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.

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

“…However, HO-1 expression was not observed to be associated with VEGF expression, as determined by univariate analysis. This result conflicts with the results of previous studies (17,35), which reported that VEGF, particularly VEGF-C and -D, were demonstrated to induce lymphangiogenesis. Therefore, HO-1 may stimulate lymphangiogenesis through mechanisms independent of VEGF signaling.…”

“…Concordant with previous reports (17,34), HO-1 expression is significantly and independently associated with COX-2 expression, which was determined using a multivariate model that included various other pathological features. However, HO-1 expression was not observed to be associated with VEGF expression, as determined by univariate analysis.…”

“…A previous study reported that HO-1 expression levels are significantly associated with malignant aggressiveness and prognosis in patients with bladder cancer (17). However, the prognostic value of HO-1 expression requires further investigation.…”

“…However, to the best of our knowledge, this study is the first to demonstrate that HO-1 expression levels are correlated with lymphangiogenesis. The association between HO-1 expression and lymphangiogenesis has only previously been investigated in bladder cancer (17), and further studies are required. The current study demonstrated that HO-1 expression levels are not correlated with angiogenesis, contradictory to the results of previous reports (29).…”

High Glucose Promotes Tumor Invasion and Increases Metastasis-Associated Protein Expression in Human Lung Epithelial Cells by Upregulating Heme Oxygenase-1 via Reactive Oxygen Species or the TGF-β1/PI3K/Akt Signaling Pathway

“…Previous studies have demonstrated that heme oxygenase-1 (HO-1) is up-regulated in malignancies and subsequently regulates tumor aggressiveness and various cancer-related factors [12,13]. Inducible HO-1 belongs to a member of the heat shock protein family, which catalyzes the rate-limiting step of heme degradation into bilirubin, carbon monoxide (CO) and ferrous iron.…”