Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis.

Glutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin-proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.

Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis.

PURPOSE: As a vital component of the hepatitis B virus (HBV) nucleocapsid, HBV core protein (HBC) contributes to hepatocarcinogenesis. Here, we aimed to assess the effects of RANGAP1 and KDM2A on tumorigenesis induced by HBC. METHODS: Co-immunoprecipitation (Co-IP) combined with mass spectrometry were utilized to identify the proteins with the capacity to interact with HBC. The gene and protein levels of RANGAP1 and KDM2A in hepatocellular carcinoma (HCC) and HBV-positive HCC tissues were evaluated using different cohorts. The roles of RANGAP1 and KDM2A in HCC cells mediated by HBC were investigated in vitro and in vivo. Co-IP and western blot were used to estimate the interaction of HBC with RANGAP1 and KDM2A and assess RANGAP1 stabilization regulated by HBC. RESULTS: We discovered that HBC could interact with RANGAP1 and KDM2A, the levels of which were markedly elevated in HCC tissues. Relying on RANGAP1 and KDM2A, HBC facilitated HCC cell growth and migration. The increased stabilization of RANGAP1 mediated by HBC was relevant to the disruption of the interaction between RANGAP1 and an E3 ligase SYVN1. RANGAP1 interacted with KDM2A, and it further promoted KDM2A stabilization by disturbing the interaction between KDM2A and SYVN1. HBC enhanced the interaction of KDM2A with RANGAP1 and upregulated the expression of KDM2A via RANGAP1 in HCC cells. CONCLUSIONS: These findings demonstrate a novel mechanism by which HBC facilitates hepatocarcinogenesis. RANGAP1 and KDM2A could act as potential molecular targets for treating HBV-associated malignancy.

Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis.

BACKGROUND: GRP78 has been implicated in hepatocarcinogenesis. However, the clinical relevance, biological functions and related regulatory mechanisms of GRP78 in hepatitis B virus (HBV)-associated hepatoma carcinoma (HCC) remain elusive. METHODS: The association between GRP78 expression and HBV-related HCC was investigated. The effects of HBV X protein (HBX) on GRP78 and MAN1B1 expression, biological functions of GRP78 and MAN1B1 in HBX-mediated HCC cells and mechanisms related to TRIM25 on GRP78 upregulation to induce MAN1B1 expression in HBX-related HCC cells were examined. RESULTS: GRP78 expression was correlated with poor prognosis in HBV-positive HCC. HBX increased MAN1B1 protein expression depending on GRP78, and HBX enhanced the levels of MAN1B1 to promote proliferation, migration and PI3-K/mTOR signalling pathway activation in HCC cells. GRP78 activates Smad4 via its interaction with Smad4 to increase MAN1B1 expression in HBX-expressing HCC cells. TRIM25 enhanced the stability of GRP78 by inhibiting its ubiquitination. HBX binds to GRP78 and TRIM25 and accelerates their interaction of GRP78 and TRIM25, leading to an increase in GRP78 expression. CONCLUSIONS: HBX enhances the stability of GRP78 through TRIM25 to increase the expression of MAN1B1 to facilitate tumorigenesis, and we provide new insights into the molecular mechanisms underlying HBV-induced malignancy.

Hepatitis B virus X protein increases LASP1 SUMOylation to stabilize HER2 and facilitate hepatocarcinogenesis.

