title: High expression of HuR in cytoplasm, but not nuclei, is associated with malignant aggressiveness and prognosis in bladder cancer.
abstract: BACKGROUND
  Human antigen R (HuR) regulates the stability of mRNA and is associated with cell proliferation, angiogenesis, and lymphangiogenesis. However, the clinical significance and pathological role of HuR in bladder cancer remains unclear. The main objective of this investigation was to clarify the relationships between HuR expression and clinical significance and cancer cell proliferation, angiogenesis, lymphangiogenesis, and expressions of cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-A, -C, and -D.
  
  
  METHODS
  All expressions were examined by immunohistochemical techniques in 122 formalin-fixed specimens of bladder cancer patients. HuR expression was evaluated separately with cytoplasmic and nuclear staining. Cell proliferation, angiogenesis and lymphangiogenesis were measured as the percentage of Ki-67-positive cell (proliferation index, PI), CD34-stained vessels (microvessel density, MVD), and D2-40-stained vessels (lymph vessel density, LVD). Relationships between each HuR expression and clinicopathological features, prognosis, and expressions of COX-2 and VEGFs were analyzed by multi-variate analyses. HuR expression was also investigated in 10 mice of N-Butyl-N-[4-hydroxybutil] nitrosamine (BBN) induced bladder cancer model.
  
  
  RESULTS
  In human tissues, high cytoplasmic expression was seen in 5% and 25.4% of normal and cancer cells, respectively. Nuclear HuR expression bore no significant relationship to any pathological features. However, cytoplasmic HuR expression appeared positively associated with pT stage and grade (P<0.001). In mouse tissues, similar trends were confirmed. Cytoplasmic expression correlated with PI, MVD, and LVD, as well as expression of VEGF-A and -C, but not VEGF-D. High cytoplasmic expression of HuR was a significant predictor of metastasis and cause-specific survival, and was identified as a prognostic correlative factor for metastasis (hazard ratio, 4.75; P = 0.028) in a multivariate analysis model that included pathological features.
  
  
  CONCLUSIONS
  Cytoplasmic HuR appears to play important roles in cell proliferation, progression, and survival of bladder cancer patients. Its expression was associated with angiogenesis, lymphangiogenesis, and expressions of VEGF-A and -C.
authors.affiliation: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. int.doc.miya@m3.dion.ne.jp
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Miyata
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sagara
authors.forename: Kensuke
authors.initials: K
authors.lastname: Mitsunari
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuo
authors.forename: Kojiro
authors.initials: K
authors.lastname: Ohba
authors.forename: Hideki
authors.initials: H
authors.lastname: Sakai
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D009389:Neovascularization, Pathologic; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D