High Expression of HuR in Cytoplasm, but Not Nuclei, Is Associated with Malignant Aggressiveness and Prognosis in Bladder Cancer

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.

Human antigen R as a predictive marker for response to gemcitabine-based chemotherapy in advanced cisplatin-resistant urothelial cancer

“…Similar findings have also been observed in patients with various malignancies, including bladder cancer (8). Therefore, the pathological role and biological characteristics of HuR in Figure 1.…”

“…Associations between HuR expression and response in second-line chemotherapy. numerous types of malignancy have been investigated in vivo and in vitro (5)(6)(7)(8)(9)(10)28). To the best of our knowledge, the first study that identified upregulated HuR expression as a significant marker for an improved response to GEM-based chemotherapy in patients with pancreatic cancer was published in 2009 (11).…”

“…HuR expression was evaluated as previously described (8). Briefly, immunohistochemical analyses were performed using formalin-fixed, paraffin-embedded tissue sections.…”

“…HuR expression was evaluated based on an immunoreactive staining score, as previously reported (8,11). HuR expression was evaluated separately in cancer cell cytoplasm and nuclei.…”

“…Various molecules that are associated with cell proliferation, migration, immune response and angiogenesis have previously been identified as targets of HuR (3)(4)(5). Increased expression levels of HuR are significantly associated with malignant aggressiveness and poor survival in various types of cancer, including urothelial cancer (UC) (6)(7)(8)(9)(10).…”