69 results on '"Ji-Hua Ren"'
Search Results
2. RNA-binding protein RPS7 promotes hepatocellular carcinoma progression via LOXL2-dependent activation of ITGB1/FAK/SRC signaling
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Yu-Jiao Zhou, Min-Li Yang, Xin He, Hui-Ying Gu, Ji-Hua Ren, Sheng-Tao Cheng, Zhou Fu, Zhen-Zhen Zhang, and Juan Chen
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Hepatocellular carcinoma ,RNA-binding protein ,Ribosomal protein S7 ,Lysyl oxidase-like 2 ,Focal adhesion ,Metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Metastasis is one of the leading cause contributes to treatment failure and poor prognosis of hepatocellular carcinoma (HCC) patients. The underlying mechanism of HCC metastasis remains to be determined. Although several RNA binding proteins (RBPs) have been found to participate in tumorigenesis and progression of liver cancer, the role of RBPs in HCC patients with extrahepatic metastases is poorly understood. Methods By performing RNA-seq of primary HCC tissues (including HCC with extrahepatic metastasis and those did not develop metastasis), we identified a set of HCC metastasis-associated RBPs candidates. Among which, ribosomal protein S7 (RPS7) was found to be remarkably increased in HCC tissues and be strongly related to HCC poor survival. Overexpression or CRISPR-Cas9–mediated knockout were applied to investigate the role of RPS7 on the metastasis-associated phenotypes of HCC cells. RNA sequencing, RIP, RNA-pull down, dual luciferase reporter assay, nascent RNA capture assay, and RNA decay and so on, were applied to reveal the underlying mechanism of RPS7 induced HCC metastasis. Results Gain- and loss- of function analyses revealed that RPS7 promoted HCC cells adhesion, migration and invasion capabilities, as well as lung metastasis. Mechanistically, we uncovered that lysyl oxidase-like 2 (LOXL2) was a critical downstream target of RPS7. RPS7 could stabilize LOXL2 mRNA by binding to AUUUA motifs in the 3155–3375 region of the 3’UTR of LOXL2 mRNA, thus increased LOXL2 expression via elevating LOXL2 mRNA abundance. Further research revealed that LOXL2 could accelerate focal adhesion formation through maintaining the protein stability of ITGB1 and activating ITGB1-mediated FAK/SRC signaling pathway, and thereby contribute to the pro-metastasis effect of RPS7. Conclusions Taken together, our data reveal a novel function of RPS7 in HCC metastasis, also reveal the critical roles of the RPS7/LOXL2/ITGB1 axis in HCC metastasis and shed new light on the exploration of molecular drugs against HCC.
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- 2024
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3. Rapamycin inhibits hepatitis B virus covalently closed circular DNA transcription by enhancing the ubiquitination of HBx
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Yuan Zhang, Liang Li, Sheng-Tao Cheng, Yi-Ping Qin, Xin He, Fan Li, Dai-Qing Wu, Fang Ren, Hai-Bo Yu, Jing Liu, Juan Chen, Ji-Hua Ren, and Zhen-Zhen Zhang
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rapamycin ,hepatitis B virus ,HBx ,covalently closed circular DNA ,transcription ,Microbiology ,QR1-502 - Abstract
Hepatitis B virus (HBV) infection is still a serious public health problem worldwide. Antiviral therapies such as interferon and nucleos(t)ide analogs efficiently control HBV replication, but they cannot eradicate chronic hepatitis B (CHB) because of their incapacity to eliminate endocellular covalently closed circular DNA (cccDNA). Thus, there is a necessity to develop new strategies for targeting cccDNA. As cccDNA is difficult to clear, transcriptional silencing of cccDNA is a possible effective strategy. HBx plays a vitally important role in maintaining the transcriptional activity of cccDNA and it could be a target for blocking the transcription of cccDNA. To screen new drugs that may contribute to antiviral therapy, the ability of 2,000 small-molecule compounds to inhibit HBx was examined by the HiBiT lytic detection system. We found that the macrolide compound rapamycin, which is clinically used to prevent acute rejection after organ transplantation, could significantly reduce HBx protein expression. Mechanistic studies demonstrated that rapamycin decreased the stability of the HBx protein by promoting its degradation via the ubiquitin-proteasome system. Moreover, rapamycin inhibited HBV RNA, HBV DNA, and cccDNA transcription levels in HBV-infected cells. In addition, HBx deficiency abrogated the inhibition of cccDNA transcription induced by rapamycin. Similar results were also confirmed in a recombinant cccDNA mouse model. In summary, we report a new small-molecule, rapamycin, which targets HBx to block HBV cccDNA transcription and inhibit HBV replication. This approach can identify new strategies to cure CHB.
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- 2022
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4. Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity
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Si-Yu Yuan, Hai-Bo Yu, Zhen Yang, Yi-Ping Qin, Ji-Hua Ren, Sheng-Tao Cheng, Fang Ren, Betty Yuen Kwan Law, Vincent Kam Wai Wong, Jerome P. L. Ng, Yu-Jiao Zhou, Xin He, Ming Tan, Zhen-Zhen Zhang, and Juan Chen
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hepatitis B virus ,HBsAg ,pimobendan ,anti-HBV agents ,drug repurposing ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.
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- 2022
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5. HBx Mediated Increase of DDX17 Contributes to HBV-Related Hepatocellular Carcinoma Tumorigenesis
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Mei-Ling Dong, Xu Wen, Xin He, Ji-Hua Ren, Hai-Bo Yu, Yi-Ping Qin, Zhen Yang, Min-Li Yang, Chong-Yang Zhou, Hui Zhang, Sheng-Tao Cheng, and Juan Chen
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DDX17 ,HBx ,HCC ,metastasis ,ZWINT ,Immunologic diseases. Allergy ,RC581-607 - Abstract
HBV is strongly associated with HCC development and DEAD-box RNA helicase 17 (DDX17) is a very important member of the DEAD box family that plays key roles in HCC development by promoting cancer metastasis. However, the important role of DDX17 in the pathogenesis of HBV-related HCC remains unclear. In this study, we investigated the role of DDX17 in the replication of HBV and the development of HBV-associated HCC. Based on data from the GEO database and HBV-infected cells, we found that DDX17 was upregulated by the HBV viral protein X (HBx). Mechanistically, increased DDX17 expression promoted HBV replication and transcription by upregulating ZWINT. Further study showed that DDX17 could promote HBx-mediated HCC metastasis. Finally, the promotive effect of DDX17 on HBV and HBV-related HCC was confirmed in vivo. In summary, the results revealed the novel role of DDX17 in the replication of HBV and the metastasis of HBV-associated HCC.
