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Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma

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

Abstract

Background

Transcription factor prospero homeobox 1 (PROX1) has been identified as a master regulator of lymphangiogenesis associated with metastasis. Although PROX1 expression has been investigated in several cancers, its clinical significance remains controversial and needs further validation. In this study, we investigated the clinical and functional significance of PROX1 and PROX1 regulator hypoxia-inducible factor 1α (HIF1α) in esophageal squamous cell carcinoma (ESCC).

Methods

A total of 117 samples from ESCC patients were analyzed for PROX1, HIF1α, and E-cadherin expression by immunohistochemistry; correlation with clinicopathological characteristics was determined. PROX1 function was evaluated in PROX1 small interfering RNA (siRNA)-transfected human ESCC cells in vitro by assessing cell proliferation and migration.

Results

PROX1 expression was higher in ESCC than in normal tissues. Patients with higher PROX1 expression (n = 26) had increased nuclear accumulation of HIF1α (p = 0.004) and more advanced metastasis, both lymph node (N factor; p = 0.09) and hematogenous (M factor; p = 0.04), than those with lower PROX1 expression (n = 91). In addition, high PROX1 and HIF1α expression correlated with low levels of E-cadherin, an epithelial cell marker. Analysis of overall and cancer-specific survival indicated that elevated PROX1 expression was significantly correlated with poor prognosis (p = 0.0064). PROX1 downregulation in ESCC cells inhibited cellular proliferation and migration (p < 0.05). Hypoxia restored PROX1 levels that were reduced by PROX1-specific siRNA.

Conclusion

Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.

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Acknowledgment

This work was supported by the Promotion Plan for the platform of Human Resource Development for Cancer and New Paradigms–Establishing Centers for Fostering Medical Researchers of the Future; programs of the Ministry of Education, Culture, Sports, Science and Technology of Japan; Gunma University Initiative for Advanced Research (GIAR); and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS; Grant Numbers 21591690, 22591450, 23591857, 15K10085, and 15K20902).

Disclosure

Masahiko Nishiyama has received a research Grant from Yakult Honsha Co. Ltd.

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    Authors and Affiliations

    1. Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan

      Takehiko Yokobori MD, PhD, Susumu Rokudai PhD & Masahiko Nishiyama MD, PhD

    2. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan

      Pinjie Bao MSc, Minoru Fukuchi MD, PhD, Bolag Altan MD, PhD, Daigo Ozawa MD, PhD, Tuya Bai MSc, Yuji Kumakura MD, Hiroaki Honjo MD, Keigo Hara MD, Makoto Sakai MD, PhD, Makoto Sohda MD, PhD, Tatsuya Miyazaki MD, PhD & Hiroyuki Kuwano MD, PhD, FACS

    3. Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Japan

      Munenori Ide MD, PhD & Tetsunari Oyama MD, PhD

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    Correspondence to Takehiko Yokobori MD, PhD or Minoru Fukuchi MD, PhD.

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    Takehiko Yokobori and Pinjie Bao contributed equally to this work.

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    Yokobori, T., Bao, P., Fukuchi, M. et al. Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 22 (Suppl 3), 1566–1573 (2015). https://doi.org/10.1245/s10434-015-4831-6

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