HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism

Chiu, Amy P.; Tschida, Barbara R.; Sham, Tung-Ting; Lo, Lilian H.; Moriarity, Branden S.; Li, Xiaoxiao; Lo, Ronald; Hinton, David E.; Rowlands, Dewi K.; Chan, Chi-On; Mok, Daniel K. W.; Largaespada, David A.; Warner, Nadia; Keng, Vincent W.

doi:10.1158/1541-7786.mcr-18-1127

Cited by 28 publications

(25 citation statements)

References 46 publications

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“…Coincidentally, HBx may promote proliferation of liver cells by altering the expression of genes that participated in arachidonic acid metabolism 46 . Our group has reported that the integration of HBx fragment can be detected in clinical hepatocellular carcinoma tissues 31 .…”

Section: Discussionmentioning

confidence: 99%

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice

et al. 2020

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Rationale: Chronic ethanol consumption as a public health problem worldwide boosts the development of chronic liver diseases in hepatitis B virus (HBV)-infected patients. Arachidonic acid metabolite prostaglandin E2 (PGE2) activates regulatory T cells (Tregs) function. Here, we aim to investigate the underlying mechanism by which chronic ethanol consumption enriches the HBV-induced abnormal lipid metabolism and Tregs. Methods: The si-RNAs were used to weaken the expression of SWELL1 in HepG2, HepG2.2.15 and K180 cancer cell lines, followed by RNA sequencing from HepG2 cells. Arachidonic acid metabolite PGE2 and LTD4 were measured by ELISA assay in vivo and in vitro. Western blot analysis and RT-qPCR were used to examine HBx and SWELL1 and transcriptional factor Sp1 in clinical HCC samples and cell lines. The effect of chronic ethanol consumption on Tregs was tested by flow cytometry in HBV-Tg mice. The splenic Tregs were collected and analyzed by RNA sequencing. Results: The cooperative effect of ethanol and HBV in abnormal lipid metabolism was observed in vivo and in vitro . The depression of SWELL1 (or HBx) resulted in the reduction of lipid content and arachidonic acid metabolite, correlating with suppression of relative gene atlas. Ethanol and SWELL1 elevated the levels of PGE2 or LTD4 in the liver of mice and cell lines. Interestingly, the ethanol modulated abnormal lipid metabolism through activating HBx/Sp1/SWELL1/arachidonic acid signaling. Chronic ethanol consumption remarkably increased the population of PBL Tregs and splenic Tregs in HBV-Tg mice, consistently with the enhanced expression of PD-L1 in vivo and in vitro . Mechanically, RNA-seq data showed that multiple genes were altered in the transcriptomic atlas of Tregs sorting from ethanol-fed mice or HBV-Tg mice. Conclusion: The chronic ethanol intake enriches the HBV-enhanced abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activates Tregs in mice.

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Section: Discussionmentioning

confidence: 99%

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice

et al. 2020

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“…Growing evidence showed that the PHLPP family members could suppress the tumorigenesis, because of their involvements in the blockage of growth factor‐induced signaling pathway by the attenuation of AKT signaling . FOXO1 was also highlighted to be a downstream target of AKT signaling to suppress tumor development . Huang et al reported that PHLPP2 displayed an important effect on the invasiveness of BC cells by the regulation of lncRNA MEG3/miR‐27a axis .…”

Section: Discussionmentioning

confidence: 99%

LncRNA MBNL1‐AS1 represses cell proliferation and enhances cell apoptosis via targeting miR‐135a‐5p/PHLPP2/FOXO1 axis in bladder cancer

