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C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism.

ABSTRACT: Chronic hepatitis B virus (HBV) infection is strongly associated with the initiation and development of hepatocellular carcinoma (HCC). However, the genetic alterations and pathogenesis mechanisms remain significantly unexplored, especially for HBV-induced metabolic reprogramming. Analysis of integration breakpoints in HBV-positive HCC samples revealed the preferential clustering pattern within the 3'-end of X gene in the HBV genome, leading to the production of C-terminal truncated X protein (Ct-HBx). In this study, we not only characterized the oncogenic role of two Ct-HBx (HBx-120 and HBx-134) via in vitro and in vivo functional assays but also deciphered their underlying molecular mechanisms. Gene expression profiling by transcriptome sequencing identified potential targets of Ct-HBx and novel malignant hallmarks such as glycolysis, cell cycle, and m-TORC1 signaling in Ct-HBx-expressing cells. TXNIP, a well-established regulator of glucose metabolism, was shown to be downregulated by Ct-HBx and play a pivotal role in Ct-HBx-mediated HCC progression. Suppression of TXNIP is frequently observed in HCC patients with Ct-HBx expression and significantly (P = 0.015) correlated to a poorer prognosis. Re-introduction of TXNIP attenuated the metabolic reprogramming induced by the Ct-HBx and inhibited the tumor growth in the mice model. Further study suggested that Ct-HBx could downregulate TXNIP via a transcriptional repressor nuclear factor of activated T cells 2 (NFACT2). Collectively, our findings indicate that TXNIP plays a critical role in Ct-HBx-mediated hepatocarcinogenesis, serving as a novel therapeutic strategy in HCC treatment.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7878188 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TXNIP regulates peripheral glucose metabolism in humans.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure.Methods and findingsWe combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM.ConclusionsTXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

| S-EPMC1858708 | biostudies-literature

The oncoprotein HBXIP promotes glucose metabolism reprogramming via downregulating SCO2 and PDHA1 in breast cancer.

Project description:The glucose metabolism reprogramming is a hallmark of cancer. The oncoprotein hepatitis B X-interacting protein (HBXIP) functions in the development of breast cancer. In this study, we supposed that HBXIP might be involved in the glucose metabolism reprogramming in breast cancer. We showed that HBXIP led to increases in generation of intracellular glucose and lactate, as well as decreases in generation of reactive oxygen species. Expression of synthesis of cytochrome c oxidase 2 (SCO2) and pyruvate dehydrogenase alpha 1 (PDHA1), two factors of metabolic switch from oxidative phosphorylation to aerobic glycolysis, was suppressed by HBXIP. In addition, miR-183/182 and miR-96 directly inhibited the expression of SCO2 and PDHA1 through targeting their mRNA coding sequences (CDSs), respectively. Interestingly, HBXIP elevated the miR-183/96/182 cluster expression through hypoxia-inducible factor 1α (HIF1α). The stability of HIF1α was enhanced by HBXIP through disassociating interaction of von Hippel-Lindau protein (pVHL) with HIF1α. Moreover, miR-183 increased the levels of HIF1α protein through directly targeting CDS of VHL mRNA, forming a feedback loop of HIF1α/miR-183/pVHL/HIF1α. In function, HBXIP-elevated miR-183/96/182 cluster enhanced the glucose metabolism reprogramming in vitro. HBXIP-triggered glucose metabolism reprogramming promoted the growth of breast cancer in vivo. Thus, we conclude that the oncoprotein HBXIP enhances glucose metabolism reprogramming through suppressing SCO2 and PDHA1 in breast cancer.

| S-EPMC4694983 | biostudies-literature

USP16 Downregulation by Carboxyl-terminal Truncated HBx Promotes the Growth of Hepatocellular Carcinoma Cells.