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- 2022
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6. SIRT2 Promotes HBV Transcription and Replication by Targeting Transcription Factor p53 to Increase the Activities of HBV Enhancers and Promoters
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Dai-Qing Wu, Qiu-Ying Ding, Na-Na Tao, Ming Tan, Yuan Zhang, Fan Li, Yu-Jiao Zhou, Mei-Ling Dong, Sheng-Tao Cheng, Fang Ren, Juan Chen, and Ji-Hua Ren
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hepatitis B virus ,SIRT2 ,p53 ,transcription ,cccDNA ,Microbiology ,QR1-502 - Abstract
Chronic hepatitis B (CHB) virus infection is one of the leading causes of cirrhosis and liver cancer. Although the major drugs against CHB including nucleos(t)ide analogs and PEG-interferon can effectively control human hepatitis B virus (HBV) infection, complete cure of HBV infection is quite rare. Targeting host factors involved in the viral life cycle contributes to developing innovative therapeutic strategies to improve HBV clearance. In this study, we found that the mRNA and protein levels of SIRT2, a class III histone deacetylase, were significantly upregulated in CHB patients, and that SIRT2 protein level was positively correlated with HBV viral load, HBsAg/HBeAg levels, HBcrAg, and ALT/AST levels. Functional analysis confirmed that ectopic SIRT2 overexpression markedly increased total HBV RNAs, 3.5-kb RNA and HBV core DNA in HBV-infected HepG2-Na+/taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, SIRT2 silencing inhibited HBV transcription and replication. In addition, we found a positive correlation between SIRT2 expression and HBV RNAs synthesis as well as HBV covalently closed circular DNA transcriptional activity. A mechanistic study suggested that SIRT2 enhances the activities of HBV enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The levels of HBV EnI/Xp and EnII/Cp-bound p53 were modulated by SIRT2. Both the mutation of p53 binding sites in EnI/Xp and EnII/Cp as well as overexpression of p53 abolished the effect of SIRT2 on HBV transcription and replication. In conclusion, our study reveals that, in terms of host factors, a SIRT2-targeted program might be a more effective therapeutic strategy for HBV infection.
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- 2022
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7. KAT2A Promotes Hepatitis B Virus Transcription and Replication Through Epigenetic Regulation of cccDNA Minichromosome
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Yi-Ping Qin, Hai-Bo Yu, Si-Yu Yuan, Zhen Yang, Fang Ren, Qing Wang, Fan Li, Ji-Hua Ren, Sheng-Tao Cheng, Yu-Jiao Zhou, Xin He, Hong-Zhong Zhou, Yuan Zhang, Ming Tan, Min-Li Yang, Da-Peng Zhang, Xu Wen, Mei-Ling Dong, Hui Zhang, Jing Liu, Zhi-Hong Li, Yao Chen, Ai-Long Huang, Wei-Xian Chen, and Juan Chen
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lysine acetyltransferase 2A (KAT2A) ,hepatitis B virus (HBV) ,covalently closed circular DNA (cccDNA) ,histone modification ,succinylation ,Microbiology ,QR1-502 - Abstract
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Sufficient maintenance of the HBV covalently closed circular DNA (cccDNA), which serves as a template for HBV transcription, is responsible for the failure of antiviral therapies. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation and methylation of cccDNA-bound histone 3 (H3) and histone 4 (H4), the potential contributions of histone succinylation and related host factors remain obscured. Here, by screening a series of succinyltransferases and desuccinylases, we identified KAT2A as an important host factor of HBV transcription and replication. By using HBV-infected cells and mouse models with HBV infection, KAT2A was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Mechanism studies showed that KAT2A is mainly located in the nucleus and could bind to cccDNA through interaction with HBV core protein (HBc). Moreover, we confirmed histone H3K79 succinylation (H3K79succ) as a histone modification on cccDNA minichromosome by using the cccDNA ChIP-Seq approach. Importantly, KAT2A silencing specifically reduced the level of cccDNA-bound succinylated H3K79. In conclusion, KAT2A promotes HBV transcription and replication through epigenetic machinery, and our findings may provide new insight into the treatment of HBV infection.
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- 2022
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8. NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma
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Hong-Zhong Zhou, Han-Qing Zeng, Ding Yuan, Ji-Hua Ren, Sheng-Tao Cheng, Hai-Bo Yu, Fang Ren, Qing Wang, Yi-Ping Qin, Ai-Long Huang, and Juan Chen
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NQO1 ,SIRT6 ,XIAP ,Hepatocellular carcinoma ,Apoptosis ,Medicine ,Cytology ,QH573-671 - Abstract
Abstract Background Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. Methods Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. Results We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. Conclusions Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.
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- 2019
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9. Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production
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Fang Ren, Xiao Yang, Zhong-Wen Hu, Vincent Kam Wai Wong, Hong-Yan Xu, Ji-Hua Ren, Shan Zhong, Xiao-Jiong Jia, Hui Jiang, Jie-Li Hu, Xue-Fei Cai, Wen-Lu Zhang, Fang-Long Yao, Hai-Bo Yu, Sheng-Tao Cheng, Hong-Zhong Zhou, Ai-Long Huang, Betty Yuen Kwan Law, and Juan Chen
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Keywords: Hepatitis B virus, Hepatitis B surface antigen (HBsAg), 6-Aminonicotinamide (6-AN), Anti-HBV drugs
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- 2019
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10. SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α
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Hui Jiang, Sheng-Tao Cheng, Ji-Hua Ren, Fang Ren, Hai-Bo Yu, Qing Wang, Ai-Long Huang, and Juan Chen
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OSS_128167 ,SIRT6 ,hepatitis B virus ,antiviral ,core promoter ,peroxisome proliferator-activated receptors α ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.
