Abstract
Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer[1]
The cancer stem cells (CSC) theory postulates that tumor is composed by heterogeneous cells with different grades of differentiation, in which only the CSC are capable of sustaining the tumor and giving rise to proliferating but progressively differentiating cells
The origin of CSC is still uncertain but it was proposed that they may derive from the dedifferentiation of hepatocytes or by mutations occurring in the activated stem cells (SC) niche[4,5]
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer[1]. In around 80% of patients, HCC is preceded by cirrhosis or advanced fibrosis[2]. The greater majority of HBV-related HCC develops in cirrhotic liver; HBV may act as an oncogenic factor in its absence[4]. The direct oncogenic effect of HBV is related with the integration of the viral DNA sequence into the host genome; the role of viral proteins in cancer development is still unclear. The HBV-transgenic mouse C57BL/6J-TG(ALB1HBV)44BRI/J (TG) develops a progressive hepatic damage from chronic hepatitis until HCC as a consequence of the overproduction and the accumulation of the envelope protein (HBV surface antigen, HBsAg) into hepatocytes[6,7]. To understand the activation of hepatic SC compartment during liver injury and its role in the process of hepatocarcinogenesis by the insult of HBsAg, we evaluated the expression of different accepted SC markers during the progression of the disease from early hepatic inflammation until HCC
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