m6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma.

Vascular endothelial growth factor A (VEGFA) plays a critical role as a potent angiogenesis factor and is highly expressed in hepatocellular carcinoma (HCC). Although the expression of VEGFA has been strongly linked to the aggressive nature of HCC, the specific posttranscriptional modifications that might contribute to VEGFA expression and HCC angiogenesis are not yet well understood. In this study, we aimed to investigate the epitranscriptome regulation of VEGFA in HCC. A comprehensive analysis integrating MeRIP-seq, RNA-seq, and crosslinking-immunprecipitation-seq data revealed that VEGFA was hypermethylated in HCC and identified the potential m6A regulators of VEGFA including a m6A methyltransferase complex component RBM15 and the two readers, YTHDF2 and IGF2BP3. Through rigorous cell and molecular biology experiments, RBM15 was validated as a key component of methyltransferase complex responsible for m6A methylation of VEGFA, which was subsequently recognized and stabilized by IGF2BP3 and YTHDF2, leading to enhanced VEGFA expression and VEGFA-related functions such as human umbilical vascular endothelial cells (HUVEC) migration and tube formation. In the HCC xenograft model, knockdown of RBM15, IGF2BP3, or YTHDF2 resulted in reduced expression of VEGFA, accompanied by significant inhibition of tumor growth closely associated with VEGFA expression and angiogenesis. Furthermore, our analysis of HCC clinical samples identified positive correlations between the expression levels of VEGFA and the regulators RBM15, IGF2BP3, and YTHDF2. Collectively, these findings offer novel insights into the posttranscriptional modulation of VEGFA and provide potential avenues for alternative approaches to antiangiogenesis therapy targeting VEGFA.

Broadband Photodetection of Centimeter-Scale T-Phase Gallium Telluride Grown by Molecular Beam Epitaxy.

Two-dimensional (2D) semiconductors have recently attracted considerable attention due to their promising applications in future integrated electronic and optoelectronic devices. Large-scale synthesis of high-quality 2D semiconductors is an increasingly essential requirement for practical applications, such as sensing, imaging, and communications. In this work, homogeneous 2D GaTe films on a centimeter scale are epitaxially grown on fluorphlogopite mica substrates by molecular beam epitaxy (MBE). The epitaxial GaTe thin films showed an atomically 2D layered lattice structure with a T phase, which has not been discovered in the GaTe geometric isomer. Furthermore, semiconducting behavior and high mobility above room temperature were found in T-GaTe epitaxial films, which are essential for application in semiconducting devices. The T-GaTe-based photodetectors demonstrated respectable photodetection performance with a responsivity of 13 mA/W and a fast response speed. By introducing monolayer graphene as the substrate, we successfully realized high-quality GaTe/graphene heterostructures. The performance has been significantly improved, such as the responsivity was enhanced more than 20 times. These results highlight a feasible scheme for exploring the crystal phase of 2D GaTe and realizing the controlled growth of GaTe films on large substrates, which could promote the development of broadband, high-performance, and large-scale photodetection applications.

A Centimeter-Scale Type-II Weyl Semimetal for Flexible and Fast Ultra-Broadband Photodetection from Ultraviolet to Sub-Millimeter Wave Regime.

Flexible photodetectors with ultra-broadband sensitivities, fast response, and high responsivity are crucial for wearable applications. Recently, van der Waals (vdW) Weyl semimetals have gained much attention due to their unique electronic band structure, making them an ideal material platform for developing broadband photodetectors from ultraviolet (UV) to the terahertz (THz) regime. However, large-area synthesis of vdW semimetals on a flexible substrate is still a challenge, limiting their application in flexible devices. In this study, centimeter-scale type-II vdW Weyl semimetal, Td -MoTe2 films, are grown on a flexible mica substrate by molecular beam epitaxy. A self-powered and flexible photodetector without an antenna demonstrated an outstanding ability to detect electromagnetic radiation from UV to sub-millimeter (SMM) wave at room temperature, with a fast response time of ≈20 µs, a responsivity of 0.53 mA W-1 (at 2.52 THz), and a noise-equivalent power (NEP) of 2.65 nW Hz-0.5 (at 2.52 THz). The flexible photodetectors are also used to image shielded items with high resolution at 2.52 THz. These results can pave the way for developing flexible and wearable optoelectronic devices using direct-grown large-area vdW semimetals.

DPred_3S: identifying dihydrouridine (D) modification on three species epitranscriptome based on multiple sequence-derived features.

Introduction: Dihydrouridine (D) is a conserved modification of tRNA among all three life domains. D modification enhances the flexibility of a single nucleotide base in the spatial structure and is disease- and evolution-associated. Recent studies have also suggested the presence of dihydrouridine on mRNA. Methods: To identify D in epitranscriptome, we provided a prediction framework named "DPred_3S" based on the machine learning approach for three species D epitranscriptome, which used epitranscriptome sequencing data as training data for the first time. Results: The optimal features were evaluated by the F-score and integration of different features; our model achieved area under the receiver operating characteristic curve (AUROC) scores 0.955, 0.946, and 0.905 for Saccharomyces cerevisiae, Escherichia coli, and Schizosaccharomyces pombe, respectively. The performances of different machine learning algorithms were also compared in this study. Discussion: The high performances of our model suggest the D sites can be distinguished based on their surrounding sequence, but the lower performance of cross-species prediction may be limited by technique preferences.

M1ARegpred: Epitranscriptome Target Prediction of N1-methyladenosine (m1A) Regulators Based on Sequencing Features and Genomic Features.

BACKGROUND: N1-methyladenosine (m1A) is a reversible post-transcriptional modification in mRNA, which has been proved to play critical roles in various biological processes through interaction with different m1A regulators. There are several m1A regulators existing in the human genome, including YTHDF1-3 and YTHDC1. METHODS: Several techniques have been developed to identify the substrates of m1A regulators, but their binding specificity and biological functions are not yet fully understood due to the limitations of wet-lab approaches. Here, we submitted the framework m1ARegpred (m1A regulators substrate prediction), which is based on machine learning and the combination of sequence-derived and genome-derived features. RESULTS: Our framework achieved area under the receiver operating characteristic (AUROC) scores of 0.92 in the full transcript model and 0.857 in the mature mRNA model, showing an improvement compared to the existing sequence-derived methods. In addition, motif search and gene ontology enrichment analysis were performed to explore the biological functions of each m1A regulator. CONCLUSIONS: Our work may facilitate the discovery of m1A regulators substrates of interest, and thereby provide new opportunities to understand their roles in human bodies.

Research Progress for RNA Modifications in Physiological and Pathological Angiogenesis.

As a critical layer of epigenetics, RNA modifications demonstrate various molecular functions and participate in numerous biological processes. RNA modifications have been shown to be essential for embryogenesis and stem cell fate. As high-throughput sequencing and antibody technologies advanced by leaps and bounds, the association of RNA modifications with multiple human diseases sparked research enthusiasm; in addition, aberrant RNA modification leads to tumor angiogenesis by regulating angiogenesis-related factors. This review collected recent cutting-edge studies focused on RNA modifications (N6-methyladenosine (m6A), N5-methylcytosine (m5C), N7-methylguanosine (m7G), N1-methyladenosine (m1A), and pseudopuridine (Ψ)), and their related regulators in tumor angiogenesis to emphasize the role and impact of RNA modifications.

m5CRegpred: Epitranscriptome Target Prediction of 5-Methylcytosine (m5C) Regulators Based on Sequencing Features.

5-methylcytosine (m5C) is a common post-transcriptional modification observed in a variety of RNAs. m5C has been demonstrated to be important in a variety of biological processes, including RNA structural stability and metabolism. Driven by the importance of m5C modification, many projects focused on the m5C sites prediction were reported before. To better understand the upstream and downstream regulation of m5C, we present a bioinformatics framework, m5CRegpred, to predict the substrate of m5C writer NSUN2 and m5C readers YBX1 and ALYREF for the first time. After features comparison, window lengths selection and algorism comparison on the mature mRNA model, our model achieved AUROC scores 0.869, 0.724 and 0.889 for NSUN2, YBX1 and ALYREF, respectively in an independent test. Our work suggests the substrate of m5C regulators can be distinguished and may help the research of m5C regulators in a special condition, such as substrates prediction of hyper- or hypo-expressed m5C regulators in human disease.

Sensitive fluorescent detection of exosomal microRNA based on enzymes-assisted dual-signal amplification.

The analysis of microRNAs (miRNAs) in exosomes offers significant information for a rapid and non-invasive diagnosis of cancer. However, the clinical utility of miRNAs as biomarkers is often hampered by their low abundance in exosomes. Herein, we develop a dual-signal amplification biosensor for the sensitive detection of exosomal miRNA-21 (miR-21). In the presence of a cognate target, it hybridizes with a biotin-modified capture probe (Cp) to form a DNA-RNA heteroduplex that serves as a substrate for duplex-specific nuclease (DSN). With the assistance of DSN, the Cps are enzymatically hydrolyzed and numerous DNA catalysts are released, leading to the first signal amplification. After magnetic isolation, the DNA catalyst remaining in the supernatant triggers a strand displacement reaction based on the nicking-assisted reactant recycling strategy, without depleting the reactants, to implement the second signal amplification. Using this dual-signal amplification concept, our biosensor achieves a limit of detection of miR-21 of 0.34 fM, with a linear range of 0.5-100 fM. The receiver operating characteristic curve generated during clinical sample analysis indicates that the exosomal miR-21 outperforms serum carcinoembryonic antigen in discriminating between patients with gastric cancer (GC) and patients with precancerous (PC) lesions (area under the curve: 0.89 versus 0.74, n = 40). Moreover, the proposed biosensor exhibits an 83.9% accuracy in classifying patients with GC or PC lesions and healthy donors using a confusion matrix. Furthermore, patients with GC with or without metastases are discriminated using the proposed biosensor. Our technology may expand the applications of DNA-based biosensor-enabled cancer diagnostic tools.

Hepatitis B Virus Small Envelope Protein Promotes Hepatocellular Carcinoma Angiogenesis via Endoplasmic Reticulum Stress Signaling To Upregulate the Expression of Vascular Endothelial Growth Factor A.

Hepatocellular carcinoma (HCC) is a hypervascular tumor, and accumulating evidence has indicated that stimulation of angiogenesis by hepatitis B virus (HBV) may contribute to HCC malignancy. The small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV protein and has a close clinical association with HCC; however, whether SHBs contributes to HCC angiogenesis remains unknown. This study reports that the forced expression of SHBs in HCC cells promoted xenograft tumor growth and increased the microvessel density (MVD) within the tumors. Consistently, HBsAg was also positively correlated with MVD counts in HCC patients' specimens. The conditioned media from the SHBs-transfected HCC cells increased the capillary tube formation and migration of human umbilical vein endothelial cells (HUVECs). Intriguingly, the overexpression of SHBs increased vascular endothelial growth factor A (VEGFA) expression at both the mRNA and protein levels. Higher VEGFA expression levels were also observed in xenograft tumors transplanted with SHBs-expressing HCC cells and in HBsAg-positive HCC tumor tissues than in their negative controls. As expected, in the culture supernatants, the secretion of VEGFA was also significantly enhanced from HCC cells expressing SHBs, which promoted HUVEC migration and vessel formation. Furthermore, all three unfolded protein response (UPR) sensors, inositol-requiring enzyme 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK), and activating transcription factor 6 (ATF6), associated with ER stress were found to be activated in SHBs-expressing cells and correlated with VEGFA protein expression and secretion. Taken together, these results suggest an important role of SHBs in HCC angiogenesis and may highlight a potential target for preventive and therapeutic intervention for HBV-related HCC and its malignant progression. IMPORTANCE Chronic hepatitis B virus infection is one of the important risk factors for the development and progression of hepatocellular carcinoma (HCC). HCC is characteristic of hypervascularization even at early phases of the disease due to the overexpression of angiogenic factors like vascular endothelial growth factor A (VEGFA). However, a detailed mechanism of HBV-induced angiogenesis remains to be established. In this study, we demonstrate for the first time that the most abundant HBV protein, i.e., small surface antigen (SHBs), can enhance the angiogenic capacity of HCC cells by the upregulation of VEGFA expression both in vitro and in vivo. Mechanistically, SHBs induced endoplasmic reticulum (ER) stress, which consequently activated unfolded protein response (UPR) signaling to increase VEGFA expression and secretion. This study suggests that SHBs plays an important proangiogenic role in HBV-associated HCC and may represent a potential target for antiangiogenic therapy in HCC.

