Receptor inositol 1,4,5-trifosfato do tipo 3 participa da manutenção tumoral em carcinoma hepatocelular humano

Abstract

Hepatocellular carcinoma (HCC) accounts more than 90% of primary malignant neoplasms of the liver. Chronic liver diseases predispose to HCC, promoting the development of fibrosis, cirrhosis and changes in intracellular signal transduction. Several liver functions are regulated by the intracellular calcium (Ca2+), including proliferation and cell death. Inositol 1,4,5triphosphate receptor (ITPR) is the exclusive channel of intracellular Ca2+ release in the liver. In light of the fact that ITPR3 expression, an isoform absent in normal hepatocytes, is a common event in pathogenesis and development of HCC, our hypothesis is that established tumors maintain its expression, functioning in its progression. Here, 53 HCC liver samples and clinical data from patients affected by three different etiologies were used: hepatitis C virus (HCV), alcoholic liver disease (ALD) and cryptogenic cirrhosis (CC). Hematoxylin and Eosin (H&E), for counting mitotic figures, and immunohistochemistry for staining ITPR3 and ssDNA, were used to evaluate the intensity of this calcium channel expression and apoptotic profile, respectively. The correlation between ITPR3 and clinical parameters was evaluated by comparing the means of the ITPR3-staining intensity in the tumor and in the cirrhotic parenchyma with the clinical parameters, and percentage of apoptosis or mitosis. The results showed that the intensity of ITPR3 staining inversely correlates with the mitotic indexes, and with percentage of apoptosis in all HCC etiologies analyzed. In addition, the mitotic index significantly correlated with apoptosis. Together, these data show a compensatory intracellular event underlying hepatocarcinogenesis which involves ITPR3, where more deaths due to apoptosis lead to proliferation and tumor maintenance. Therefore, we conclude that ITPR3 expression is a common event throughout the process of hepatocarcinogenesis to tumor establishment, influencing proliferation and cell death by apoptosis.