The hepatitis B virus (HBV) X protein (HBX), a viral macromolecule, plays a vital role in the development of HBV-related hepatocellular carcinoma (HCC). Increased expression of HER2 is linked to HBV infection, and HBX is responsible for HER2 upregulation in HCC. Nevertheless, the underlying molecular mechanisms are not yet fully understood. In the study, we discovered that HBX promoted HER2 expression to facilitate the sensitization of the insulin signaling pathway and enhance the growth and migration of HCC cells. Mechanistically, the viral protein enhanced the stability of HER2 by preventing its ubiquitination-mediated proteasomal degradation through LASP1, which could bind to HER2. Furthermore, increased SUMOylation of LASP1 contributed to the upregulation of HER2 and the interaction of LASP1 with HER2. In addition, RANBP2 and RANGAP1 were found to interact with LASP1 and promote SUMOylation of LASP1 to upregulate HER2 expression in HBX-associated hepatoma cells. In summary, our work provides a novel insight into hepatocarcinogenesis mediated by HBX and estimates the detailed mechanisms related to the increase in HER2 regulated by the viral protein, which might help provide a theoretical basis for identifying novel targets for HBV-positive HCC treatment.

The emerging role of DEAD/H-box helicases in hepatitis B virus infection.

DEAD/H-box helicases are an essential protein family with a conserved motif containing unique amino acid sequences (Asp-Glu-Ala-Asp/His). Current evidence indicates that DEAD/H-box helicases regulate RNA metabolism and innate immune responses. In recent years, DEAD/H-box helicases have been reported to participate in the development of a variety of diseases, including hepatitis B virus (HBV) infection, which is a significant risk factor for hepatic fibrosis, cirrhosis, and liver cancer. Furthermore, emerging evidence suggests that different DEAD/H-box helicases play vital roles in the regulation of viral replication, based on the interaction of DEAD/H-box helicases with HBV and the modulation of innate signaling pathways mediated by DEAD/H-box helicases. Besides these, HBV can alter the expression and activity of DEAD/H-box helicases to facilitate its biosynthesis. More importantly, current investigation suggests that targeting DEAD/H-box helicases with appropriate compounds is an attractive treatment strategy for the virus infection. In this review, we delineate recent advances in molecular mechanisms relevant to the interplay of DEAD/H-box helicase and HBV and the potential of targeting DEAD/H-box helicase to eliminate HBV infection.

Antimicrobial and Anti-Inflammatory Activities of MAF-1-Derived Antimicrobial Peptide Mt6 and Its D-Enantiomer D-Mt6 against Acinetobacter baumannii by Targeting Cell Membranes and Lipopolysaccharide Interaction.

Antibiotic resistance in Acinetobacter baumannii is on the rise around the world, highlighting the urgent need for novel antimicrobial drugs. Antimicrobial peptides (AMPs) contribute to effective protection against infections by pathogens, making them the most promising options for next-generation antibiotics. Here, we report two designed, cationic, antimicrobial-derived peptides: Mt6, and its dextroisomer D-Mt6, belonging to the analogs of MAF-1, which is isolated from the instar larvae of houseflies. Both Mt6 and D-Mt6 have a broad-spectrum antimicrobial activity that is accompanied by strong antibacterial activities, especially against A. baumannii planktonic bacteria and biofilms. Additionally, the effect of D-Mt6 against A. baumannii is stable in a variety of physiological settings, including enzyme, salt ion, and hydrogen ion environments. Importantly, D-Mt6 cleans the bacteria on Caenorhabditis elegans without causing apparent toxicity and exhibits good activity in vivo. Both Mt6 and D-Mt6 demonstrated synergistic or additive capabilities with traditional antibiotics against A. baumannii, demonstrating their characteristics as potential complements to combination therapy. Scanning electron microscopy (SEM) and laser scanning confocal microscope (LSCM) experiments revealed that two analogs displayed rapid bactericidal activity by destroying cell membrane integrity. Furthermore, in lipopolysaccharide (LPS)-stimulated macrophage cells, these AMPs drastically decreased IL-1ß and TNF-a gene expression and protein secretion, implying anti-inflammatory characteristics. This trait is likely due to its dual function of directly binding LPS and inhibiting the LPS-activated mitogen-activated protein kinase (MAPK) signaling pathways in macrophages. Our findings suggested that D-Mt6 could be further developed as a novel antimicrobial/anti-inflammatory agent and used in the treatment of A. baumannii infections. IMPORTANCE Around 700,000 people worldwide die each year from antibiotic-resistant pathogens. Acinetobacter baumannii in clinical specimens increases year by year, and it is developing a strong resistance to clinical drugs, which is resulting in A. baumannii becoming the main opportunistic pathogen. Antimicrobial peptides show great potential as new antibacterial drugs that can replace traditional antibiotics. In our study, Mt6 and D-Mt6, two new antimicrobial peptides, were designed based on a natural peptide that we first discovered in the hemlymphocytes of housefly larvae. Both Mt6 and D-Mt6 showed broad-spectrum antimicrobial activity, especially against A. baumannii, by damaging membrane integrity. Moreover, D-Mt6 showed better immunoregulatory activity against LPS induced inflammation through its LPS-neutralizing and suppression on MAPK signaling. This study suggested that D-Mt6 is a promising candidate drug as a derived peptide against A. baumannii.

