Análise do efeito do etanol sobre a expressão de proteínas de diferenciação do epitélio escamoso no esôfago de camundongos BALB/c

Abstract

Esophageal cancer (EC) is one of the ten most common and aggressive cancers worldwide and the developing countries, including Brazil, are among the most incident regions . Despite recent advances in anticancer therapies, less than 10% of the patients with this disease have a survival rate higher than five years after diagnosis and this is a consequence of late diagnosis, since the symptoms only appear in advanced stages. Because of this background there is a big search for methods and diagnostic biomarkers that enable the detection of the disease in early stages and thus increase patient survival. The discrimination between tumor and normal mucosa can be done endoscopically, however, for early detection of esophageal tumors it would be important to discriminate healthy mucosa from precursor lesions, such as dysplasia. A typical difference between normal tissue and dysplasia is the loss of cellular differentiation, suggesting that differentiation markers may be potential targets to be used as biomarkers for cancer early detection. Cytokeratins (CK) and esophagin (SPRR3) are involved in cell differentiation in squamous epithelium. SPRR3 has been studied as a potential biomarker for the detection of tumors in their initial stages of development. In CE it has been described a loss of SPRR3 expression compared to healthy mucosa. Furthermore, it has been shown that the combined analysis of the expression of the two variants of SPRR3 (SPRR3-v1 and SPRR3- v2) is able to discriminate the esophageal mucosa from healthy individuals from the tumors and adjacent mucosa from patients with high sensitivity and specificity. Besides, a significant association was found between lower expression of SPRR3-v2 and alcohol consumption. This finding led to the hypothesis that alcohol can lead to carcinogenesis by stimulating proliferation and/or differentiation loss of squamous epithelium and thereby contribute to the tumor development . To test this hypothesis we conducted an experimental model using BALB/c mice treated daily with ethanol at different concentrations for different time intervals. We analyzed animal toxicity and pathological alterations in the esophageal epithelium. Furthermore, we analyzed the expression profile of proteins involved in cellular differentiation and proliferation that could suggest changes in the esophageal epithelium induced by ethanol, which were SPRR3, CK5/8 and CK14 and Ki67. Inflammation was the only histological abnormality found, however, occurred randomly and can t therefore be associated with ethanol. Changes in the expression pattern of the proteins analyzed were found in inflamed areas. However, most of the samples showed no histological changes nor alterations in protein expression, suggesting that in the esophageal epithelium of BALB/c ethanol is not capable of inducing proliferation and/or loss of cell differentiation.