Expressão de proteínas das vias de sinalização intracelular mitogen activated protein kinases (MAPK) e PI3K/AKT/mTOR e sua associação com parâmetros clínico-patológicos e desfechos clínicos em portadores de carcinoma hepatocelular de acordo com a etiologia da hepatopatia crônica subjacente

Abstract

Background: Different etiologies of chronic liver disease (CLD) potentially lead to hepatocellular carcinoma (HCC) by multiple mechanisms, that can be translated into clinicopathological and prognostic differences. Understanding this process might improve many challenging aspects of HCC care, including identification of response predictors to treatment modalities, such as liver transplantation (LT). Thus, we evaluated the expression of proteins of MAPK and PI3K/Akt/mTOR pathways, important signalling cascades in HCC, and investigated their association with clinical and histopathological parameters, as well as long-term outcome, according to the etiology of the CLD. Methods: Demographic, clinical, laboratory and histopathological data from a cohort of 134 patients who underwent LT for HCC treatment at a referral center in Brazil were retrospectively selected and compared according to the etiological group of the underlying CLD. Event, defined as or tumor recurrence or death from any cause, and event-free survival (EFS) were analyzed. Of these, 80 were aleatory selected: 41 viral (V) (Hepatis B or C virus infection – HBV or HCV), 39 nonviral (NV) (alcohol abuse and cryptogenic) etiology. Their explanted liver was accessed for tumoral microvascular invasion (MIV) and histological grade. Moreover, expression of proteins in tumor and cirrhosis were evaluated by immunohistochemistry (IHQ) and RT-PCR was performed in tumoral tissue for quantitative mRNA expression. Results: Etiologic groups were similar regarding laboratory and clinicopathological indices. Event occurred in 37 patients (28.5%), and median EFS were 75 months (range, 24-116 months). Pathways proteins were often strongly expressed in tumors, but strong expression (SE) of KRAS was more frequent in tumor of V group (26.8%) than NV group (7.7%, p=0.024) or cirrhosis (0%, p=0.004). The SE of PI3K, in both etiologies, was higher in tumor than cirrhosis (p= 0.048 and p<0.01), but not if comparing the tumor groups (p=0.111). mRNA of ERK 1 and 2, PI3K and BRAF was expressed in tumor, without difference between etiologic groups or correspondence with IHQ findings. There was association between presence of three or less nodules and SE of KRAS, but no proteins expression was associated with E or EFS. Among the 80 patients in which complementary pathological data as well as molecular analysis were performed, greater age and MIV presence were independently associated to event ocurrence. MIV was also related to shorter EFS. Conclusion: Differences regarding clinical outcome among etiologic groups of CLD in HCC patients who underwent LT were not demonstrated and no predictor was identified. Data suggest that HBV and HCV can lead to HCC by different mechanisms comparing to NV etiology. Moreover, KRAS and PI3K could have a role on carcinogenesis, given that their strong expression was more frequent in tumor than in cirrhosis. However, prognostic and therapeutic implications of these findings need to be stablished.