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Epithelial to Mesenchymal Transition is Associated with Shorter Disease-Free Survival in Hepatocellular Carcinoma

  • Translational Research and Biomarkers
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Abstract

Background

Epithelial to mesenchymal transition (EMT) is involved in cancer cell invasion and metastasis as well as chemoresistance. Elucidation of EMT in hepatocellular carcinoma (HCC) might contribute to deeper understanding of its biology.

Methods

Overall, 100 patients with HCC, who underwent resection, were analyzed. The messenger RNA (mRNA) expression of the epithelial marker E-cadherin and the mesenchymal marker Vimentin were measured, and the EMT status of each patient was determined as follows: Vimentin/E-cadherin <2 = Epithelial (E), Vimentin/E-cadherin ≥2 = Mesenchymal (M). The correlation between these values and clinicopathological factors and prognosis were analyzed statistically. Moreover, the expression of transcription factors involved in EMT (Twist-1, Snail, Slug, Zeb-1, and Zeb-2) were measured and the role of interleukin (IL)-6 in inducing EMT and chemoresistance was examined.

Results

Patients with a mesenchymal tumor were more prone to have an earlier recurrence than those with an epithelial tumor. EMT-inducing transcription factors were more highly expressed in mesenchymal tumors than in epithelial tumors, and Twist-1 and Zeb-2 were significantly overexpressed. α-Fetoprotein (AFP) values were significantly higher in patients with epithelial tumors, and AFP-expressing HCC cell lines were more responsive to sorafenib. IL-6 expression was significantly higher in mesenchymal tumors, and knockdown of IL-6 in mesenchymal HCC cell lines increased E-cadherin expression and sensitivity to sorafenib.

Conclusions

Analysis of surgically resected tumors suggests that EMT is involved in early disease recurrence in HCC. Twist-1 and Zeb-2 might be important for inducing EMT, and IL-6 might be a potential therapeutic target for alleviating the chemoresistance of mesenchymal HCC tumors.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

    Suguru Yamada MD, PhD, FACS, Norio Okumura MD, Tsutomu Fujii MD, PhD, FACS, Hiroyuki Sugimoto MD, PhD, Shuji Nomoto MD, PhD, Shin Takeda MD, PhD & Yasuhiro Kodera MD, PhD, FACS

  2. Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA

    Lan Wei PhD, Bryan C. Fuchs PhD & Kenneth K. Tanabe MD, FACS

Authors
  1. Suguru Yamada MD, PhD, FACS
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  2. Norio Okumura MD
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  3. Lan Wei PhD
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  4. Bryan C. Fuchs PhD
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  5. Tsutomu Fujii MD, PhD, FACS
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  6. Hiroyuki Sugimoto MD, PhD
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  7. Shuji Nomoto MD, PhD
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  8. Shin Takeda MD, PhD
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  9. Kenneth K. Tanabe MD, FACS
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  10. Yasuhiro Kodera MD, PhD, FACS
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Corresponding author

Correspondence to Suguru Yamada MD, PhD, FACS.

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Yamada, S., Okumura, N., Wei, L. et al. Epithelial to Mesenchymal Transition is Associated with Shorter Disease-Free Survival in Hepatocellular Carcinoma . Ann Surg Oncol 21, 3882–3890 (2014). https://doi.org/10.1245/s10434-014-3779-2

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  • DOI: https://doi.org/10.1245/s10434-014-3779-2

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