Abstract
IntroductionHuman 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.MethodsAll 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.ResultsIn 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.ConclusionsCytoplasmic 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.
Highlights
Human antigen R (HuR) regulates the stability of mRNA and is associated with cell proliferation, angiogenesis, and lymphangiogenesis
With regard to nuclear HuR expression in cancer cells, expression was high in 88 specimens (72.1%; score 2, n = 64; score 3, n = 24) and low in 34 (27.9%; score 0, n = 1; score 1, n = 33)
The present study demonstrated that cytoplasmic HuR expression was closely associated with malignant potential, tumor progression, and outcome for bladder cancer patients
Summary
Human antigen R (HuR) regulates the stability of mRNA and is associated with cell proliferation, angiogenesis, and lymphangiogenesis. HuR has been found to be involved in the regulation of angiogenesis by interacting with the transcripts of numerous angiogenesis-promoting factors, and is known to correlate with lymphangiogenesis in a variety of pathological conditions, including cancer [3,4]. Based on these facts, it has been suggested that HuR plays important roles in carcinogenesis, tumor growth, metastasis, and prognosis in malignancies. The pathological roles and prognostic value of HuR expression in cancer patients remain contentious, and the clinical significance and predictive value for prognosis in patients with bladder cancer has yet to be clarified
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