Pathological significance and prognostic implications of heme oxygenase 1 expression in non‑muscle‑invasive bladder cancer: Correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX‑2

Matsuo,Tomohiro; Miyata,Yasuyoshi; Mitsunari,Kensuke; Yasuda,Takuji; Ohba,Kojiro; Sakai,Hideki

doi:10.3892/ol.2016.5416

Pathological significance and prognostic implications of heme oxygenase 1 expression in non‑muscle‑invasive bladder cancer: Correlation with cell proliferation, angiogenesis, lymphangiogenesis and expression of VEGFs and COX‑2

Authors:
- Tomohiro Matsuo
- Yasuyoshi Miyata
- Kensuke Mitsunari
- Takuji Yasuda
- Kojiro Ohba
- Hideki Sakai
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Affiliations: Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852‑8501, Japan
Published online on: November 22, 2016 https://doi.org/10.3892/ol.2016.5416
Pages: 275-280

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Abstract

Heme oxygenase 1 (HO-1) is a stress‑response protein and its expression is associated with malignant potential and poor prognosis in several types of cancer. The present study investigated the association between HO‑1 expression levels and the pathological features, clinical outcomes and other associated factors in patients with non‑muscle‑invasive bladder cancer (NMIBC). HO‑1 expression was evaluated using immunohistochemistry in 147 formalin‑fixed tissue specimens. The proliferation index, microvessel density, lymph vessel density and expression of cyclooxygenase (COX)‑2 and vascular endothelial growth factor (VEGF)‑A, ‑C, and ‑D were also investigated. Correlations among variables were analyzed by multivariate analysis. Survival was assessed using Kaplan‑Meier survival curves and multivariate statistics. HO‑1 expression levels in high‑grade and pT1 tumors were significantly higher compared with low‑grade and pTa tumors, and were correlated with the proliferation index (P<0.001), lymph vessel density (P=0.021) and COX‑2 expression levels (P=0.003). The proliferation index and COX‑2 expression levels were also identified as independent contributing factors in multivariate models. Kaplan‑Meier survival curves associated HO‑1 expression with a poor prognosis in metastasis‑free (P=0.047) and cause‑specific survival (P=0.017), but not with urinary tract recurrence (P=0.231). Furthermore, HO‑1 expression was identified by multivariate analysis to be a significant predictor for cause‑specific survival (hazard ratio, 4.08; 95% confidence interval, 1.06‑15.66; P=0.004). HO‑1 has an important role in the malignant aggressiveness of NMIBC and its expression is associated with cause‑specific survival. HO‑1‑associated activities are regulated by cancer cell proliferation, lymphangiogenesis and COX‑2. The results suggest that HO‑1 may be a potential therapeutic target and a useful predictive prognostic factor in patients with NMIBC.

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