title: Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan. bori45@gunma-u.ac.jp.
authors: Takehiko
authors: T
authors: Yokobori
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Pinjie
authors: P
authors: Bao
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan. mfukuchi@saitama-med.ac.jp.
authors: Minoru
authors: M
authors: Fukuchi
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Bolag
authors: B
authors: Altan
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Daigo
authors: D
authors: Ozawa
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors: Susumu
authors: S
authors: Rokudai
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Tuya
authors: T
authors: Bai
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Yuji
authors: Y
authors: Kumakura
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Hiroaki
authors: H
authors: Honjo
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Keigo
authors: K
authors: Hara
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Makoto
authors: M
authors: Sakai
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Makoto
authors: M
authors: Sohda
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Tatsuya
authors: T
authors: Miyazaki
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Munenori
authors: M
authors: Ide
authors: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors: Masahiko
authors: M
authors: Nishiyama
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Tetsunari
authors: T
authors: Oyama
authors: Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
authors: Hiroyuki
authors: H
authors: Kuwano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein