Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability

Yen, Tim Ting Chung; Yang, An-Shik; Chiu, Wen Tai; Li, Tian Neng; Wang, Lyu Han; Wu, Yi; Wang, Hui Chen; Chen, Linyi; Wang, Wen-Ching; Huang, Wenya; Chang, Chia-Wei; Chang, Ming Che; Shen, Meng‐Ru; Su, Ih Jen; Wang, Lily

doi:10.18632/oncotarget.8109

Cited by 29 publications

(31 citation statements)

References 59 publications

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“…There are other documented cases of viruses impacting centrosomes. For instance, mutated pre-hepatitis B virus particles can lead to centriole amplification through increased calcium entry [ 34 ], whereas human T cell leukemia virus type-1 (HTLV-1) causes abnormal centrosome fragmentation through the targeting of Ran-binding protein-1, leading to supernumerary centrioles [ 35 ]. Further work is needed in the case of the Flaviviridae to elucidate the mechanisms through which ZIKV and DENV alter the centriole duplication cycle.…”

Section: Resultsmentioning

confidence: 99%

Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning

et al. 2017

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Zika virus (ZIKV) causes congenital microcephaly. Although ZIKV can impair cell cycle progression and provoke apoptosis, which probably contributes to disease aetiology through depletion of neural progenitor cells, additional cellular mechanisms may be important. Here, we investigated whether ZIKV infection alters centrosome number and spindle positioning, because such defects are thought to be at the root of inherited primary autosomal recessive microcephaly (MCPH). In addition to HeLa cells, in which centrosome number and spindle positioning can be well monitored, we analysed retinal epithelial cells (RPE-1), as well as brain-derived microglial (CHME-5) and neural progenitor (ReN) cells, using immunofluorescence. We established that ZIKV infection leads to supernumerary foci containing centriolar proteins that in some cases drive multipolar spindle assembly, as well as spindle positioning defects in HeLa, RPE-1 and CHME-5 cells, but not in ReN cells. We uncovered similar phenotypes in HeLa cells upon infection with dengue virus (DENV-2), another flavivirus that does not target brain cells and does not cause microcephaly. We conclude that infection with Flaviviridae can increase centrosome numbers and impair spindle positioning, thus potentially contributing to microcephaly in the case of Zika.

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Section: Resultsmentioning

confidence: 99%

Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning

et al. 2017

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“…NeHepLxHT cells were purchased from the American Type Culture Collection (Rockville, MD, USA) and cultured in DMEM/F12 medium (Corning) supplemented with 15% FBS, 20 ng/ml epidermal growth factor, ITS Premix (5 μg/ml insulin, 5 μg/ml human transferrin, and 5 ng/ml selenic acid; BD, Franklin Lakes, NJ, USA), and 0.25 μ m dexamethasone (Sigma, St Louis, MO, USA). Stable NeHepLxHT cell lines expressing a SNAP tag (as a control) or SNAP‐tagged LHBS have been described previously . Clinical liver sections were obtained from National Cheng Kung Hospital (Tainan, Taiwan) with prior approval from the Institutional Review Board (approval number: B‐ER‐102‐154).…”

Section: Methodsmentioning

confidence: 99%

Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis

Tsai

et al. 2018

The Journal of Pathology

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Hepatitis B virus (HBV) is an aetiological factor for liver cirrhosis and hepatocellular carcinoma (HCC). Despite current antiviral therapies that successfully reduce the viral load in patients with chronic hepatitis B, persistent hepatitis B surface antigen (HBsAg) remains a risk factor for HCC. To explore whether intrahepatic viral antigens contribute directly to hepatocarcinogenesis, we monitored the mitotic progression of HBV-positive cells. Cytokinesis failure was increased in HBV-positive HepG2.2.15 and 1.3ES2 cells, as well as in HuH-7 cells transfected with a wild-type or X-deficient HBV construct, but not in cells transfected with an HBsAg-deficient construct. We show that expression of viral large surface antigen (LHBS) was sufficient to induce cytokinesis failure of immortalized hepatocytes. Premitotic defects with DNA damage and G /M checkpoint attenuation preceded cytokinesis in LHBS-positive cells, and ultimately resulted in hyperploidy. Inhibition of polo-like kinase-1 (Plk1) not only restored the G /M checkpoint in these cells, but also suppressed LHBS-mediated in vivo tumourigenesis. Finally, a positive correlation between intrahepatic LHBS expression and hepatocyte hyperploidy was detected in >70% of patients with chronic hepatitis B. We conclude that HBV LHBS provokes hyperploidy by inducing DNA damage and upregulation of Plk1; the former results in atypical chromatin structures, and the latter attenuates the function of the G /M DNA damage checkpoint. Our data uncover a mechanism by which genomic integrity of hepatocytes is disrupted by viral LHBS. These findings highlight the role of intrahepatic surface antigen as an oncogenic risk factor in the development of HCC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Recently, the ground glass hepatocytes, which harbor two HBV oncoproteins, the pre‐S mutant surface antigen and the hepatitis B X protein (HBx), have been proposed as the precursor lesions of HCC (Wu et al ., ; Yen et al ., ). HBx is an etiologic factor of HBV‐related hepatocarcinogenesis through its multiple functions in regulation of cell cycle, cell proliferation, lipid metabolism, signal transduction, and gene transcription (Arbuthnot et al ., ; Chisari et al ., ; Teng et al ., ).…”

Section: Introductionmentioning

confidence: 97%

Liver regeneration accelerates hepatitis B virus‐related tumorigenesis of hepatocellular carcinoma

et al. 2018

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Although partial hepatectomy (PH) to remove tumors provides a potential cure of hepatocellular carcinoma (HCC), long‐term survival of hepatitis B virus (HBV)‐related HCC patients after PH remains a big challenge. Early recurrence within 2 years post‐PH is associated with the dissemination of primary HCC. However, late recurrence after 2 years post‐PH is supposed due to the de novo or a secondary tumor. Since PH initiates liver regeneration (LR), we hypothesize that LR may accelerate tumorigenesis through activation of pre‐existing precancerous lesions in the remaining liver. In this study, we explored the potential role of several LR‐related factors in the de novo recurrence in a HBV X protein (HBx) transgenic mouse model receiving PH to mimic human HCC development. Following PH, we observed that tumor development was significantly accelerated from 16.9 to 10.4 months in HBx transgenic mice. The expression of suppressor of cytokine signaling (SOCS) family proteins was remarkably suppressed in livers of HBx transgenic relative to non‐transgenic mice from early to late stages after PH as compared with non‐PH mice. The expression of transforming growth factor‐β (TGF‐β)/Smad pathway, hepatocyte growth factor (HGF), Myc, signal transducer and activator of transcription 3 (STAT3), and β‐Catenin also showed a significant difference between livers of HBx transgenic and non‐transgenic mice at variable time points after PH in comparison with non‐PH mice. Taken together, our results provide an explanation for the high de novo recurrence of HBV‐related HCC after PH, probably through induction of the sequential changes of LR‐related SOCS family proteins, growth factors, and transcription factors, which may promote growth on the precancerous remnant liver.

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Hepatitis B virus PreS2-mutant large surface antigen activates store-operated calcium entry and promotes chromosome instability

Cited by 29 publications

References 59 publications

Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning

Zika virus causes supernumerary foci with centriolar proteins and impaired spindle positioning

Intrahepatic hepatitis B virus large surface antigen induces hepatocyte hyperploidy via failure of cytokinesis

Liver regeneration accelerates hepatitis B virus‐related tumorigenesis of hepatocellular carcinoma

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