Comprehensive Analysis of TRIM Family Genes in Hepatitis Virus B-Related Hepatoma Carcinoma.

Background: As significant components of E3 ligases, the tripartite motif (TRIM) proteins participate in various biological processes and facilitate the development of several diseases. Nevertheless, the correlations of TIRMs with hepatitis B virus (HBV)-positive hepatoma carcinoma (HCC) are not well elaborated. Methods: The expression profile of TRIM genes in HBV-associated HCC and related clinical information were extracted from the Cancer Genome Atla (TCGA) database and the International Cancer Genome Consortium (ICGC) database. Dependent on the ConsensusPathDB and STRING databases, the gene ontology, Reactome pathways, and protein-protein interaction were assessed. Relied on TIMER 2.0 database, the relationship of the TRIMs with immune infiltration was investigated. Using multivariate analysis and Kaplan Meier analysis, the association between TRIM genes and the prognostic value was examined. Results: A total of 17 TRIM genes, including TRIM16, TRIM17, and TRIM31 with fold change no less than 1.5, were discovered to upregulate in HBV-associated HCC in both TCGA and ICGC cohorts. Relied on gene enrichment analysis, the identified TRIMs were observed to not only be related to the interferon and cytokine signaling but also linked to the adaptive immune system. Particularly, the co-expression patterns of identified TRIMs with other E3 ligase genes and many innate immune genes that are associated with Toll-like receptor signaling, apoptosis, and SUMOylation. Besides, some of identified TRIM expressions were also linked to the infiltration levels of T cells and B cells. Additionally, several TRIM genes were associated with various clinical factors and relevant to the poor survival of HBV-associated HCC. Conclusion: Our findings could deepen our understanding of TRIMs and their correlations with HBV-associated HCC. Furthermore, some of these TRIMs may be utilized as new prognostic markers of HBV-related HCC prognosis, or act as potential molecular targets for the disease.

Regulation of epithelial-mesenchymal transition by protein lysine acetylation.

The epithelial-mesenchymal transition (EMT) is a vital driver of tumor progression. It is a well-known and complex trans-differentiation process in which epithelial cells undergo morphogenetic changes with loss of apical-basal polarity, but acquire spindle-shaped mesenchymal phenotypes. Lysine acetylation is a type of protein modification that favors reversibly altering the structure and function of target molecules via the modulation of lysine acetyltransferases (KATs), as well as lysine deacetylases (KDACs). To date, research has found that histones and non-histone proteins can be acetylated to facilitate EMT. Interestingly, histone acetylation is a type of epigenetic regulation that is capable of modulating the acetylation levels of distinct histones at the promoters of EMT-related markers, EMT-inducing transcription factors (EMT-TFs), and EMT-related long non-coding RNAs to control EMT. However, non-histone acetylation is a post-translational modification, and its effect on EMT mainly relies on modulating the acetylation of EMT marker proteins, EMT-TFs, and EMT-related signal transduction molecules. In addition, several inhibitors against KATs and KDACs have been developed, some of which can suppress the development of different cancers by targeting EMT. In this review, we discuss the complex biological roles and molecular mechanisms underlying histone acetylation and non-histone protein acetylation in the control of EMT, highlighting lysine acetylation as potential strategy for the treatment of cancer through the regulation of EMT. Video Abstract.