Project description:Hepatitis B virus (HBV) infection is a major factor that contributes to the development of hepatocellular carcinoma (HCC). HBV X protein (HBx) has been shown to accelerate HCC progression by promoting tumour growth and metastasis. In the clinic, carboxyl-terminal truncated HBx (Ct-HBx) proteins are frequently present in HCC tumour tissues, but not in non-tumorous tissues. In this study, we analysed deubiquitinase expression profiles in cells with or without ectopic expression of the Ct-HBx proteins and observed that the expression of ubiquitin specific peptidase 16 (USP16) was substantially inhibited by Ct-HBx proteins. Liver tumour cells with forced down-regulation of USP16 exhibited increased capabilities for colony formation and tumour growth in vivo. In addition, USP16 inhibition promoted stem-like properties in tumour cells, as evidenced by their spheroid formation and chemo-responsiveness. Furthermore, ectopic expression of USP16 in tumour cells significantly abrogated the tumour promoting activities of the Ct-HBx proteins (HBxΔ35), leading to decreased tumour cell viability and tumour growth. In human HCCs, USP16 was frequently downregulated, and the decreased expression of USP16 was correlated with high tumour stages and poor differentiation status. Taken together, our study suggests that USP16 downregulation is a critical event in Ct-HBx-mediated promotion of HCC tumorigenicity and malignancy.

| S-EPMC5025738 | biostudies-literature

Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization.

Project description:The metabolic state of a cell is influenced by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we present extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as being among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM component hyaluronan and metabolism, treatment of cells and xenografts with hyaluronidase triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of the mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Because TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline enriches GLUT1 at the plasma membrane. Functionally, induction of glycolysis by hyaluronidase is required for concomitant acceleration of cell migration. This interconnection between ECM remodeling and metabolism is exhibited in dynamic tissue states, including tumorigenesis and embryogenesis.

| S-EPMC6151140 | biostudies-literature

Reprograming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis.

Project description:Hepatocellular carcinoma (HCC) is the most prevalent and highly aggressive liver malignancy with limited therapeutic options. Here, the therapeutic potential of zerumbone, a sesquiterpene derived from the ginger plant Zingiber zerumbet, against HCC was explored. Zerumbone inhibited proliferation and clonogenic survival of HCC cells in a dose-dependent manner by arresting cells at the G2-M phase and inducing apoptosis. To elucidate the underlying molecular mechanisms, a phosphokinase array was performed that showed significant inhibition of the PI3K/AKT/mTOR and STAT3 signaling pathways in zerumbone-treated HCC cells. Gene expression profiling using microarray and analysis of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) revealed that zerumbone treatment resulted in significant deregulation of genes regulating apoptosis, cell cycle, and metabolism. Indeed, tracing glucose metabolic pathways by growing HCC cells with 13C6-glucose and measuring extracellular and intracellular metabolites by 2D nuclear magnetic resonance (NMR) spectroscopy showed a reduction in glucose consumption and reduced lactate production, suggesting glycolytic inhibition. In addition, zerumbone impeded shunting of glucose-6-phosphate through the pentose phosphate pathway, thereby forcing tumor cells to undergo cell-cycle arrest and apoptosis. Importantly, zerumbone treatment suppressed subcutaneous and orthotopic growth and lung metastasis of HCC xenografts in immunocompromised mice. In conclusion, these findings reveal a novel and potentially effective therapeutic strategy for HCC using a natural product that targets cancer cell metabolism.Implications: Dietary compounds, like zerumbone, that impact cell cycle, apoptosis, and metabolic processes may have therapeutic benefits for HCC patients. Mol Cancer Res; 16(2); 256-68. ©2017 AACR.

| S-EPMC5805640 | biostudies-literature

Carboxyl-terminal truncated HBx contributes to invasion and metastasis via deregulating metastasis suppressors in hepatocellular carcinoma.

