Expression of MAPK and PI3K/AKT/mTOR Proteins according to the Chronic Liver Disease Etiology in Hepatocellular Carcinoma
Paulo Henrique Costa Diniz, Serena Dafne do Carmo Silva, Paula Vieira Teixeira Vidigal, Marcelo Antônio Pascoal-Xavier, Cristiano Xavier Lima, Luciana Costa Faria, Teresa Cristina Abreu Ferrari
Abstract
Aims. Chronic liver disease (CLD) of different etiologies leads to hepatocellular carcinoma (HCC) by multiple mechanisms that may be translated into clinicopathological differences. We evaluated the tissue expression of the MAPK and PI3K/Akt/mTOR pathway proteins and their association with long-term outcome and other parameters, according to the etiology of the CLD, in HCC patients. Methods. Clinicopathological data from 80 patients who underwent orthotopic liver transplantation for HCC treatment in a Brazilian referral center were compared according to CLD etiology. Event (tumor recurrence or death from any cause) occurrence and event-free survival (EFS) were analyzed. Pathway protein expression was assessed by immunohistochemistry (IHQ) in both tumor and underlying cirrhosis and by RT-PCR in tumor tissue. Results. Strong expression (SE) of KRAS was more frequent in tumors arising from viral (26.8%) than the nonviral group of liver disease (7.7%, <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"> <a:mi>p</a:mi> <a:mo>=</a:mo> <a:mn>0.024</a:mn> </a:math> ) and also than cirrhotic parenchyma (0%, <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"> <c:mi>p</c:mi> <c:mo>=</c:mo> <c:mn>0.004</c:mn> </c:math> ). SE of PI3K was more frequent in tumor than in cirrhosis ( <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"> <e:mi>p</e:mi> <e:mo>=</e:mo> <e:mn>0.048</e:mn> </e:math> , <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"> <g:mi>p</g:mi> <g:mo><</g:mo> <g:mn>0.01</g:mn> </g:math> ), without differences in its tumor expression among etiologic groups <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"> <i:mfenced open="(" close=")" separators="|"> <i:mrow> <i:mi>p</i:mi> <i:mo>=</i:mo> <i:mn>0.111</i:mn> </i:mrow> </i:mfenced> </i:math> . mRNA of ERK, PI3K, and BRAF was expressed in the tumor, without differences between CLD etiologies, and there was no association with IHQ findings. Older age and microvascular invasion (MIV) were the only parameters independently associated with the event. MIV was also associated with shorter EFS. Conclusions. Hepatitis B and C virus can lead to HCC by different mechanisms compared with nonviral hepatopathy. KRAS and PI3K may have a role in carcinogenesis. The prognostic and therapeutic implications need to be investigated.