Expression of MAPK and PI3K/AKT/mTOR Proteins according to the Chronic Liver Disease Etiology in Hepatocellular Carcinoma

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%, p = 0.024 ) and also than cirrhotic parenchyma (0%, p = 0.004 ). SE of PI3K was more frequent in tumor than in cirrhosis ( p = 0.048 , p < 0.01 ), without differences in its tumor expression among etiologic groups p = 0.111 . 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.

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“…MAPK and EGFR signaling are other important pathways that promote the malignant behavior of HCC. Phosphorylation of MAPK signaling regulates the proliferation, differentiation, apoptosis and angiogenesis of HCC [ 44 ]. Sueangoen and Wang et al reported that EGFR is upregulated in various human cancers, and high expression of EGFR leads to dismal clinical outcomes [ 45 , 46 ].…”

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“…The development and progression of liver cancer involve BioMed Research International multiple procedures, many of which have a synergistic effect. Through a series of phosphorylation events in the MAPK and PI3K/Akt pathways, downstream signals may activate transcription factors to change the expression of proteins in important cellular processes (such as proliferation and differentiation), apoptosis, cell cycle process, tumorigenesis, tumor growth and angiogenesis [65]. MAPK and PI3K/Akt pathways may represent a promising therapeutic target or otherwise cause destructive diseases.…”

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“…Their continuous activation can promote glycolysis of tumor cells. In the pathway, AKT is a serine/threonine kinase whose expression is significantly enhanced in HCC tissues [32], which can induce the expression of HK II and the activation and phosphorylation of sphosphofructokinase-2 (PFK2) to enhance glycolysis of HCC cells [32]. Combretastatin A4 phosphate (CA4P) can also reduce HIF-1α through PI3K/AKT/mTOR signaling pathway and synergistically inhibit HCC [33].…”