Hepatic SATB1 induces paracrine activation of hepatic stellate cells and is upregulated by HBx

Gong, Jin; Tu, Wei; Han, Jian; He, Jianzhong; Liu, Jingmei; Han, Ping; Wang, Yunwu; Li, Mengke; Liu, Mei; Liao, Jiazhi; Tian, Dean

doi:10.1038/srep37717

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…However, in contrast to HCV, the direct involvement of HBV infection in HSC activation remains less defined. A recent study showed that the HBV encoded x protein (HBx) induces overexpression of the special AT-rich binding protein 1 (SATB1) in hepatocytes, which in turn promotes the activation and proliferation of HSCs through the secretion of CTGF and PDGF [193]. Moreover, Liu et al observed that HBV can transiently infect and replicate in cultured HSCs in-vitro and that production of HBV S protein (HBs) affects their proliferation and expression of collagen type I [194].…”

Section: Chronic Hepatitis Bmentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

755

440

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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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Section: Chronic Hepatitis Bmentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

755

440

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“…HBx induces severe lipid accumulation in HBx-Tg hybrid mice [38], and alters the production of ECM by modulating the expression of membrane-type matrix metalloproteinase-1 and fibronectin [53,54]. More convincing evidence is the induction of liver fibrosis in HBV and HBx Tg mice exposed to carbon tetrachloride (CCl4) [55][56][57]. Gong et al [57] reported that SATB1 expression is significantly up-regulated in liver fibrotic tissues from HBV chronic patients and HBV Tg mouse model, and knockdown of SATB1 in the liver significantly alleviates the fibrosis induced by CCl4 exposure in the HBV-Tg mouse model.…”

Section: Hbx Enhances the Development Of Liver Fibrosis In Tg Micementioning

confidence: 99%

“…More convincing evidence is the induction of liver fibrosis in HBV and HBx Tg mice exposed to carbon tetrachloride (CCl4) [55][56][57]. Gong et al [57] reported that SATB1 expression is significantly up-regulated in liver fibrotic tissues from HBV chronic patients and HBV Tg mouse model, and knockdown of SATB1 in the liver significantly alleviates the fibrosis induced by CCl4 exposure in the HBV-Tg mouse model. Increased expression of SATB1 in hepatocytes enhances the activation and proliferation of hepatic stellate cells (HSCs) by secreting connective tissue growth factor (CTGF), Interleukin-6 (IL-6) and platelet derived growth factor-A (PDGF-AA).…”

Section: Hbx Enhances the Development Of Liver Fibrosis In Tg Micementioning

confidence: 99%

“…Necrosis is followed by progressive fibrosis. As mentioned above, liver fibrosis in transgenic mice for HBV and HBx is induced by exposure to CCl4 [55][56][57]. CCl4 treatment is widely applied to produce liver fibrosis in normal mice and rats since this model most closely resembles clinical human liver cirrhosis among the different experimental models of liver fibrosis [76][77][78].…”

Section: Hbx Enhances the Development Of Liver Fibrosis In Tg Micementioning

confidence: 99%

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Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein

2020

Lab Anim Res

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The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11-18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.

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“…We then designed a series of in vitro and in vivo studies to observe whether HBV induced HCC progression via enhancement of the expression and secretion of ENPP2. Finally, since in liver tissue HBV infection not only transforms host cell hepatocytes and activates HSC through viral antigens (Martin-Vilchez et al, 2008;Zan et al, 2013;Gong et al, 2016;Zhang et al, 2020) and possibly through ENPP2 from hepatocytes (Kaffe et al, 2017), we analyzed the role of activated HSC (aHSC) in HBV-related HCC progression. These data can improve our understanding of the molecular mechanisms in HBV-related HCC malignancy.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

Deng

Chen

Zhou

et al. 2021

Front. Mol. Biosci.

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Background: Hepatitis B virus (HBV) infection is a major risk factor causing hepatocellular carcinoma (HCC) development, but the molecular mechanisms are not fully elucidated. It has been reported that virus infection induces ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) expression, the latter participates in tumor progression. Therefore, the aim of the present study was to investigate whether HBV induced HCC malignancy via ENPP2.Methods: HCC patient clinical data were collected and prognosis was analyzed. Transient transfection and stable ectopic expression of the HBV genome were established in hepatoma cell lines. Immunohistochemical staining, RT-qPCR, western blot, and ELISA assays were used to detect the expression and secretion of ENPP2. Finally, CCK-8, colony formation, and migration assays as well as a subcutaneous xenograft mouse model were used to investigate the influence of HBV infection, ENPP2 expression, and activated hepatic stellate cells (aHSCs) on HCC progression in vitro and in vivo.Results: The data from cancer databases indicated that the level of ENPP2 was significant higher in HCC compared within normal liver tissues. Clinical relevance analysis using 158 HCC patients displayed that ENPP2 expression was positively correlated with poor overall survival and disease-free survival. Statistical analysis revealed that compared to HBV-negative HCC tissues, HBV-positive tissues expressed a higher level of ENPP2. In vitro, HBV upregulated ENPP2 expression and secretion in hepatoma cells and promoted hepatoma cell proliferation, colony formation, and migration via enhancement of ENPP2; downregulation of ENPP2 expression or inhibition of its function suppressed HCC progression. In addition, aHSCs strengthened hepatoma cell proliferation, migration in vitro, and promoted tumorigenesis synergistically with HBV in vivo; a loss-function assay further verified that ENPP2 is essential for HBV/aHSC-induced HCC progression.Conclusion: HBV enhanced the expression and secretion of ENPP2 in hepatoma cells, combined with aHSCs to promote HCC progression via ENPP2.

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Hepatic SATB1 induces paracrine activation of hepatic stellate cells and is upregulated by HBx

Cited by 14 publications

References 41 publications

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein

Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

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