Regulation of Pattern-Recognition Receptor Signaling by HBX During Hepatitis B Virus Infection.

As a small DNA virus, hepatitis B virus (HBV) plays a pivotal role in the development of various liver diseases, including hepatitis, cirrhosis, and liver cancer. Among the molecules encoded by this virus, the HBV X protein (HBX) is a viral transactivator that plays a vital role in HBV replication and virus-associated diseases. Accumulating evidence so far indicates that pattern recognition receptors (PRRs) are at the front-line of the host defense responses to restrict the virus by inducing the expression of interferons and various inflammatory factors. However, depending on HBX, the virus can control PRR signaling by modulating the expression and activity of essential molecules involved in the toll-like receptor (TLR), retinoic acid inducible gene I (RIG-I)-like receptor (RLR), and NOD-like receptor (NLR) signaling pathways, to not only facilitate HBV replication, but also promote the development of viral diseases. In this review, we provide an overview of the mechanisms that are linked to the regulation of PRR signaling mediated by HBX to inhibit innate immunity, regulation of viral propagation, virus-induced inflammation, and hepatocarcinogenesis. Given the importance of PRRs in the control of HBV replication, we propose that a comprehensive understanding of the modulation of cellular factors involved in PRR signaling induced by the viral protein may open new avenues for the treatment of HBV infection.

The interaction of canonical Wnt/ß-catenin signaling with protein lysine acetylation.

Canonical Wnt/ß-catenin signaling is a complex cell-communication mechanism that has a central role in the progression of various cancers. The cellular factors that participate in the regulation of this signaling are still not fully elucidated. Lysine acetylation is a significant protein modification which facilitates reversible regulation of the target protein function dependent on the activity of lysine acetyltransferases (KATs) and the catalytic function of lysine deacetylases (KDACs). Protein lysine acetylation has been classified into histone acetylation and non-histone protein acetylation. Histone acetylation is a kind of epigenetic modification, and it can modulate the transcription of important biological molecules in Wnt/ß-catenin signaling. Additionally, as a type of post-translational modification, non-histone acetylation directly alters the function of the core molecules in Wnt/ß-catenin signaling. Conversely, this signaling can regulate the expression and function of target molecules based on histone or non-histone protein acetylation. To date, various inhibitors targeting KATs and KDACs have been discovered, and some of these inhibitors exert their anti-tumor activity via blocking Wnt/ß-catenin signaling. Here, we discuss the available evidence in understanding the complicated interaction of protein lysine acetylation with Wnt/ß-catenin signaling, and lysine acetylation as a new target for cancer therapy via controlling this signaling.

Cellular retinol binding protein-1 inhibits cancer stemness via upregulating WIF1 to suppress Wnt/ß-catenin pathway in hepatocellular carcinoma.