Mid-Infrared Photodetection of Type-II Dirac Semimetal 1T-PtTe2 Grown by Molecular Beam Epitaxy.

Mid-infrared (MIR) photodetection is of significance in civil and military applications because it shows superiority in absorbing the vibration of various molecules and covering atmospheric transmission windows. Recently, the PtTe2, a typical type-II Dirac semimetal, has come under the spotlight due to its unique photodetection sensibility in the MIR region and robust stability in the atmosphere. Here, the high-quality and large-scale 1T-PtTe2 thin films with air stability were grown by molecular beam epitaxy. Broadband photoresponse of the photodetectors of PtTe2 from 420 nm to 10.7 µm shows high responsivity and detectivity of 0.2 mA W-1 and 2.6 × 107 Jones at 10.7 µm and 1.6 mA W-1 and 2.2 × 108 Jones at 4.7 µm under the atmosphere, respectively. Moreover, the photodetectors exhibit high sensitivity in visible and near-infrared regions (8.2 mA W-1 at 650 nm and 15.6 mA W-1 at 960 nm). The power- and polarization-dependent photoresponse measurements reveal the linear relationship of power photoresponse and obvious anisotropic photoresponse (the ratio of anisotropy ellipse is 8.3 at 10.7 µm), respectively. These results suggest that the PtTe2 could be expected to be an advanced photodetection material for polarization angle-sensitive detection, infrared imaging, and photodetection from the visible to MIR range.

Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling.

Chronic hepatitis B virus (HBV) infection is one of the major global health problems. Although the small protein of hepatitis B virus surface antigen (HBsAg), SHBs, is the most abundant HBV viral protein, its pathogenic role and molecular mechanism in malignant progression of HBV-related hepatocellular carcinoma (HCC) remain largely unknown. Here we reported that SHBs expression induced epithelial-mesenchymal transition (EMT) process in HCC cells and significantly increased their migratory and invasive ability as well as metastatic potential. Mechanistically, SHBs expression in HCC cells induced endoplasmic reticulum (ER) stress that activated the activating transcription factor 4 (ATF4) to increase the expression and secretion of fibroblast growth factor 19 (FGF19). The autocrine released FGF19 in turn activated JAK2/STAT3 signaling for induction of EMT process in HCC. Notably, SHBs was positively correlated with the expression of mesenchymal markers, the phosphorylation status of JAK2 and STAT3 as well as FGF19 levels in human HCC samples. HCC patients with SHBs positive had a more advanced clinical stage and worse prognosis. These results suggest an important role of SHBs in the metastasis and progression of HCC and may highlight a potential target for preventive and therapeutic intervention of HBV-related HCC and its malignant progression.

Electrostatically Enhanced Electron-Phonon Interaction in Monolayer 2H-MoSe2 Grown by Molecular Beam Epitaxy.

The enhancement of electron-phonon interaction provides a reasonable explanation for gate-tunable phonon properties in some semiconductors where multiple inequivalent valleys are simultaneously occupied upon charge doping, especially in few-layer transition metal dichalcogenides (TMDs). In this work, we report var der Waals epitaxy of 2H-MoSe2 by molecular beam epitaxy (MBE) and gate-tunable phonon properties in monolayer and bilayer MoSe2. In monolayer MoSe2, we find that out-of-plane phonon mode A1g exhibits a strong softening and shifting toward lower wavenumbers at a high electron doping level, while in-plane phonon mode E2g1 remains unchanged. The softening and shifting of the out-of-plane phonon mode could be attributed to the increase of electron-phonon interaction and the simultaneous occupation of electrons in multiple inequivalent valleys. In bilayer MoSe2, no corresponding changes of phonon modes are detected at the same doping level, which could originate from the occupation of electrons only in single valleys upon high electron doping. This study demonstrates electrostatically enhanced electron-phonon interaction in monolayer MoSe2 and clarifies the relevance between occupation of multiple valleys and phonon properties by comparing Raman spectra of monolayer and bilayer MoSe2 at different doping levels.

PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury.

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIPL/S), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury.

Field-Free Deterministic Magnetization Switching with Ultralow Current Density in Epitaxial Au/Fe4N Bilayer Films.

Current-induced magnetization switching was investigated in Au/Fe4N bilayer films grown by a plasma-assisted molecular beam epitaxy (PA-MBE) system. Depending on lattice distortion and interfacial coupling induced by substrates, the Fe4N layer could be divided into two sublayers having different magnetic anisotropies. The bottom sublayer shows perpendicular magnetic anisotropy (PMA), while the top one has in-plane magnetic anisotropy (IMA). Coupling between the two sublayers provides an extra in-plane effective field and enables a field-free magnetization switching in the bilayer films. By summarizing a series of Hall measurements, a switching phase diagram was obtained. Temperature-dependent switching behaviors demonstrate that the threshold current density for the field-free magnetization switching, which is much smaller than that of pervious reports, increases with decreasing temperature and shows similar temperature dependences to those of coercivity.

Charge Density Wave Phase Transitions in Large-Scale Few-Layer 1T-VTe2 Grown by Molecular Beam Epitaxy.

Charge density wave (CDW) as a novel effect in two-dimensional transition metal dichalcogenides (TMDs) has obtained a rapid rise of interest for its physical nature and potential applications in oscillators and memory devices. Here, we report var der Waals epitaxial growth of centimeter-scale 1T-VTe2 thin films on mica by molecular beam epitaxy. The VTe2 thin films showed sudden resistance change at temperatures of 240 and 135 K, corresponding to two CDW phase transitions driven by temperature. Moreover, the phase transitions can be driven by an electric field due to local Joule heating, and the corresponding resistance states are nonvolatile and controllable, which could be applied to the memory device where the logic states can be switched by an electric field. The multistage CDW phase transitions in the VTe2 thin films could be contributed to electron-phonon coupling in the two-dimensional VTe2, which is supported by twice pronounced Raman blue shifts of the vibration modes associated with in-plane phonons at CDW phase transition temperature. The results open up a new platform for understanding the microscopic physical essence and electrical control of CDW phases of TMDs, expanding the functionalities of these materials for memory applications.

Broad spectral response of an individual tellurium nanobelt grown by molecular beam epitaxy.

The detection of broad wavelengths from the near-ultraviolet to near-infrared regime using functional semiconductor nanostructures is of great importance in either fundamental research or technological application. In this work, we report high-performance optoelectronic nanodevices based on a single Te nanobelt grown by molecular beam epitaxy. The photodetector demonstrates a fast photoresponse time (a rise time of 510 µs and a decay time of 300 µs), a high photoresponsivity of 254.2 A W-1, an external quantum efficiency of 8.6 × 104%, a large detectivity of 8.3 × 108 Jones, on/off ratio of 3 orders, broadband response from the near-ultraviolet to near-infrared region, and robust photocurrent stability and reproducibility. The photodetector with superior performances based on the individual one-dimensional Te nanobelt consequently shows great promise for further optoelectronic device applications.

AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury.

Tumor necrosis factor-α (TNF-α) is a highly pleiotropic cytokine executing biological functions as diverse as cell proliferation, metabolic activation, inflammatory responses, and cell death. TNF-α can induce multiple mechanisms to initiate apoptosis in hepatocytes leading to the subsequent liver injury. Since the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathway is known to have a protective role in death factor-mediated apoptosis, it is our hypothesis that activation of Akt may represent a therapeutic strategy to alleviate TNF-α-induced hepatocyte apoptosis and liver injury. We report here that the Akt activator SC79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8. Furthermore, pretreatment of the PI3K/Akt inhibitor LY294002 reverses all the SC79-induced hepatoprotective effects. These results strongly indicate that SC79 protects against TNF-α-induced hepatocyte apoptosis and suggests that SC79 is likely a promising therapeutic agent for ameliorating the development of liver injury. NEW & NOTEWORTHY SC79 protects hepatocytes from TNF-α-mediated apoptosis and mice from Gal/LPS-induced liver injury and damage. Cytoprotective effects of SC79 against TNF-α act through both AKT-mediated activation of NF-κB and upregulation of FLIPL/S.

