Abstract
Heme oxygenase-1 (HO-1) is an enzyme contributing to the development and progression of different cancer types. HO-1 plays a role in pathological angiogenesis in bladder cancer and contributes to the resistance of this cancer to therapy. It also regulates the expression of microRNAs in rhabdomyosarcoma and non-small cell lung cancer. The expression of HO-1 may be regulated by hypoxia inducible factors (HIFs) and Nrf2 transcription factor. The expression of HO-1 has not so far been examined in relation to Nrf2, HIF-1α, and potential mediators of angiogenesis in human bladder cancer. We measured the concentration of proinflammatory and proangiogenic cytokines and the expression of cytoprotective and proangiogenic mRNAs and miRNAs in healthy subjects and patients with bladder cancer. HO-1 expression was upregulated together with HIF-1α, HIF-2α, and Nrf2 in bladder cancer in comparison to healthy tissue. VEGF was elevated both at mRNA and protein level in the tumor and in sera, respectively. Additionally, IL-6 and IL-8 were increased in sera of patients affected with urothelial bladder cancer. Moreover, miR-155 was downregulated whereas miR-200c was elevated in cancer biopsies in comparison to healthy tissue. The results indicate that the increased expression of HO-1 in bladder cancer is paralleled by changes in the expression of other potentially interacting genes, like Nrf2, HIF-1α, HIF-2α, IL-6, IL-8, and VEGF. Further studies are necessary to also elucidate the potential links with miR-155 and miR-200c.
Highlights
Bladder cancer is the 7th most common cancer in men and 17th in women, and is more frequent in well-developed regions, where 60% of all incidents occur
Our results confirm previous data showing the increased production of proinflammatory and proangiogenic cytokines in patients affected by bladder cancer, and suggesting their diagnostic importance [20,54,55,56]
IL-6 was correlated with higher clinical stage, higher recurrence rate, and reduced survival of patients with bladder cancer [58]
Summary
Bladder cancer (urothelial cancer) is the 7th most common cancer in men and 17th in women, and is more frequent in well-developed regions, where 60% of all incidents occur. Non-muscle-invasive bladder cancer is characterized by a high rate of recurrence—despite the total resection of the tumor it reappears in 75% of patients. The five-year survival rate is around 57% [1,2]. The major cause of development of bladder cancer is long-term exposure to environmental risk factors. The primary culprits are smoking, chemical compounds binding DNA (like aromatic amines), or arsenic (the metabolism of which is associated with the generation of reactive oxygen species) [2]. Recent data indicate the role of oxidative stress in the progression of bladder cancer [3]
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