BACKGROUND: CRBP-1, a cytosolic chaperone of vitamin A, is identified in a serious number of cancers; however, its biological role in hepatocellular carcinoma (HCC) needs to be further explored. The aim of our present study is to explore the roles and mechanisms of CRBP-1 in regulating liver cancer by using in vitro and in vivo biology approaches. METHODS: The expression level of CRBP-1 was detected using immunohistochemistry in HCC and matching adjacent non-tumorous liver tissues. Following established stable CRBP-1 overexpressed HCC cell lines, the cell growth and tumorigenicity were investigated both in vitro and in vivo. Intracellular retinoic acid was quantified by ELISA. The relationship between CRBP-1 and WIF1 was validated by using dual luciferase and ChIP analyses. RESULTS: The low expression of CRBP-1 was observed in HCC tissues compared to the normal liver tissues, while high CRBP-1 expression correlated with clinicopathological characteristics and increased overall survival in HCC patients. Overexpression of CRBP-1 significantly inhibited cell growth and tumorigenicity both in vitro and in vivo. Moreover, overexpression of CRBP-1 suppressed tumorsphere formation and cancer stemness related genes expression in HCC. Mechanically, CRBP-1 inhibited Wnt/ß-catenin signaling pathway to suppress cancer cell stemness of HCC. Furthermore, our results revealed that CRBP-1 could increase the intracellular levels of retinoic acid, which induced the activation of RARs/RXRs leading to the transcriptional expression of WIF1, a secreted antagonist of the Wnt/ß-catenin signaling pathway, by physically interacting with the region on WIF1 promoter. CONCLUSION: Our findings reveal that CRBP-1 is a crucial player in the initiation and progression of HCC, which provide a novel independent prognostic biomarker and therapeutic target for the diagnosis and treatment of HCC.

Sirtuins as Potential Therapeutic Targets for Hepatitis B Virus Infection.

Sirtuins (SIRTs) are well-known histone deacetylases that are capable of modulating various cellular processes in numerous diseases, including the infection of hepatitis B virus (HBV), which is one of the primary pathogenic drivers of liver cirrhosis and hepatocellular carcinoma. Mounting evidence reveals that HBV can alter the expression levels of all SIRT proteins. In turn, all SIRTs regulate HBV replication via a cascade of molecular mechanisms. Furthermore, several studies suggest that targeting SIRTs using suitable drugs is a potential treatment strategy for HBV infection. Here, we discuss the molecular mechanisms associated with SIRT-mediated upregulation of viral propagation and the recent advances in SIRT-targeted therapy as potential therapeutic modalities against HBV infection.

Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target.

As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.

Hepatitis B virus X protein promotes vimentin expression via LIM and SH3 domain protein 1 to facilitate epithelial-mesenchymal transition and hepatocarcinogenesis.

BACKGROUND: Hepatitis B virus (HBV) X protein (HBX) has been reported to be responsible for the epithelial-mesenchymal transition (EMT) in HBV-related hepatocellular carcinoma (HCC). Vimentin is an EMT-related molecular marker. However, the importance of vimentin in the pathogenesis of HCC mediated by HBX has not been well determined. METHODS: The expression of vimentin induced by HBX, and the role of LIM and SH3 domain protein 1 (LASP1) in HBX-induced vimentin expression in hepatoma cells were examined by western blot and immunohistochemistry analysis. Both the signal pathways involved in the expression of vimentin, the interaction of HBX with vimentin and LASP1, and the stability of vimentin mediated by LASP1 in HBX-positive cells were assessed by western blot, Co-immunoprecipitation, and GST-pull down assay. The role of vimentin in EMT, proliferation, and migration of HCC cells mediated by HBX and LASP1 were explored with western blot, CCK-8 assay, plate clone formation assay, transwell assay, and wound healing assay. RESULTS: Vimentin expression was increased in both HBX-positive hepatoma cells and HBV-related HCC tissues, and the expression of vimentin was correlated with HBX in HBV-related HCC tissues. Functionally, vimentin was contributed to the EMT, proliferation, and migration of hepatoma cells mediated by HBX. The mechanistic analysis suggested that HBX was able to enhance the expression of vimentin through LASP1. On the one hand, PI3-K, ERK, and STAT3 signal pathways were involved in the upregulation of vimentin mediated by LASP1 in HBX-positive hepatoma cells. On the other hand, HBX could directly interact with vimentin and LASP1, and dependent on LASP1, HBX was capable of promoting the stability of vimentin via protecting it from ubiquitination mediated protein degradation. Besides these, vimentin was involved in the growth and migration of hepatoma cells mediated by LASP1 in HBX-positive hepatoma cells. CONCLUSION: Taken together, these findings demonstrate that, dependent on LASP1, vimentin is crucial for HBX-mediated EMT and hepatocarcinogenesis, and may serve as a potential target for HBV-related HCC treatment. Video abstract.