Hepatitis B Spliced Protein (HBSP) Suppresses Fas-Mediated Hepatocyte Apoptosis via Activation of PI3K/Akt Signaling.

Hepatitis B spliced protein (HBSP) is known to associate with viral persistence and pathogenesis; however, its biological and clinical significance remains poorly defined. Acquired resistance to Fas-mediated apoptosis is thought to be one of the major promotors for hepatitis B virus (HBV) chronicity and malignancy. The purpose of this study was to investigate whether HBSP could protect hepatocytes against Fas-initiated apoptosis. We showed here that HBSP mediated resistance of hepatoma cells or primary human hepatocytes (PHH) to agonistic anti-Fas antibody (CH11)- or FasL-induced apoptosis. Under Fas signaling stimulation, expression of HBSP inhibited Fas aggregation and prevented recruitment of the adaptor molecule Fas-associated death domain (FADD) and procaspase-8 (or FADD-like interleukin-1ß-converting enzyme [FLICE]) into the death-inducing signaling complex (DISC) while increasing recruitment of cellular FLICE-inhibitory protein L (FLIPL) into the DISC. Those effects may be mediated through activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway as evidenced by increased cellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3) content and PI3K activity and enhanced phosphorylation of mTORC2 and PDPK1 as well as Akt itself. Confirmedly, inhibition of PI3K by LY294002 reversed the effect of HBSP on Fas aggregation, FLIPL expression, and cellular apoptosis. These results indicate that HBSP functions to prevent hepatocytes from Fas-induced apoptosis by enhancing PI3K/Akt activity, which may contribute to the survival and persistence of infected hepatocytes during chronic infection.IMPORTANCE Our study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The antiapoptotic activity of HBSP is important for understanding hepatitis B virus pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may downregulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that Akt is centrally involved in Fas-induced hepatocyte apoptosis and revealed that interventions directed at inhibiting the activation or functional activity of Akt may be of therapeutic value in this process.

Hepatitis B Virus Surface Antigen Enhances the Sensitivity of Hepatocytes to Fas-Mediated Apoptosis via Suppression of AKT Phosphorylation.

The Fas receptor/ligand system plays a prominent role in hepatic apoptosis and hepatocyte death. Although hepatitis B virus (HBV) surface Ag (HBsAg) is the most abundant HBV protein in the liver and peripheral blood of patients with chronic HBV infection, its role in Fas-mediated hepatocyte apoptosis has not been disclosed. In this study, we report that HBsAg sensitizes HepG2 cells to agonistic anti-Fas Ab CH11-induced apoptosis through increasing the formation of SDS-stable Fas aggregation and procaspase-8 cleavage but decreasing both the expression of cellular FLIPL/S and the recruitment of FLIPL/S at the death-inducing signaling complex (DISC). Notably, HBsAg increased endoplasmic reticulum stress and consequently reduced AKT phosphorylation by deactivation of phosphoinositide-dependent kinase-1 (PDPK1) and mechanistic target of rapamycin complex 2 (mTORC2), leading to enhancement of Fas-mediated apoptosis. In a mouse model, expression of HBsAg in mice injected with recombinant adenovirus-associated virus 8 aggravated Jo2-induced acute liver failure, which could be effectively attenuated by the AKT activator SC79. Based on these results, it is concluded that HBsAg predisposes hepatocytes to Fas-mediated apoptosis and mice to acute liver failure via suppression of AKT prosurviving activity, suggesting that interventions directed at enhancing the activation or functional activity of AKT may be of therapeutic value in Fas-mediated progressive liver cell injury and liver diseases.