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The E2F Transcription Factor 1 Transactives Stathmin 1 in Hepatocellular Carcinoma

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

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.

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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).

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Authors and Affiliations

  1. Institute of Biomedical Science, National Sun Yat-sen University, Kaohsiung, Taiwan

    Yi-Ling Chen MS, Chien-Feng Li MD, Kuo-Chan Horng MS, Wen-Ren Wu MS & Yow-Ling Shiue PhD

  2. Department of Surgery, Chi-Mei Foundation Medical Center, Tainan, Taiwan

    Yih-Huei Uen MD

  3. Department of Electrical Engineering, Southern Taiwan University, Tainan, Taiwan

    Yih-Huei Uen MD

  4. Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan

    Chien-Feng Li MD & Li-Ching Wu PhD

  5. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan

    Chien-Feng Li MD

  6. Division of Physiology, Livestock Research Institute, Council of Agriculture, Executive Yuan, Tainan, Taiwan

    Lih-Ren Chen PhD

  7. Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan

    Lih-Ren Chen PhD

  8. The Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

    Hong-Yu Tseng MS

  9. Department of Pathology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Hsuan-Ying Huang MD

  10. Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan

    Yow-Ling Shiue PhD

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  1. Yi-Ling Chen MS
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Correspondence to Yow-Ling Shiue PhD.

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Chen, YL., Uen, YH., Li, CF. et al. The E2F Transcription Factor 1 Transactives Stathmin 1 in Hepatocellular Carcinoma. Ann Surg Oncol 20, 4041–4054 (2013). https://doi.org/10.1245/s10434-012-2519-8

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  • DOI: https://doi.org/10.1245/s10434-012-2519-8

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