Ductular reaction, cytokeratin 7 positivity, and gamma-glutamyl transferase in multistage hepatocarcinogenesis in rats

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and is characterized by multistage formation. The presence of ductular reaction, cytokeratin 7 positivity (PCK7), and increased levels of gamma glutamyltransferase (γGT) has been observed during liver carcinogenesis and contribute to tumor progression. Our goal was to evaluate the ductular reaction in multistage carcinogenesis and to correlate PCK7 and γGT levels with tumor incidence, histological characteristics, liver DNA damage index, and the expression of oxidative stress proteins. HCC was induced in 24 male Wistar rats weighing 145-150 g by chronic and intermittent exposure to 50 or 100 mg/kg diethylnitrosamine (DEN). Six control animals received only vehicle. Blood was collected to determine hepatic enzyme levels. Animals were divided into three groups: control (CO), precancerous lesions (PL), and advanced HCC. Liver samples were obtained for immunohistochemical analyses and the measurement of protein expression. Statistical analyses included Tukey's test and Pearson's correlation analyses. We observed an extensive ductular reaction in advanced HCC and a strong correlation between PCK7 and levels of γGT and the poor prognosis and aggressiveness of HCC. The extent of PCK7 and high γGT levels were associated with overexpression of inducible nitric oxide synthase (iNOS) and heat shock factor protein 1 (HSF-1). However, PCK7 and γGT levels were negatively correlated with protein expression of nuclear factor erythroid 2-related factor 2 (NRF2) and inducible heat shock protein 70 (iHSP70). These findings suggest that ductular reaction is involved in the progression of multistage hepatocarcinogenesis.

Differential expression of hepatic cancer stemness and hypoxia markers in residual cancer after locoregional therapies for hepatocellular carcinoma

“…[48] Studies showed an extensive DR in advanced HCC and a strong correlation between cytokeratin 7 expression and the poor prognosis and aggressiveness of HCC. [49] In our data, strong expression of both hepatic CSC markers (CD24 and EpCAM) and hypoxia marker (CA9) was detected in DR cells. We speculated that hypoxia might be involved in proliferative DRs, eventually contributing to the development of an aggressive HCC phenotype.…”

Diagnostic value of fibrinogen to prealbumin ratio and gamma-glutamyl transpeptidase to platelet ratio in the progression of AFP-negative hepatocellular carcinoma

“…FPR fibrinogen to prealbumin ratio, GPR gamma-glutamyl transpeptidase to platelet ratio, AFP-NHCC alpha-fetoprotein-negative hepatocellular carcinoma, AFP alpha-fetoprotein, CH chronic hepatitis, LC liver cirrhosis, BCLC Barcelona Clinic Liver Cancer elevated in metabolic-induced hepatic injury [40], was observed in this study. Salvatore et al [41] demonstrated that the level of serum GGT elevated with the process of liver carcinogenesis and promoted tumor progression in an HCC animal model of male Wistar rats. Serum levels of GGT could also help with the selection of further treatment and clinical outcomes for patients with HCC [42].…”

Two novel online nomograms for predicting the survival of individual patients undergoing partial hepatectomy for huge hepatocellular carcinoma

“…37 The current study confirmed the 2) was a significant predictor of poor survival (HR 1.765, P＜0.001), which echoed some published results consummately. [37][38][39] Though AFP level is not included as an indicator in the other four current staging or scoring systems, as a classic tumor marker for HCC, it has long been known that AFP can measure the response to hepatectomy and predict individual survival. Further, the inclusion of AFP improved the predictive performance of the current models; the C-indices of the two nomograms were 0.745 for OS and 0.738 for DFS with AFP but only 0.740 for OS and 0.737 for DFS without AFP.…”