Expressão nuclear de IGF-1R (insulin-like growth factor-1 receptor) e sua associação com parâmetros clínico-patológicos e desfechos clínicos em portadores de carcinoma hepatocelular

Abstract

Introduction: hepatocellular carcinoma (HCC), the most common primary tumor of the liver, ranks as the sixth most commonly diagnosed malignancy and the third leading cause of cancer deaths in the world. Despite the therapeutic advances, the prognosis remains poor, which reflects the need to better understand the complex mechanisms involved in the carcinogenesis of this neoplasm. IGF-1R (Insulin-like Growth Factor-1 Receptor) is a transmembrane receptor with tyrosine kinase domains, which acts, together with its ligands, in physiological growth as well as in pathological processes. In hepatocarcinogenesis, IGF- 1R activation can trigger intracellular signaling cascades, which lead to events necessary for the initiation, promotion and development of cancer. Current evidence points to another characteristic of IGF-1R, which stands it out among other receptors: its ability to translocate to the nucleus, which could allow the modulation of growth events at a level of genomic control, contributing to neoplastic transformation. Clarifying the role of IGF-1R in HCC may contribute to a better understanding of this complex disease. Objective: this study aims to evaluate the nuclear expression of IGF-1R in samples of hepatocellular carcinoma submitted to liver transplantation or partial liver resection, and to investigate its association with clinicopathological parameters and clinical outcomes. Methodology: an immunohistochemical evaluation of the nuclear expression of IGF-1R was performed in samples from liver explants or partial surgical resections, between the years 2000 to 2020, for the treatment of HCC at the Hospital das Clínicas da Universidade Federal de Minas Gerais (HC-UFMG). Medical records were reviewed to collect clinical data and specimen slides were reviewed to collect pathological data. Results: of the patients included in the study (n=111), the main etiologies of the chronic liver disease were hepatitis C virus (44.1%), hepatitis B virus (16.2%), ethanolic (16.2%) %) and cryptogenic (17.1%). IGF-1R expression was demonstrated in the nucleus of tumor cells and in the adjacent cirrhotic parenchyma. In univariate analysis, a higher nuclear expression of IGF-1R was observed in HCC than in cirrhosis (p < 0.001). and in moderately/poorly differentiated tumors (p < 0.001), a higher nuclear expression was also demonstrated, in cirrhosis, in cases of hepatitis B (p = 0.002). In the multivariate model, higher nuclear expression of IGF-1R was observed in the tumor than in cirrhosis (p<0.001) and higher nuclear expression in tumors classified as moderately/poorly differentiated (p<0.001). However, no statistically significant association was observed between the presence of immunoexpression and cases of cirrhosis caused by HBV (p=0.999). No association was observed between clinical outcomes and other variables with the nuclear expression of IGF-1R in the tumor or in the area of cirrhosis (p > 0.05). Discussion: data show greater nuclear expression of IGF-1R in HCC than in adjacent cirrhotic parenchyma, suggesting that its translocation may be one of the initial events in hepatocarcinogenesis. Despite the lack of association with long-term clinical outcomes, receptor expression is independently associated with the degree of differentiation, which is a histopathological parameter of poor prognosis. However, further studies are needed to further assess the association with different etiologies, given the heterogeneity of the disease.