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- 2019
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11. Interleukin-34 inhibits hepatitis B virus replication in vitro and in vivo.
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Sheng-Tao Cheng, Hua Tang, Ji-Hua Ren, Xiang Chen, Ai-Long Huang, and Juan Chen
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Medicine ,Science - Abstract
The hepatitis B virus (HBV) infection could activate the immune system and induce extensive inflammatory response. As the most important inflammatory factor, interleukins are critical for anti-viral immunity. Here we investigated whether interleukin-34 (IL-34) play a role in HBV infection.In this study, we first found that both serum IL-34 and IL-34 mRNA in PBMCs in chronic HBV patients was significantly decreased compared to the healthy controls. Furthermore, both IL-34 protein and mRNA levels were declined hepatoma cells expressing HBV. In addition, the clinical parameters analysis found that serum IL-34 was significantly associated with HBV DNA (P = 0.0066), ALT (P = 0.0327), AST (P = 0.0435), TB (P = 0.0406), DB (P = 0.0368) and AFP (P = 0.0225). Correlation analysis also found that serum IL-34 negatively correlated with HBV DNA copies, ALT and AST. In vitro studies found that IL-34 treatment in HepAD38 and HepG2.2.15 cells markedly inhibited HBV DNA, total RNA, 3.5kb mRNA and HBc protein. In vivo studies further demonstrated IL-34 treatment in HBV transgenic mice exhibited greater inhibition on HBV DNA, total RNA, 3.5kb mRNA and HBc protein, suggesting the effect to IL-34 on HBV is likely due to host innate or adaptive immune response.Our study identified a novel interleukin, IL-34, which has anti-viral activity in HBV replication in hepatocytes in vitro and in vivo. These data suggest a rationale for the use of IL-34 in the HBV treatment.
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- 2017
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12. Protective Role of Sirtuin3 (SIRT3) in Oxidative Stress Mediated by Hepatitis B Virus X Protein Expression.
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Ji-Hua Ren, Xiang Chen, Li Zhou, Na-Na Tao, Hong-Zhong Zhou, Bo Liu, Wan-Yu Li, Ai-Long Huang, and Juan Chen
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Medicine ,Science - Abstract
The hepatitis B virus (HBV) infection is accompanied by the induction of oxidative stress, especially mediated by HBV X protein (HBx). Oxidative stress has been implicated in a series of pathological states, such as DNA damage, cell survival and apoptosis. However, the host factor by which cells protect themselves under this oxidative stress is poorly understood.In this study, we first confirmed that HBV infection significantly induced oxidative stress. Moreover, viral protein HBx plays a major role in the oxidative stress induced by HBV. Importantly, we found that mitochondrial protein SIRT3 overexpression could decrease reactive oxygen species (ROS) induced by HBx while SIRT3 knockdown increased HBx-induced ROS. Importantly, SIRT3 overexpression abolished oxidative damage of HBx-expressing cells as evidenced by γH2AX and AP sites measurements. In contrast, SIRT3 knockdown promoted HBx-induced oxidative damage. In addition, we also observed that oxidant H2O2 markedly promoted HBV replication while the antioxidant N-acetyl-L-cysteine (NAC) inhibited HBV replication. Significantly, SIRT3 overexpression inhibited HBV replication by reducing cellular ROS level.Collectively, these data suggest HBx expression induces oxidative stress, which promotes cellular oxidative damage and viral replication during HBV pathogenesis. Mitochondrial protein SIRT3 protected HBx expressing-cells from oxidative damage and inhibited HBV replication possibly by decreased cellular ROS level. These studies shed new light on the physiological significance of SIRT3 on HBx-induced oxidative stress, which can contribute to the liver pathogenesis.
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- 2016
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13. Supplementary Figure 2 from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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SIRT6 depletion increased cell sensitivity to doxorubicin. Cells in different groups with or without doxorubicin treatment were subjected to flow cytometry with Annexin V/PI (A) and to PARP cleavage analysis (B). *, p
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- 2023
14. Supplementary Figure 4 from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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SIRT6 regulates cell apoptosis via Bax signaling. mRNA microarray analysis indicated alternations in several key regulators in the Bax-mediated apoptotic pathway. *, p
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- 2023
15. Supplementary Figure 3 from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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SIRT6 overexpression promotes the proliferation of the immortalized liver cell line MIHA. (A) Trypan blue exclusion assay with MIHA cells transduced with lentiviruses expressing plenti6-SIRT6 or the corresponding empty vector. Cell numbers were counted at the indicated number of days. *, p
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- 2023
16. Table S1 from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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Primers of real-time PCR
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- 2023
17. Data from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo.Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. Clin Cancer Res; 22(13); 3372–82. ©2016 AACR.
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- 2023
18. Supplementary Figure 1 from SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
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Juan Chen, Ai-Long Huang, Wan-Yu Li, Ke Chen, Xiang Chen, Hua Tang, Li Zhou, Ji-Hua Ren, Na-Na Tao, Zhen-Zhen Zhang, Yong Chen, and Long-Kuan Ran
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Western blot analysis of SIRT6 in 53 paired HCC tissues (T) and adjacent non-tumor liver tissues (N). β-actin was used as a loading control.
