNational Sun Yat-sen UniversityKaohsiungTaiwan
  2. 2.Department of SurgeryChi-Mei Foundation Medical CenterTainanTaiwan
  3. 3.Department of Electrical EngineeringSouthern Taiwan UniversityTainanTaiwan
  4. 4.Department of PathologyChi-Mei Foundation Medical CenterTainanTaiwan
  5. 5.National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
  6. 6.Division of PhysiologyLivestock Research Institute, Council of Agriculture, Executive YuanTainanTaiwan
  7. 7.Department of BiotechnologySouthern Taiwan UniversityTainanTaiwan
  8. 8.The Institute of Basic Medical SciencesNational Cheng Kung UniversityTainanTaiwan
  9. 9.Department of PathologyChang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of MedicineKaohsiungTaiwan
  10. 10.Department of Biological SciencesNational Sun Yat-sen UniversityKaohsiungTaiwan

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