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.