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- 2023
19. Ciliatoside A, isolated from Peristrophe japonica, inhibits HBsAg expression and cccDNA transcription by inducing autophagy
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Fang, Ren, primary, Ming, Tan, additional, Ng, Jerome P.L., additional, An Guo, Wu, additional, Si Yu, Yuan, additional, Hui, Zhang, additional, Ji Hua, Ren, additional, Sheng Tao, Cheng, additional, Juan, Zhang, additional, Hang Hong, Lo, additional, Wong, Vincent Kam Wai, additional, Law, Betty Yuen Kwan, additional, and Juan, Chen, additional
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- 2023
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20. Genome-wide association study of SARS-CoV-2 infection in Chinese population
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Jie Fan, Quan-Xin Long, Ji-Hua Ren, Hao Chen, Meng-Meng Li, Zheng Cheng, Juan Chen, Li Zhou, and Ai-Long Huang
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Minor Histocompatibility Antigens ,Microbiology (medical) ,China ,Infectious Diseases ,SARS-CoV-2 ,Intracellular Signaling Peptides and Proteins ,COVID-19 ,Humans ,General Medicine ,Aminopeptidases ,Polymorphism, Single Nucleotide ,Microbiology ,Genome-Wide Association Study - Abstract
Coronavirus disease 2019 (COVID-19) is a global public health concern. The purpose of this study was to investigate the association between genetic variants and SARS-CoV-2 infection and the COVID-19 severity in Chinese population. A total of 256 individuals including 87 symptomatic patients (tested positive for SARS-CoV-2), 84 asymptomatic cases, and 85 close contacts of confirmed patients (tested negative for SARS-CoV-2) were recruited from February 2020 to May 2020. We carried out the whole exome genome sequencing between the individuals and conducted a genetic association study for SARS-CoV-2 infection and the COVID-19 severity. In total, we analyzed more than 100,000 single-nucleotide polymorphisms. The genome-wide association study suggested potential correlation between genetic variability in POLR2A, ANKRD27, MAN1A2, and ERAP1 genes and SARS-CoV-2 infection susceptibility. The most significant gene locus associated with SARS-CoV-2 infection was located in POLR2A (p = 5.71 × 10
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- 2022
21. Ciliatoside A, Isolated from Peristrophe Japonica, Inhibits Hbsag Expression and Cccdna Transcription by Inducing Autophagy
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Fang Ren, Ming Tan, Jerome P.L. Ng, An Guo Wu, Si Yu Yuan, Hui Zhang, Ji-Hua Ren, Sheng-Tao Cheng, Juan Zhang, Vincent Kam Wai Wong, Betty Yuen Kwan Law, and Juan Chen
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
22. Pimobendan Inhibits HBV Transcription and Replication by Suppressing HBV Promoters Activity
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Si-Yu Yuan, Hai-Bo Yu, Zhen Yang, Yi-Ping Qin, Ji-Hua Ren, Sheng-Tao Cheng, Fang Ren, Betty Yuen Kwan Law, Vincent Kam Wai Wong, Jerome P. L. Ng, Yu-Jiao Zhou, Xin He, Ming Tan, Zhen-Zhen Zhang, and Juan Chen
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Pharmacology ,Pharmacology (medical) - Abstract
Current anti-HBV therapeutic strategy relies on interferon and nucleos(t)ide-type drugs with the limitation of functional cure, inducing hepatitis B surface antigen (HBsAg) loss in very few patients. Notably, the level of HBsAg has been established as an accurate indicator to evaluate the drug efficacy and predict the disease prognosis, thus exploring a novel drug targeting HBsAg will be of great significance. Herein, by screening 978 compounds from an FDA-approved drug library and determining the inhibitory function of each drug on HBsAg level in HepG2.2.15 cells supernatant, we identified that pimobendan (Pim) has a powerful antiviral activity with relatively low cytotoxicity. The inhibitory effect of Pim on HBsAg as well as other HBV markers was validated in HBV-infected cell models and HBV-transgenic mice. Mechanistically, real-time PCR and dual-luciferase reporter assay were applied to identify the partial correlation of transcription factor CAAT enhancer-binding protein α (C/EBPα) with the cccDNA transcription regulated by Pim. This indicates Pim is an inhibitor of HBV transcription through suppressing HBV promoters to reduce HBV RNAs levels and HBsAg production. In conclusion, Pim was identified to be a transcription inhibitor of cccDNA, thereby inhibiting HBsAg and other HBV replicative intermediates both in vitro and in vivo. This report may provide a promising lead for the development of new anti-HBV agent.
- Published
- 2021
23. SIRT2 Promotes HBV Transcription and Replication by Targeting Transcription Factor p53 to Increase the Activities of HBV Enhancers and Promoters
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Dai-Qing Wu, Qiu-Ying Ding, Na-Na Tao, Ming Tan, Yuan Zhang, Fan Li, Yu-Jiao Zhou, Mei-Ling Dong, Sheng-Tao Cheng, Fang Ren, Juan Chen, and Ji-Hua Ren
- Subjects
Microbiology (medical) ,Microbiology - Abstract
Chronic hepatitis B (CHB) virus infection is one of the leading causes of cirrhosis and liver cancer. Although the major drugs against CHB including nucleos(t)ide analogs and PEG-interferon can effectively control human hepatitis B virus (HBV) infection, complete cure of HBV infection is quite rare. Targeting host factors involved in the viral life cycle contributes to developing innovative therapeutic strategies to improve HBV clearance. In this study, we found that the mRNA and protein levels of SIRT2, a class III histone deacetylase, were significantly upregulated in CHB patients, and that SIRT2 protein level was positively correlated with HBV viral load, HBsAg/HBeAg levels, HBcrAg, and ALT/AST levels. Functional analysis confirmed that ectopic SIRT2 overexpression markedly increased total HBV RNAs, 3.5-kb RNA and HBV core DNA in HBV-infected HepG2-Na+/taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, SIRT2 silencing inhibited HBV transcription and replication. In addition, we found a positive correlation between SIRT2 expression and HBV RNAs synthesis as well as HBV covalently closed circular DNA transcriptional activity. A mechanistic study suggested that SIRT2 enhances the activities of HBV enhancer I/HBx promoter (EnI/Xp) and enhancer II/HBc promoter (EnII/Cp) by targeting the transcription factor p53. The levels of HBV EnI/Xp and EnII/Cp-bound p53 were modulated by SIRT2. Both the mutation of p53 binding sites in EnI/Xp and EnII/Cp as well as overexpression of p53 abolished the effect of SIRT2 on HBV transcription and replication. In conclusion, our study reveals that, in terms of host factors, a SIRT2-targeted program might be a more effective therapeutic strategy for HBV infection.