Hepatitis B Virus Core Protein Mediates the Upregulation of C5α Receptor 1 via NF-κB Pathway to Facilitate the Growth and Migration of Hepatoma Cells.

PURPOSE: C5α receptor 1 (C5ΑR1) is associated with the development of various human cancers. However, whether it is involved in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is poorly understood. We explored the expression, biological role, and associated mechanisms of C5AR1 in HBV-related hepatoma cells. MATERIALS AND METHODS: The expression of C5ΑR1 mediated by HBV and HBV core protein (HBc) was detected in hepatoma cells. The function of nuclear factor кB (NF-κB) pathway in HBc-induced C5AR1 expression was assessed. The roles of C5ΑR1 in the activation of intracellular signal pathways, the upregulation of inflammatory cytokines, and the growth and migration of hepatoma cells mediated by HBc, were investigated. The effect of C5α in the development of HCC mediated by C5AR1 was also measured. RESULTS: C5ΑR1 expression was increased in HBV-positive hepatoma cells. Dependent on HBc, HBV enhanced the expression of C5ΑR1 at the mRNA and protein levels. Besides, HBc could promote C5ΑR1 expression via the NF-κB pathway. Based on the C5ΑR1, HBc facilitated the activation of JNK and ERK pathways and the expression and secretion of interleukin-6 in hepatoma cells. Furthermore, C5ΑR1 was responsible for enhancing the growth and migration of hepatoma cells mediated by HBc. Except these, C5α could promote the malignant development of HBc-positive HCC via C5AR1. CONCLUSION: We provide new insight into the mechanisms of hepatocarcinogenesis mediated by HBc. C5ΑR1 has a significant role in the functional abnormality of hepatoma cells mediated by HBc, and might be utilized as a potential therapeutic target for HBV-related HCC.

Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignancy with high incidence and mortality rates worldwide. Alcohol dehydrogenases (ADHs) are huge family of dehydrogenase enzymes and associated with the prognosis of various cancers. However, comprehensive analysis of prognostic implications related to ADHs in HCC is still lacking and largely unknown. METHODS: The expression profiles and corresponding clinical information of HCC were obtained from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test was employed to evaluate the expression of ADHs. Cox regression and Kaplan-Meier analyses were used to investigate the association between clinicopathological characteristics and survival. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses were performed and visualized using R/BiocManager package. RESULTS: We found that the expression of ADH1A, ADH1B, ADH1C, ADH4, and ADH6 was significantly downregulated in HCC samples compared to normal liver samples. Our univariate and multivariate Cox regression analyses results showed that high expression of ADH1A, ADH1B, ADH1C, ADH4, and ADH6 was considered as an independent factor with an improved prognosis for the survival of HCC patients. Moreover, our Kaplan-Meier analysis results also revealed that high expression of AHD1A, ADH1B, ADH1C, ADH4, and ADH6 was significantly associated with good survival rate in HCC patients. In addition, GO, KEGG, and GSEA analyses unveiled several oncogenic signaling pathways were negatively associated high expression of ADHs in HCC. CONCLUSION: In the present study, our results provide the potential prognostic biomarkers or molecular targets for the patients with HCC.

Correction to: Role of hepatitis B virus X protein in regulating LIM and SH3 protein 1 (LASP-1) expression to mediate proliferation and migration of hepatoma cells.

An amendment to this paper has been published and can be accessed via the original article.

Hepatitis B virus core protein promotes the expression of neuraminidase 1 to facilitate hepatocarcinogenesis.

