title: Heme oxygenase-1 expression is associated with tumor aggressiveness and outcomes in patients with bladder cancer: a correlation with smoking intensity.
abstract: Heme oxygenase (HO)-1 is upregulated in malignancies and, in turn, regulates other cancer-related factors. Although HO-1 expression has been associated with cigarette smoking under various pathologic conditions, little is known about their association in patients with bladder cancer. HO-1 expression was assessed in 215 formalin-fixed bladder cancer specimens by immunohistochemistry. Microvessel density, lymph vessel density (LVD), proliferation index (PI), and expression of the vascular endothelial growth factor (VEGF)-A, -C, and -D, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-2, and MMP-9 were investigated by similar methods. Multivariate analyses were performed to evaluate the pathologic role and predictive value of HO-1 expression. Our results demonstrated that HO-1 expression was positively associated with T stage, lymph node metastasis, and grade. HO-1 expression was also positively correlated with PI, LVD, and expression levels of VEGF-D, COX-2, MMP-2, and MMP-9 (P < 0.001). In addition, multivariate analyses showed that HO-1 expression positively correlated with smoking intensity. Positive HO-1 expression was a significant predictor of subsequent metastasis (P = 0.008) and poor cause-specific survival (P < 0.001). Similarly, multivariate analyses showed that HO-1 expression was a predictor of cause-specific survival (hazard ratio = 3.13, P = 0.013). In conclusion, pathologic changes of HO-1-related factors were dependent on smoking intensity. Smoking upregulated HO-1 expression, and HO-1 was associated with malignant behavior of bladder cancer. Cancer cell proliferation, lymphangiogenesis, and expression levels of VEGF-D, COX-2, and MMP-2 played important roles in these HO-1-related effects. The clinical correlations of HO-1 were regulated by a complex mechanism that depended on smoking intensity.
authors: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical, Sciences, Nagasaki, Japan. Electronic address: int.doc.miya@m3.dion.ne.jp.
authors: Yasuyoshi
authors: Y
authors: Miyata
authors: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical, Sciences, Nagasaki, Japan.
authors: Shigeru
authors: S
authors: Kanda
authors: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical, Sciences, Nagasaki, Japan.
authors: Kensuke
authors: K
authors: Mitsunari
authors: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical, Sciences, Nagasaki, Japan.
authors: Akihiro
authors: A
authors: Asai
authors: Department of Nephro-Urology, Nagasaki University Graduate School of Biomedical, Sciences, Nagasaki, Japan.
authors: Hideki
authors: H
authors: Sakai
mesh_terms: D000368:Aged; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D012907:Smoking / Q000009:adverse effects*; D016019:Survival Analysis; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology*
chemical_list: D051547:Heme Oxygenase-1