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- 2021
24. Antibody responses to SARS-CoV-2 in patients with COVID-19
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Hua Wen Liu, Jun Yuan, Jin Jing Li, Hai Jun Deng, Shao Bo Wu, Xiao Ping Cui, Man Man Zhu, Fang Gong, Juan Chen, Jie Li Hu, Xiao He Luo, Zhi Jie Li, Xiao Feng Li, Wen Guang Tian, Li Hu, Liu Ping, Chun Hui Lang, Jing Wang, Kun Deng, Yuan Hu, Kun Wang, Li Hua Yu, Jing Fu Qiu, Deqiang Wang, Cheng Jun Xue, Yong Zhang, Bai Zhong Liu, Xiao-li Zhang, Yin Yin Xu, Yong Lin, Qing Jun Yang, Fan Zhang, Xian Xiang Zhang, Zhan Mo, Xue Fei Cai, Yao Kai Chen, Qin Li, Ailong Huang, Ji Hua Ren, Xia Mao Liu, De Chun Zhang, Ni Tang, Quanxin Long, Gui Cheng Wu, Jiang Lin Xiang, Li Wang, Pu Liao, Xiaojun Tang, Hong Xin Du, Zheng Zhou, and Chang Chun Niu
- Subjects
Adult ,Male ,0301 basic medicine ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Antibodies, Viral ,Antiviral Agents ,Asymptomatic ,General Biochemistry, Genetics and Molecular Biology ,Serology ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Seroconversion ,Pandemics ,Aged ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,General Medicine ,Middle Aged ,medicine.disease ,Pneumonia ,Titer ,030104 developmental biology ,Immunoglobulin M ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Antibody Formation ,Immunology ,biology.protein ,Female ,Antibody ,medicine.symptom ,Coronavirus Infections ,business - Abstract
We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT-PCR results and for the identification of asymptomatic infections.
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- 2020
25. DDX17-regulated alternative splicing that produced an oncogenic isoform of PXN-AS1 to promote HCC metastasis
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Haijun Deng, Juan Chen, Lu Zheng, Min-Li Yang, Ji-Hua Ren, Sheng-Tao Cheng, Ailong Huang, Yu-Jiao Zhou, Dayong Gu, Fan Li, Hong-Zhong Zhou, Weixian Chen, Jin Wang, and Yong Xu
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Male ,Carcinoma, Hepatocellular ,Carcinogenesis ,Biology ,Metastasis ,DEAD-box RNA Helicases ,Proto-Oncogene Proteins c-myc ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Isoforms ,Neoplasm Metastasis ,Enhancer ,Cell Proliferation ,Hepatology ,Alternative splicing ,Liver Neoplasms ,Intron ,Promoter ,Oncogenes ,medicine.disease ,RNA Helicase A ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,Alternative Splicing ,MicroRNAs ,RNA splicing ,Cancer research ,RNA, Long Noncoding ,Signal Transduction - Abstract
Background & aims The mechanism underlying hepatocellular carcinoma (HCC) metastasis remains unclear, many oncogenes are known to regulate this process. However, the role of alternative splicing (AS) in pro-metastatic HCC is poorly understood. Approach & results By performing RNA-seq of 9 pairs of primary HCC tissues with extrahepatic metastasis (EHMH) and 9 pairs of metastasis-free HCC tissues (MFH), we depicted the AS landscape in HCC and found that a higher frequency of AS events in EHMH compared with MFH. Moreover, 28 differentially expressed splicing regulators were identified in EHMH compared with MFH. Among these, DEAD-box RNA helicase 17 (DDX17) was significantly upregulated in EHMH and was also strongly associated with patient outcome. Functional studies indicated that DDX17 knockout inhibited the degradation of the extracellular matrix, and diminished the invasive ability of HCC cells. A significant reduction in lung metastasis induced by DDX17 deficiency was also demonstrated in a diethylnitrosamine (DEN)-induced DDX17HKO mouse model. Mechanistically, high DDX17 induced intron 3 retention of PXN-AS1 and produced a novel transcript (termed PXN-AS1-IR3). The novel transcript PXN-AS1-IR3 acted as an important promoter of HCC metastasis by inducing MYC transcription activation via recruitment the complex of Tex10 and p300 to MYC enhancer region, which leading to transcriptional activation of several metastasis-associated downstream genes. Finally, the PXN-AS1-IR3 level was significantly higher in serum and HCC tissues with extrahepatic metastasis. Conclusions DDX17 and PXN-AS1-IR3 act as important metastatic promoters by modulating MYC signaling, suggesting that DDX17 and PXN-AS1-IR3 may be potential prognostic markers for metastatic HCC.
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- 2021
26. SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome
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Xiao-Feng Shi, Fang Ren, Lin He, Yuan Hu, Yong Chen, Hai-Bo Yu, Wen Lu Zhang, Ji-Hua Ren, Hong Zhong Zhou, Zhen Zhen Zhang, Hui Jiang, Quanxin Long, Sheng-Tao Cheng, Xue Fei Cai, Weixian Chen, Hong Mei Xu, Ailong Huang, Zhong Wen Hu, Betty Yuen Kwan Law, Juan Chen, Shan Zhong, Jie Li Hu, and Vincent Kam Wai Wong
- Subjects
0301 basic medicine ,Hepatitis B virus ,Transcription, Genetic ,Virus Replication ,Catalysis ,Histones ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Hepatitis B, Chronic ,Minichromosome ,Histone methylation ,Humans ,Sirtuins ,biology ,General Medicine ,cccDNA ,Hepatitis B ,Chromatin ,Cell biology ,030104 developmental biology ,Histone ,Acetylation ,030220 oncology & carcinogenesis ,Histone methyltransferase ,DNA, Viral ,biology.protein ,Histone Methyltransferases ,DNA, Circular - Abstract
Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3–9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection.
