Background: Heme oxygenase-1 (HO-1) is an enzyme catalyzing the reaction of heme degradation to biliverdin, carbon monoxide and iron ions. HO-1 plays an important role in cytoprotection, angiogenesis and regulation of inflammatory response. It has been shown to facilitate the progression of many types of tumors. In our previous experiments we demonstrated that overexpression of HO-1 in tumor cells led to decrease in survival time of melanoma-bearing mice, inhibition of inflammatory reaction, and increase in tumor vascularization and number of metastases in lungs. However, role of HO-1 in tumor initiation has not been investigated yet. Therefore, the aim of this study was to elucidate the role of HO-1 in the first step of tumorigenesis, namely in tumor induction.

Methods and results: Induction of cutaneous squamous cell carcinoma (SCC) in mice, by topical chemical [7,12-dimethylbenzanthracene (DMBA) and phorbol 12-myristate 13-acetate (PMA)] application, is a multistep process involving papilloma formation and progression to carcinoma. To investigate the role of HO-1 in the tumor initiation this two-step model of chemical carcinogenesis was applied to HO-1 knockout (HO-1^-/-) and HO-1 wild type (HO-1^+/+) mice. Initiator in this process was 0.1 µM DMBA dissolved in 100 µl of acetone that was applied once to the dorsal shaved skin of each animal. Two weeks later, twice-weekly applications of PMA -5 nmol dissolved in 100 µL of acetone-to the same area began and were continued for 28 weeks. Tumor development was monitored in all mice (10-12 per group).

HO-1^-/- mice were more sensitive to DMBA/PMA treatment than their wild type littermates (40% versus 73% of alive animals at 28^th week). Moreover, tumor initiation was delayed in HO-1^+/+ animals in comparison to HO-1^-/- animals (from 4^th week to 6^th week) and all HO-1^-/- mice developed tumors till 17^th week comparing to 100% of tumor-bearing animals at 26^th week in case of HO-1^+/+ counterparts. Additionally, HO-1 knockout mice grew bigger tumors than their wild type counterparts and this tendency maintained for whole experiment. Interestingly, there were not differences in number of tumors growing on mice of different genotypes. Furthermore, preliminary data suggest some variation in proinflammatory and proangiogenic cytokines in sera samples and in tumor lysates from HO-1^-/- and HO-1^+/+ mice as measured by ELISA test. G-CSF and VEGFR-1 seemed to be upregulated in sera, whereas VEGF and KC appeared to be increased in tumor lysates from HO-1^-/- mice comparing to those from HO-1^+/+ mice. On the other hand, TNF and IL-1 showed slight upregulation in tumor lysates from HO-1^+/+ mice.

Conclusions: HO-1 appears to protect mice against SCC induced by DMBA/PMA treatment as HO-1^-/- animals developed tumors earlier than their wild type counterparts. It suggests that despite its permissive proangiogenic and prometastatic activities in the growing tumors, HO-1 can play a protective role in tumor initiation.

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