HO1 EXPRESSION AND IMMUNOHISTOCHEMICAL LOCALIZATION IN A MICE MODEL OF CHEMICALLY INDUCE HEPATOCARCINOGENESIS

Heme oxygenase (HO) breaks down the pro-oxidant heme into carbon monoxide, iron, and the antioxidant biliverdin. The isoform HO1 plays an effective role to counteract oxidative damage and to control inflammation. Prolonged cellular damage due to chronic inflammation is one of the reasons leading to the development of tumors. We have previously demonstrated the role of oxidative stress in early stages of hepatocarcinogenesis (HCC) and the relevance of HO1 in this process. The aim of this work was to investigate HO1 expression and localization along the different stages of chemically induced HCC and the occurring morphological changes. To provoke sustained oxidative stress and chronic inflammation, CF1 mice received dietary p-dimethylamino-azobenzene (DAB, 0.5%, w/w) during a whole period of 14 months. HO1 expression increased along the experimental trial in morphologically normal hepatocytes in DAB treated animals. HO1 expression diminished in altered hepatic foci (AHF) and oval cells, early preneoplastic lesions. Otherwise, marked HO1 overexpression was detected in Kupffer's cells and non fixed macrophagic cells surrounding necrotic and nodular areas. Adenomas were detected after 104 days of intoxication with decreased HO1 immunostaining. In hepatocellular carcinoma (at 10 months) an inverse relationship was found between the immunohistochemical expression of HO1 and tumor differentiation degrees, which was negative in poorly differentiated tumors. These findings support the proposal of a protective role played by HO1 in oxidative stress and suggest that this protein expression would be critical in the inflammation process generated during carcinogenesis induced by chronic intoxication. Even more promising is the observation that in our experimental model of HCC down modulation of HO1 expression correlated with malignancy progression. Our data point out HO1 as a potential therapeutic target.