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- 2021
27. A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A
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Ji-Hua Ren, Sheng-Tao Cheng, Zhong-Wen Hu, Hui Jiang, Hai-Bo Yu, Yuan Hu, Hong-Yan Xu, Hong-Zhong Zhou, Xue-Fei Cai, Li Zhou, Juan Chen, Vincent Kam Wai Wong, Hong-Mei Xu, Hua Tang, Yi Liu, Betty Yuen Kwan Law, Jieli Hu, Weixian Chen, Fang Ren, Lin He, Ailong Huang, and Da-Peng Chen
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Adult ,0301 basic medicine ,Biology ,Virus Replication ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Hepatitis B, Chronic ,0302 clinical medicine ,Interferon ,Cytidine Deaminase ,medicine ,Humans ,Gene silencing ,Genetic Predisposition to Disease ,APOBEC Deaminases ,Child ,Hepatitis B virus ,Hepatology ,Infant ,Interferon-alpha ,virus diseases ,Hep G2 Cells ,cccDNA ,Hepatitis B ,medicine.disease ,Virology ,digestive system diseases ,030104 developmental biology ,Viral replication ,HBeAg ,Case-Control Studies ,Child, Preschool ,Ubiquitin-Conjugating Enzymes ,030211 gastroenterology & hepatology ,DNA, Circular ,Viral load ,medicine.drug - Abstract
Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.
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- 2019
28. Down-regulation of argininosuccinate lyase induces hepatoma cell apoptosis through activating Bax signaling pathway
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Rui Gong, Sheng-Tao Cheng, Lin Xiang He, Juan Chen, Fang Ren, Hong-Zhong Zhou, and Ji-Hua Ren
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0301 basic medicine ,Arginine ,Proliferation ,Apoptosis ,Biochemistry ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,ASL ,otorhinolaryngologic diseases ,Gene silencing ,HCC ,Molecular Biology ,neoplasms ,Genetics (clinical) ,Chemistry ,Cell growth ,Cell Biology ,Argininosuccinate lyase ,digestive system diseases ,030104 developmental biology ,Cell culture ,Bax ,030220 oncology & carcinogenesis ,Cancer research ,Signal transduction - Abstract
Argininosuccinate lyase (ASL) plays an important role in the hepatic urea cycle, and can catalyze the reversible reaction of argininosuccinate to arginine and fumarate. However, the function of ASL in hepatocellular carcinoma (HCC) is not fully understood. In this study, we found that ASL expression was frequently upregulated in HCC tissues and HCC cell lines. Knock down of ASL inhibited cell proliferation and induced apoptosis in HCC cells. Mechanistic studies revealed the BCL2-associated X protein (Bax) signaling pathway which determines cancer cell apoptosis was regulated by ASL. Moreover, the depletion of Bax restored the inhibition of cell growth and reduced apoptosis initiated by ASL silencing. Together, the study demonstrated that ASL regulated HCC cell growth and apoptosis by modulating Bax signaling. Thus, the therapeutic targeting of ASL may offer options for HCC treatment.
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- 2018
29. AGK2, A SIRT2 Inhibitor, Inhibits Hepatitis B Virus Replication In Vitro And In Vivo
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Sheng-Tao Cheng, Zhong-Wen Hu, Ji-Hua Ren, Juan Chen, Hui Jiang, and Hai-Bo Yu
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0301 basic medicine ,HBsAg ,Hepatitis B virus ,AGK2 ,medicine.disease_cause ,Virus Replication ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Sirtuin 2 ,SIRT2 ,medicine ,HBV ,Animals ,Humans ,Hepatitis B e Antigens ,Furans ,Hepatitis B Surface Antigens ,biology ,RNA ,virus diseases ,General Medicine ,Hep G2 Cells ,Hepatitis B ,Virology ,digestive system diseases ,HBx ,030104 developmental biology ,HBeAg ,chemistry ,Cell culture ,Sirtuin ,biology.protein ,Quinolines ,DNA ,Research Paper - Abstract
Sirtuin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD +)-dependent class III histone deacetylase. We have reported that HBx (hepatitis B virus X protein)-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis. However, the potential anti-HBV effect of AGK2, a selective inhibitor of SIRT2, has not been reported. Here, the role of AGK2 on HBV replication was examined in the HepAD38 and HepG2-NTCP cell lines. The HBV genome was stably integrated in HepAD38 cell line which expresses HBV under the control of tetracycline. The HepG2-NTCP cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) receptor are susceptible to HBV infection. We found that AGK2 exhibited a robust anti-HBV activity with minimal hepatotoxicity. AGK2 inhibited the expression of HBV total and 3.5kb RNAs, DNA replicative intermediates and HBV core protein (HBc). Moreover, AGK2 treatment suppressed the secretion of the hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg). Importantly, AGK2 treatment inhibited serum HBV DNA, HBeAg and HBsAg levels as well as hepatic HBV DNA, RNA and HBc in the HBV transgenic mice. The results indicated that AGK2, as a SIRT2 inhibitor, might be a new therapeutic option for controlling HBV infection.
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- 2018
30. LncRNA HOTAIR modulates hepatitis B virus transcription and replication by enhancing SP1 transcription factor
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Xiao Yang, Hai-Bo Yu, Yi-Ping Qin, Ji-Hua Ren, Fang Ren, Juan Chen, Yuan Zhang, Ailong Huang, Yu-Jiao Zhou, Sheng-Tao Cheng, Ming Tan, and Chun-Li Song
- Subjects
0301 basic medicine ,Adult ,Male ,HBsAg ,Hepatitis B virus ,Cirrhosis ,Sp1 Transcription Factor ,medicine.disease_cause ,Virus Replication ,Viral Transcription ,03 medical and health sciences ,0302 clinical medicine ,Hepatitis B, Chronic ,Transcription (biology) ,Medicine ,Humans ,Gene Regulatory Networks ,Gene Silencing ,Promoter Regions, Genetic ,Sp1 transcription factor ,business.industry ,virus diseases ,HOTAIR ,Promoter ,General Medicine ,Hep G2 Cells ,medicine.disease ,digestive system diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA, Long Noncoding ,business ,Liver cancer - Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. Nearly 257 million people worldwide have been infected with HBV, resulting in 887,000 people dying of cirrhosis or liver cancer caused by chronic hepatitis B (CHB) annually. Therefore, identification of new targets against HBV is urgently needed. Long noncoding RNAs (LncRNAs) have gained widespread attention in recent years due to their function in cancer, inflammation and other diseases. Notably, a growing number of lncRNAs have been found to play a role in HBV development. In the present study, we first identified a famous lncRNA, HOTAIR, which was significantly up-regulated in HBV-infected cells and PBMCs from CHB patients. Furthermore, we evaluated the clinical relevance of HOTAIR in 20 CHB patients and found that higher levels of HOTAIR expression were associated with higher ALT/AST levels and were positively correlated with HBsAg and HBV DNA levels. In addition, functional analysis showed that HOTAIR promoted HBV transcription and replication by elevating the activities of HBV promoters via modulation of the levels of cccDNA-bound SP1. In conclusion, our study reveals that HOTAIR expression is correlated with the clinicopathological and physiological characteristics of HBV. Thus, HOTAIR may serve as a novel HBV diagnostic and therapeutic biomarker based on its ability to facilitate HBV transcription and replication.