Project description:Hepatitis B virus (HBV) X protein (HBx), a trans-regulator, is frequently expressed in truncated form without carboxyl-terminus in hepatocellular carcinoma (HCC), but its functional mechanisms are not fully defined. In this report, we investigated frequency of this natural HBx mutant in HCCs and its functional significance. In 102 HBV-infected patients with HCC, C-terminal truncation of HBx, in contrast to full-length HBx, were more prevalent in tumors (70.6%) rather than adjacent non-tumorous tissues (29.4%) (p = 0.0032). Furthermore, two naturally-occurring HBx variants (HBx?31), which have 31 amino acids (aa) deleted (codons 123-125/124-126) at C-terminus were identified in tumors and found that the presence of HBx?31 significantly correlated with intrahepatic metastasis. We also show that over-expression of HBx?31 enhanced hepatoma cell invasion in vitro and metastasis in vivo compared to full-length HBx. Interestingly, HBx?31 exerts this function via down-regulating Maspin, RhoGDI? and CAPZB, a set of putative metastasis-suppressors in HCC, in part, by enhancing the binding of transcriptional repressor, myc-associated zinc finger protein (MAZ) to the promoters through physical association with MAZ. Notably, these HBx?31-repressed proteins were also significantly lower expression in a subset of HCC tissues with C-terminal HBx truncation than the adjacent non-tumorous tissues, highlighting the clinical significance of this novel HBx?31-driven metastatic molecular cascade. Our data suggest that C-terminal truncation of HBx, particularly breakpoints at 124aa, plays a role in enhancing hepatoma cell invasion and metastasis by deregulating a set of metastasis-suppressors partially through MAZ, thus uncovering a novel mechanism for the progression of HBV-associated hepatocarcinogenesis.

| S-EPMC5342405 | biostudies-literature

C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells.

Project description:Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx. [BMB Reports 2019; 52(5): 330-335].

| S-EPMC6549916 | biostudies-literature

Carboxyl-terminal truncated HBx regulates a distinct microRNA transcription program in hepatocellular carcinoma development.

Project description:BACKGROUND: The biological pathways and functional properties by which misexpressed microRNAs (miRNAs) contribute to liver carcinogenesis have been intensively investigated. However, little is known about the upstream mechanisms that deregulate miRNA expressions in this process. In hepatocellular carcinoma (HCC), hepatitis B virus (HBV) X protein (HBx), a transcriptional trans-activator, is frequently expressed in truncated form without carboxyl-terminus but its role in miRNA expression and HCC development is unclear. METHODS: Human non-tumorigenic hepatocytes were infected with lentivirus-expressing full-length and carboxyl-terminal truncated HBx (Ct-HBx) for cell growth assay and miRNA profiling. Chromatin immunoprecipitation microarray was performed to identify the miRNA promoters directly associated with HBx. Direct transcriptional control was verified by luciferase reporter assay. The differential miRNA expressions were further validated in a cohort of HBV-associated HCC tissues using real-time PCR. RESULTS: Hepatocytes expressing Ct-HBx grew significantly faster than the full-length HBx counterparts. Ct-HBx decreased while full-length HBx increased the expression of a set of miRNAs with growth-suppressive functions. Interestingly, Ct-HBx bound to and inhibited the transcriptional activity of some of these miRNA promoters. Notably, some of the examined repressed-miRNAs (miR-26a, -29c, -146a and -190) were also significantly down-regulated in a subset of HCC tissues with carboxyl-terminal HBx truncation compared to their matching non-tumor tissues, highlighting the clinical relevance of our data. CONCLUSION: Our results suggest that Ct-HBx directly regulates miRNA transcription and in turn promotes hepatocellular proliferation, thus revealing a viral contribution of miRNA deregulation during hepatocarcinogenesis.

| S-EPMC3150371 | biostudies-other

Differential gene expression profiling of MIHA cells transfected with C-terminal truncated HBx mutants

2016-08-02 | GSE71993 | GEO

Differential gene expression profiling of MIHA cells transfected with C-terminal truncated HBx mutants

Project description:To compare the differentially expressed transcriptomes between MIHA cells transfected with empty vector control or different C-terminal truncated HBx mutants (14 or 35 amino acid carboxyl-terminal truncation - i.e. d14 and d35) mRNA profiles of MIHA cells stably overexpressing empty vector control or different C-terminal truncated HBx mutants (delta 14 and delta 35) were generated by PolyA mRNA sequencing using Illumina HiSeq 1500 platform

2016-08-02 | E-GEOD-71993 | biostudies-arrayexpress

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