Neuraminidase 1 (NEU1) has been reported to be associated with hepatocellular carcinoma (HCC). However, the function and associated molecular mechanisms of NEU1 in hepatitis B virus (HBV)-related HCC have not been well investigated. In the present study, the expression of NEU1 mediated by HBV and HBV core protein (HBc) was measured in hepatoma cells. The expression of NEU1 protein was detected via immunohistochemical analysis in HBV-associated HCC tissues. The role of NEU1 in the activation of signaling pathways and epithelial-mesenchymal transition (EMT) and the proliferation and migration of hepatoma cells mediated by HBc was assessed. We found that NEU1 was upregulated in HBV-positive hepatoma cells and HBV-related HCC tissues. HBV promoted NEU1 expression at the mRNA and protein level via HBc in hepatoma cells. Mechanistically, HBc was able to enhance the activity of the NEU1 promoter through NF-κB binding sites. In addition, through the increase in NEU1 expression, HBc contributed to activation of downstream signaling pathways and EMT in hepatoma cells. Moreover, NEU1 facilitated the proliferation and migration of hepatoma cells mediated by HBc. Taken together, our findings provide novel insight into the molecular mechanism underlying the oncogenesis mediated by HBc and demonstrate that NEU1 plays a vital role in HBc-mediated functional abnormality in HCC. Thus, NEU1 may serve as a potential therapeutic target in HBV-associated HCC.

Integrative analysis of highly mutated genes in hepatitis B virus-related hepatic carcinoma.

Gene mutation is responsible for the development of hepatocellular carcinoma (HCC) with hepatitis B virus (HBV) infection; however, the characteristics and associated biological functions of highly mutated genes, in which the mutation frequencies are at least 5% in HCC patients with HBV infection, are not clearly evaluated. In the study, we analyzed the information regarding somatic mutation obtained by whole-exome sequencing in 280 HBV-related HCC tissues from public databases and published studies. Via integrative analysis, 78 genes, including TP53, TTN, MUC16, CTNNB1, and PCLO were summarized as highly mutated genes, and some of these mutated genes were further identified as cancer driver genes. Besides, we discovered that the highly mutated genes were enriched with various biological functions and pathways. The expression of many of highly mutated genes was found to be significantly altered in HBV-related HCC, and several highly mutated genes were related to a variety of clinical factors and associated with the poor survival of the disease. Taken together, these results could enrich our understanding of highly mutated genes and their relationships with HBV-related HCC. Some of the identified highly mutated genes might be used as novel biomarkers of disease prognosis, or as molecular targets for the treatment of HCC with HBV infection.

Interleukin-34 mediated by hepatitis B virus X protein via CCAAT/enhancer-binding protein α contributes to the proliferation and migration of hepatoma cells.

OBJECTIVES: Interleukin-34 (IL-34) is associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, the role and associated mechanisms of IL-34 in HBV-related HCC remain unclear. In this study, the expression, biological function and associated mechanisms of IL-34 in HBV-related HCC cells were investigated. METHODS: IL-34 expression induced by HBV and HBV X (HBX) gene was measured in hepatoma cells. The role of CCAAT/enhancer-binding protein α (CEBP/α) in HBX-induced IL-34 expression was examined. The signal pathways involved in the expression of CEBP/α and IL-34 induced by HBX were assessed. The role of IL-34 in the proliferation and migration of HCC cells, and related mechanisms were explored. RESULTS: Dependent on HBX, HBV increased IL-34 expression in hepatoma cells, and HBX upregulated and interacted with CEBP/α to enhance the activity of IL-34 promoters. CEBP/α mediated by HBX was associated with the activation of PI3-K and NF-κB pathways to promote IL-34 expression. Via CSF1-R and CD138, IL-34 promoted the proliferation and migration of hepatoma cells, and contributed to the activation of ERK and STAT3 pathways and the upregulation of Bcl-xl and c-Myc mediated by HBX. CONCLUSION: We demonstrate that IL-34 contributes to HBX-mediated functional abnormality of HCC cells and provides a novel insight into the molecular mechanism of carcinogenesis mediated by HBX.