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- 2020
31. Cytokine biomarkers of COVID-19
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Jingfu Qiu, Ni Tang, Juan Chen, Pu Liao, Xiaojun Tang, Yong Zhang, Ji-Hua Ren, Bei-zhong Liu, Yin-yin Xu, Ailong Huang, Haijun Deng, Zhan Mo, Quanxin Long, and Jieli Hu
- Subjects
Coronavirus disease 2019 (COVID-19) ,business.industry ,medicine.medical_treatment ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Serum samples ,Asymptomatic ,Cytokine ,Immune system ,Healthy individuals ,Immunology ,medicine ,Hepatocyte growth factor ,medicine.symptom ,business ,medicine.drug - Abstract
We used a new strategy to screen cytokines associated with SARS-CoV-2 infection. Cytokines that can classify populations in different states of SARS-CoV-2 infection were first screened in cross-sectional serum samples from 184 subjects by 2 statistical analyses. The resultant cytokines were then analyzed for their interrelationships and fluctuating features in sequential samples from 38 COVID-19 patients. Three cytokines, M-CSF, IL-8 and SCF, which were clustered into 3 different correlation groups and had relatively small fluctuations during SARS-CoV-2 infection, were selected for the construction of a multiclass classification model. This model discriminated healthy individuals and asymptomatic and nonsevere patients with accuracy of 77.4% but was not successful in classifying severe patients. Further searching led to a single cytokine, hepatocyte growth factor (HGF), which classified severe from nonsevere COVID-19 patients with a sensitivity of 84.6% and a specificity of 97.9% under a cutoff value of 1128 pg/ml. The level of this cytokine did not increase in nonsevere patients but was significantly elevated in severe patients. Considering its potent antiinflammatory function, we suggest that HGF might be a new candidate therapy for critical COVID-19. In addition, our new strategy provides not only a rational and effective way to focus on certain cytokine biomarkers for infectious diseases but also a new opportunity to probe the modulation of cytokines in the immune response.
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- 2020
32. A Peptide-Based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Coronavirus Disease 2019
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Yong Lin, Deqiang Wang, Wen-Guang Tian, Juan Chen, Yao-kai Chen, Xiao-li Zhang, Kai Fan, Kun Wang, Jing Wang, Haijun Deng, Quanxin Long, Yuan Hu, Yanmeng Chen, Ji-Hua Ren, Ni Tang, Jiang-Lin Xiang, Guicheng Wu, Jie Wei, Dao-Xin Wang, Chun-Yang Gan, Changlong He, Xue-Fei Cai, Liu Ping, Zhijie Li, Lu-Yi Huang, Ailong Huang, Pu Liao, Hong-xin Du, Bei-zhong Liu, Jie Li Hu, A-mei Chen, Qingzhu Gao, Fachun Zhou, and Peng Hu
- Subjects
Male ,0301 basic medicine ,Antibodies, Viral ,Immunoglobulin G ,Serology ,law.invention ,Immunoenzyme Techniques ,COVID-19 Testing ,0302 clinical medicine ,law ,Immunology and Allergy ,030212 general & internal medicine ,Polymerase chain reaction ,biology ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Middle Aged ,chemiluminescence immunoassay ,AcademicSubjects/MED00290 ,Real-time polymerase chain reaction ,Infectious Diseases ,Female ,Antibody ,Coronavirus Infections ,Adult ,COVID-19 Vaccines ,Pneumonia, Viral ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,Betacoronavirus ,Viral Proteins ,03 medical and health sciences ,Major Article ,medicine ,Humans ,Serologic Tests ,AcademicSubjects/MED00860 ,Pandemics ,Clinical Laboratory Techniques ,SARS-CoV-2 ,Serological Test ,business.industry ,COVID-19 ,medicine.disease ,Pneumonia ,030104 developmental biology ,Immunoglobulin M ,Immunoassay ,Luminescent Measurements ,Immunology ,biology.protein ,Peptides ,business - Abstract
Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel β-coronavirus, causes severe pneumonia and has spread throughout the globe rapidly. The disease associated with SARS-CoV-2 infection is named coronavirus disease 2019 (COVID-19). To date, real-time reverse-transcription polymerase chain reaction (RT-PCR) is the only test able to confirm this infection. However, the accuracy of RT-PCR depends on several factors; variations in these factors might significantly lower the sensitivity of detection. Methods In this study, we developed a peptide-based luminescent immunoassay that detected immunoglobulin (Ig)G and IgM. The assay cutoff value was determined by evaluating the sera from healthy and infected patients for pathogens other than SARS-CoV-2. Results To evaluate assay performance, we detected IgG and IgM in the sera from confirmed patients. The positive rate of IgG and IgM was 71.4% and 57.2%, respectively. Conclusions Therefore, combining our immunoassay with real-time RT-PCR might enhance the diagnostic accuracy of COVID-19.
