P53 and proliferating cell nuclear antigen (PCNA) expression in non‐tumoral liver diseases

Abstract

The tumor suppressor gene p53 is known to be involved in the negative regulation of cell growth. Proliferating cell nuclear antigen (PCNA), which is a nuclear protein and a component of the DNA replication process, is also involved in growth regulation. Both have been studied as progression markers in various tumors including hepatocellular carcinoma. In the present study, the aberrant p53 protein and PCNA expressions in non-tumoral liver diseases were investigated. Using monoclonal antibodies anti-p53 (D07-DAKO) and anti-PCNA (PC10-DAKO), 149 samples were stained, including 10 normal and 10 tumoral control liver tissues. p53 Overexpression was detected in 52 specimens (35%) whereas PCNA positivity was found in 96 (64%). There were 21 different pathological entities but most of the positive samples could be grouped into four types of diseases; namely, non-specific reactive hepatitis, steatohepatitis, chronic hepatitis and cirrhosis. Statistical analyses performed on these groups revealed that p53 positivity was found to be significantly higher in steatohepatitis (P < 0.05), while PCNA positivity did not show any statistical significance. The number of samples showing both p53 and PCNA positivity was 42 but their coexistence was not found to be significant. Certain cytological alterations like nuclear pleomorphism, steatosis and cholestasis, in addition to necroinflammatory activity, were evaluated for their possible impact on p53 and/or PCNA positivity. Necroinflammatory activity in steatohepatitis and steatosis in chronic hepatitis was found to be significant for p53 positivity (P < 0.05). In contrast, nuclear pleomorphism in non-specific reactive hepatitis was found to be significant for PCNA positivity (P < 0.05).

p53 Involvement in the Pathogenesis of Fatty Liver Disease

“…Although others have reported that p53 activation itself coincides with fatty liver in humans (28), this is the first report to describe the role of p53 in the mechanisms of hepatocellular injury accompanied by hepatic steatosis.…”

p53 immunocytochemistry and TP53 gene mutations in patients with chronic hepatitis C virus (HCV) infection.

“…Studies on TP53 alterations in normal liver samples demonstrated a linear relationship between incidence of mutations in the codon 249 and the extent of exposure to AFB1 [35]. Akyol et al in 21 different pathological entities of non-tumoral liver, demonstrated overexpression of p53 protein in 35% specimens, significantly more frequent in patients with steatohepatitis [32]. Studies in non-tumorous tissues of patients with Wilson's disease and hemochromatosis documented higher frequency of genetic aberrations (transversions and transitions) in both codons 249 and 250 of TP53 in the patients, as compared to healthy controls [34].…”

“…Few studies have dealt with incidence of genetic aberrations in TP53 in patients with non-neoplastic liver pathology or with risk factors prompting development of HCC (e.g. chronic viral infections) or the reports relate to selected exons of TP53 [32,34,35,40]. No mutations in the codon 249 were detected in North American patients with chronic hepatitis and/or liver cirrhosis as compared to 5/6 positive samples of non-neoplastic liver from Mozambican patients (HBV infection and AFB1 exposure) [40].…”

“…Most of investigators are of the opinion that genetic alterations in TP53 are related to rather late stages of hepatocellular carcinogenesis, which are common for various etiologies of chronic hepatitis [29,31]. Few reports only indicate that overexpression of p53 and mutations of TP53 may manifest themselves also in non-neoplastic hepatic lesions [26,[32][33][34], and upon exposure to AFB1 presence of 249 SER TP53 mutation is also detected [35]. Still no ideal molecular marker of various HCC developmental stages is available for epidemiological and diagnostic studies even if suitability is stressed of plasma tests for the presence of TP53 mutations, including quantitative studies (qSOMA) [9,11].…”

Synergistic Effects of Jerusalem Artichoke in Combination with Pegylated Interferon Alfa-2a and Ribavirin Against Hepatic Fibrosis in Rats

“…Importantly, it was shown before that p53 is involved in the molecular mechanisms leading to liver injuries (Blight et al, 2003;Schafer et al, 2003). Indeed, patients with various inflammatory liver diseases were found to accumulate p53 protein (Akyol et al, 1999;Panasiuk et al, 2006;Attallah et al, 2009). It has been also reported that p53 serum level was elevated in HBV-related cirrhosis patients (Shahnazari et al, 2014).…”