Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model

Anfuso, Beatrice; El-Khobar, Korri Elvanita; Ie, Susan Irawati; Avellini, Claudio; Radillo, Oriano; Raseni, Alan; Tiribelli, Claudio; Sukowati, Caecilia

doi:10.1038/s41598-018-31406-5

Cited by 13 publications

(24 citation statements)

References 16 publications

(22 reference statements)

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“…The quantification of serum ALT, AST, and LDH in all 56 animals was shown in Table 1 . As we had previously reported 14 , HBV-TG animals had a significantly higher level of serum ALT (186 ± 145 vs 47 ± 20 IU/L), AST (233 ± 133 vs 131 ± 79 IU/L), and LDH (1453 ± 339 vs 925 ± 243 IU/L) compared to WT, indicating a progressive hepatic damage in these mice.…”

Section: Resultssupporting

confidence: 72%

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Hyaluronic acid inhibition by 4-methylumbelliferone reduces the expression of cancer stem cells markers during hepatocarcinogenesis

Sukowati

Anfuso

Fiore

et al. 2019

Sci Rep

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Hyaluronic acid (HA) is a glycosaminoglycan of extracellular matrix related to cell surface which interacts with various cell types. To understand the role of HA during hepatocarcinogenesis, we assessed the effect of the inhibition of HA deposition and its association with heterogeneous hepatocellular carcinoma (HCC) cells. In this study, we used transgenic mice C57BL/6J-Tg(Alb1HBV)44Bri/J (HBV-TG) and normal C57BL/6 J (WT) for in vivo study, while HCC cells Huh7 and JHH6 as in vitro models. Both models were treated with an HA inhibitor 4-methylumbelliferone (4MU). We observed that 4MU treatments in animal model down-regulated the mRNA expressions of HArelated genes Has3 and Hyal2 only in HBV-TG but not in normal WT. As observed in vivo, in HCC cell lines, the HAS2 mRNA expression was down-regulated in Huh7 while HAS3 in JHH6, both with or without the presence of extrinsic HA. Interestingly, in both models, the expressions of various cancer stem cells (CD44, CD90, CD133, and EpCAM) were also decreased. Further, histological analysis showed that 4MU treatment with dose 25 mg/kg/day reduced fibrosis, inflammation, and steatosis in vivo, in addition to be pro-apoptotic. We concluded that the inhibition of HA reduced the expressions of HArelated genes and stem cells markers in both models, indicating a possible modulation of cells-to-cells and cells-to-matrix interaction. Hepatocellular carcinoma (HCC) is a major health problem, being the second most common cause of cancer-related death worldwide 1. More than 50% HCC cases are related to chronic hepatitis B virus (HBV) infection and chronic HBV carriers have a 100-fold relative risk for developing HCC, with an annual incidence rate of 2-6% in cirrhotic patients 2. One of the main characteristics during hepatocarcinogenesis is the disturbance in the liver architecture, shown by the accumulation of extracellular matrix (ECM) in the liver parenchyma. Hyaluronic acid (hyaluronan, HA) is a linear, large and ubiquitous non-sulfated glycosaminoglycan of the ECM 3. HA is found in almost all tissues but it is especially increased in those with active cell proliferation, regeneration, and repair, such as embryonic, inflamed, and tumor stroma tissues 4,5. It is one of the markers of fibrosis in liver diseases 6,7 and high preoperative serum HA levels can be used to predict poor prognosis in patients with HCC after hepatic resection 8. Previously published studies in various diseases models cancers had shown the relevance of HA blocking by 4-methylumbelliferone (4MU). 4MU is a derivate of 7-hydroxycoumarin (umbelliferones), substances present in

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Section: Resultssupporting

confidence: 72%

“…Our previous study showed early liver inflammation caused by the HBsAg accumulation together with an increased expression of the markers of hematopoietic stem cells markers in the liver. The progression of liver damage up-regulated different CSC populations, such as EpCAM and CD133 14 .…”

Section: Discussionmentioning

confidence: 99%

Hyaluronic acid inhibition by 4-methylumbelliferone reduces the expression of cancer stem cells markers during hepatocarcinogenesis

Sukowati

Anfuso

Fiore

et al. 2019

Sci Rep

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“…The expression of several markers such as CD133, EpCAM, and CK19 were significantly increased along liver injury. Further, there was a significant correlation between CSC markers and diagnosis [21] . Furthermore, it was recently demonstrated that PreS1 of the S gene activated the expressions of CSC markers CD133, CD117, and CD90 in normal hepatocytes and HCC cells.…”

Section: Hbvmentioning

confidence: 86%

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

Sukowati¹,

Reyes²,

Tell³

et al. 2019

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Chronic infection of hepatitis B virus (HBV) or/and hepatitis C virus (HCV) is one of major risk factors in the development of the hepatocellular carcinoma. Recent studies had shown the capacity of viral proteins in inducing the presence of the population of so-called the cancer stem cells (CSC). The integration of HBV S and X gene in the host genome indicates its direct oncogenicity. In addition, the presence HBV and HCV proteins were shown to modulate intracellular molecular pathways and epigenetic modification. This review summarizes current literature regarding direct oncogenic properties of HBV and HCV in the initiation of CSC both in in vitro and in vivo studies.

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“…The HBsAg-transgenic mouse develops progressive hepatic damage due to chronic hepatitis until the onset of HCC as a result of accumulation of the HVB virus envelope protein (HBsAg) in hepatocytes [ 43 ]. HBsAg in hepatocytes induces liver regeneration due to induction of inflammation and the associated ROS, which impairs their ability to replicate and allows the activation of hepatic stem cells [ 44 ].…”

Section: Inflammation-related Carcinogenesis Model Of Each Organmentioning

confidence: 99%

“…HBsAg in hepatocytes induces liver regeneration due to induction of inflammation and the associated ROS, which impairs their ability to replicate and allows the activation of hepatic stem cells [ 44 ]. The inflammatory response of the liver in HBsAg transgenic mice includes activated resident immune cells, perivascular fibrosis, and varying degrees of steatosis but not advanced fibrosis or cirrhosis and then, the development of HCC [ 43 ].…”

Section: Inflammation-related Carcinogenesis Model Of Each Organmentioning

confidence: 99%

Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects

Okada

Izutsu

Goto

et al. 2021

Cancers

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Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.

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Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model

Cited by 13 publications

References 16 publications

Hyaluronic acid inhibition by 4-methylumbelliferone reduces the expression of cancer stem cells markers during hepatocarcinogenesis

Hyaluronic acid inhibition by 4-methylumbelliferone reduces the expression of cancer stem cells markers during hepatocarcinogenesis

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects

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