et al. 2019

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LncRNAs have been shown to play essential roles in bladder cancer (BC) progress.Our microarrays of clinical samples firstly screened that lncRNA muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) was poorly expressed in BC tissues. However, its biological function in BC remains not well understood. Here we examined the clinical correlations with MBNL1-AS1 in BC patients. Then, 5673 and T24 cell lines were employed to investigate the role of MBNL1-AS1 in the proliferation and apoptosis of BC cells in vitro and in vivo. Furthermore, miR-135a-5p (miR-135a)/PHLPP2/FOXO1 axis was focused to explore its regulatory mechanism in BC.The results showed that MBNL1-AS1 was significantly downregulated in bladder tumor tissues, and associated with BC progression. In vitro, MBNL1-AS1 knockdown increased the number of viable cells and bromodeoxyuridine-positive cells, accelerated cell cycle, and dysregulated proliferative regulators (Ki67, p21, p27, and Cyclin D1) in BC cells. The apoptotic cells and the cleavages of caspase-3/9 were reduced in MBNL1-AS1-silenced BC cells. Overexpression of MBNL1-AS1 had opposite effects on BC cell proliferation and apoptosis. Moreover miR-135a was demonstrated to interact with MBNL1-AS1, and inhibiting miR-135a reversed the effects of shMBNL1-AS1 on BC cells. The downstream effectors (PHLPP2 and FOXO1) were positively regulated by MBNL1-AS1, but negatively regulated by miR-135a. Similar results were also observed in xenograft tumors. In conclusion, this study firstly suggests that MBNL1-AS1 acts as a tumor suppressor of BC by targeting miR-135a/PHLPP2/FOXO1 axis, providing a novel insight for BC diagnosis and treatment. K E Y W O R D S bladder cancer, FOXO1, MBNL1-AS1, miR-135a-5p, PHLPP2 | 725 WEI Et al.

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“…Secondly, Akt also enhanced MDM2-mediated ubiquitination leading to p53 (TP53) degradation [ 87 ] and catalyzed the nuclear localization and stabilization of BCL3 by phosphorylation [ 79 ], where BCL3 is the aforementioned transcription coregulator having been proven to interact with NF-κB so as to facilitate its transcriptional ability. Moreover, it even caused nuclear exclusion and cellular dysfunctions of FoxO proteins through phosphorylation and repression [ 88 ]. Therefore, as the identified target genes of FoxO proteins in the core host/pathogen cross-talk pathways, BNIP3, BMI1, SOD2, and cyclin-dependent kinase inhibitor 1 (CDKN1A) encoding p21, might probably be down-regulated.…”

Section: Resultsmentioning

confidence: 99%

Investigating Core Signaling Pathways of Hepatitis B Virus Pathogenesis for Biomarkers Identification and Drug Discovery via Systems Biology and Deep Learning Method

2020

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Hepatitis B Virus (HBV) infection is a major cause of morbidity and mortality worldwide. However, poor understanding of its pathogenesis often gives rise to intractable immune escape and prognosis recurrence. Thus, a valid systematic approach based on big data mining and genome-wide RNA-seq data is imperative to further investigate the pathogenetic mechanism and identify biomarkers for drug design. In this study, systems biology method was applied to trim false positives from the host/pathogen genetic and epigenetic interaction network (HPI-GEN) under HBV infection by two-side RNA-seq data. Then, via the principal network projection (PNP) approach and the annotation of KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, significant biomarkers related to cellular dysfunctions were identified from the core cross-talk signaling pathways as drug targets. Further, based on the pre-trained deep learning-based drug-target interaction (DTI) model and the validated pharmacological properties from databases, i.e., drug regulation ability, toxicity, and sensitivity, a combination of promising multi-target drugs was designed as a multiple-molecule drug to create more possibility for the treatment of HBV infection. Therefore, with the proposed systems medicine discovery and repositioning procedure, we not only shed light on the etiologic mechanism during HBV infection but also efficiently provided a potential drug combination for therapeutic treatment of Hepatitis B.

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HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism

Cited by 28 publications

References 46 publications

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice

Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice

LncRNA MBNL1‐AS1 represses cell proliferation and enhances cell apoptosis via targeting miR‐135a‐5p/PHLPP2/FOXO1 axis in bladder cancer

Investigating Core Signaling Pathways of Hepatitis B Virus Pathogenesis for Biomarkers Identification and Drug Discovery via Systems Biology and Deep Learning Method

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