Journal
ONCOLOGY LETTERS
Volume 13, Issue 1, Pages 275-280Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ol.2016.5416
Keywords
heme oxygenase 1; non-muscle-invasive bladder cancer; cell proliferation; angiogenesis; lymphangiogenesis; vascular endothelial growth factor; cyclooxygenase-2
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Funding
- Japanese Society for the Promotion of Science [2546487, 26462415]
- Grants-in-Aid for Scientific Research [26462415] Funding Source: KAKEN
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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 pTl 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-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.1
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