Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells

Liu, Zhixin; Dai, Xuechen; Wang, Tianci; Zhang, Chengcheng; Zhang, Wenjun; Zhang, Wei; Zhang, Qi; Wu, Kailang; Liu, Fang

doi:10.1016/j.canlet.2017.04.017

Cited by 47 publications

(47 citation statements)

References 42 publications

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“…On the other hand, information of the oncogenicity of HBsAg is still limited. Recently, it had been reported that PreS1 activated the expressions of CSC markers CD133, CD117, and CD90 in normal hepatocytes and HCC cells, indicating the new role of PreS1 in the appearance and self-renewal of CSC during HCC development 17 .…”

Section: Discussionmentioning

confidence: 99%

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

Anfuso

El-Khobar

et al. 2018

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 99%

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

Anfuso

El-Khobar

et al. 2018

Sci Rep

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“…HBx, however, is not the only HBV protein related to a stem-like phenotype. The viral PreS1 protein induces CD133, CD117 and CD90 expression in cancer cells, leading to an increase in sphere formation, migration, tumorigenesis and tumor growth in nude mice [206]. Other studies have suggested that HBV-positive cells have increased Wnt pathway activity, mediated by upregulation of EpCAM after loss of PCR2 function, leading to the expression of CSCs markers and resulting in poor prognosis [207].…”

Section: Hepatitis B and C Viral Infections In Hcc Initiation And Cscmentioning

confidence: 99%

The Cancer Stem Cell in Hepatocellular Carcinoma

Schulte

López-Gil

Sáinz

et al. 2020

Cancers

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The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

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“…SOX2 is also targeted by miR-126, which can inhibit cell proliferation in HCC cells [14]. In a previous study, it was revealed that HBV could induce the production of cancer stem cells (CSCs)-related markers (CD133, CD117, and CD90) and CSCs-related genes (Klf4, SOX2, Nanog, c-Myc, and Oct4) and facilitate the self-renewal of CSCs in human hepatoma cells [15]. The level of SOX2 in normal liver is much lower comparing to that in HBV and alpha fetoprotein (AFP)-positive HCC tissues.…”

Section: Introductionmentioning

confidence: 99%

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

Yang

et al. 2020

Viruses

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Hepatitis B virus (HBV) replication is controlled by four promoters (preS1, preS2, Cp, and Xp) and two enhancers (EnhI and EnhII). EnhII stimulates Cp activity to regulate the transcriptions of precore, core, polymerase, and pregenomic RNAs, and therefore, EnhII/Cp is essential for the regulation of HBV replication. This study revealed a distinct mechanism underlying the suppression of EnhII/Cp activation and HBV replication. On the one hand, the sex determining region Y box2 (SOX2), a transcription factor, is induced by HBV. On the other hand, SOX2, in turn, represses the expression levels of HBV RNAs, HBV core-associated DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg), thereby playing an inhibitory role during HBV replication. Further studies indicated that SOX2 bound to the EnhII/Cp DNA and repressed the promoter activation. With the deletion of the high mobility group (HMG) domain, SOX2 loses the ability to repress EnhII/Cp activation, viral RNA transcription, HBV core-associated DNA replication, HBsAg and HBeAg production, as well as fails to enter the nucleus, demonstrating that the HMG domain is required for the SOX2-mediated repression of HBV replication. Moreover, SOX2 represses HBsAg and HBeAg secretion in BALB/c mice sera, and attenuates HBV 3.5 kb RNA transcription and hepatitis B virus core protein (HBc) production in the liver tissues, demonstrating that SOX2 suppresses HBV replication in mice. Furthermore, the results revealed that the HMG domain was required for SOX2-mediated repression of HBV replication in the mice. Taken together, the above facts indicate that SOX2 acts as a new host restriction factor to repress HBV replication by binding to the viral EnhII/Cp and inhibiting the promoter activation through the HMG domain.

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Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells

Cited by 47 publications

References 42 publications

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

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

The Cancer Stem Cell in Hepatocellular Carcinoma

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

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