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- 2020
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33. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice
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Chunhui Lang, Ni Tang, Xia-mao Liu, Xue-Fei Cai, Li-hua Yu, Zhijie Li, Jianglin Xiang, Li Wang, Zheng Zhou, Wen-Guang Tian, Yin-yin Xu, Fang Gong, Xiao Feng Li, Chang-chun Niu, Pu Liao, Ji-Hua Ren, Ailong Huang, Xiaojun Tang, Deqiang Wang, Yong Zhang, Cheng-jun Xue, Jin-jing Li, De-chun Zhang, Fan Zhang, Qin Li, Qing-jun Yang, Xianxiang Zhang, Bei-zhong Liu, Shao-bo Wu, Yong Lin, Kun Wang, Yuan Hu, Jing Wang, Xiaohe Luo, Liu Ping, Zhan Mo, Xiao-ping Cui, Quanxin Long, Jieli Hu, Haijun Deng, Yao-kai Chen, Xiao-li Zhang, Guicheng Wu, Huawen Liu, Jingfu Qiu, Juan Chen, and Hong-xin Du
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,biology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Serology ,Titer ,Antibody response ,Internal medicine ,Cohort ,medicine ,biology.protein ,Seroconversion ,Antibody ,business - Abstract
BackgroundWe aim to investigate the profile of acute antibody response in COVID-19 patients, and provide proposals for the usage of antibody test in clinical practice.MethodsA multi-center cross-section study (285 patients) and a single-center follow-up study (63 patients) were performed to investigate the feature of acute antibody response to SARS-CoV-2. A cohort of 52 COVID-19 suspects and 64 close contacts were enrolled to evaluate the potentiality of the antibody test.ResultsThe positive rate for IgG reached 100% around 20 days after symptoms onset. The median day of seroconversion for both lgG and IgM was 13 days after symptoms onset. Seroconversion of IgM occurred at the same time, or earlier, or later than that of IgG. IgG levels in 100% patients (19/19) entered a platform within 6 days after seroconversion. The criteria of ‘IgG seroconversion’ and ‘> 4-fold increase in the IgG titers in sequential samples’ together diagnosed 82.9% (34/41) of the patients. Antibody test aided to confirm 4 patients with COVID-19 from 52 suspects who failed to be confirmed by RT-PCR and 7 patients from 148 close contacts with negative RT-PCR.ConclusionIgM and IgG should be detected simultaneously at the early phase of infection. The serological diagnosis criterion of seroconversion or the ‘>; 4-fold increase in the IgG titer’ is suitable for a majority of COVID-19 patients. Serologic test is helpful for the diagnosis of SARS-CoV-2 infection in suspects and close contacts.
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- 2020
34. A Peptide-based Magnetic Chemiluminescence Enzyme Immunoassay for Serological Diagnosis of Corona Virus Disease 2019 (COVID-19)
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Ji-Hua Ren, Jie Wei, Yao-kai Chen, Yuan Hu, Kun Wang, Xue-Fei Cai, Haijun Deng, Quanxin Long, Kai Fan, Fachun Zhou, Qingzhu Gao, Zhijie Li, Lu-Yi Huang, Jieli Hu, Changlong He, Juan Chen, Bei-zhong Liu, Jing Wang, Chun-Yang Gan, Xiao-li Zhang, Yong Lin, Dao-Xin Wang, Pu Liao, Ailong Huang, Deqiang Wang, Liu Ping, A-mei Chen, Jianglin Xiang, Yanmeng Chen, Wen-Guang Tian, Guicheng Wu, Hong-xin Du, Peng Hu, and Ni Tang
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chemistry.chemical_classification ,medicine.diagnostic_test ,business.industry ,Outbreak ,medicine.disease ,medicine.disease_cause ,Virology ,Serology ,law.invention ,Pneumonia ,Enzyme ,chemistry ,law ,Immunoassay ,medicine ,RNA extraction ,business ,Chemiluminescence ,Coronavirus - Abstract
A respiratory illness has been spreading rapidly in China, since its outbreak in Wuhan city, Hubei province in December 2019. The illness was caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical manifestations related to SARS-CoV-2 infection ranged from no symptom to fatal pneumonia. World Health Organization (WHO) named the diseases associated with SARS-CoV-2 infection as COVID-19. Real time RT-PCR is the only laboratory test available till now to confirm the infection. However, the accuracy of real time RT-PCR depends on many factors, including sampling location and of methods, quality of RNA extraction and training of operators etc.. Variations in these factors might significantly lower the sensitivity of the detection. We developed a peptide-based luminescent immunoassay to detect IgG and IgM. Cut-off value of this assay was determined by the detection of 200 healthy sera and 167 sera from patients infected with other pathogens than SARS-CoV-2. To evaluate the performance of this assay, we detected IgG and IgM in the 276 sera from confirmed patients. The positive rate of IgG and IgM were 71.4% (197/276) and 57.2% (158/276) respectively. By combining with real time RT-PCR detection, this assay might help to enhance the accuracy of diagnosis of SARS-CoV-2 infection.
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- 2020
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35. Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx
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Betty Yuen Kwan Law, Xue-Fei Cai, Hai-Bo Yu, Hong-Mei Xu, Juan Chen, Weixian Chen, Shan Zhong, Wenlu Zhang, Sheng-Tao Cheng, Quanxin Long, Ji-Hua Ren, Jieli Hu, Ailong Huang, Hong-Zhong Zhou, Vincent Kam Wai Wong, Yuan Hu, Zhenzhen Zhang, and Fang Ren
- Subjects
0301 basic medicine ,Dicumarol ,Hepatitis B virus ,Transcription, Genetic ,viruses ,Mice, Transgenic ,medicine.disease_cause ,Transfection ,Virus Replication ,Antiviral Agents ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Hepatitis B, Chronic ,medicine ,NAD(P)H Dehydrogenase (Quinone) ,Gene silencing ,Animals ,Humans ,Viral Regulatory and Accessory Proteins ,Gene knockdown ,Hepatology ,Chemistry ,cccDNA ,Hep G2 Cells ,Dicoumarol ,digestive system diseases ,Chromatin ,Mice, Inbred C57BL ,HBx ,Disease Models, Animal ,030104 developmental biology ,Treatment Outcome ,Viral replication ,Proteolysis ,Cancer research ,Hepatocytes ,Trans-Activators ,030211 gastroenterology & hepatology ,DNA, Circular ,medicine.drug - Abstract
Background & Aims Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. Methods We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. Results Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. Conclusions Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. Lay summary Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.
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- 2020
36. Hepatitis B virus X protein modulates upregulation of DHX9 to promote viral DNA replication
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Miao Qiao, Ji-Hua Ren, Jie Hu, Yuan Hu, Ni Tang, Jieli Hu, Bocun Shen, Juan Chen, Ailong Huang, and Yanmeng Chen
- Subjects
DNA Replication ,Hepatitis B virus ,viruses ,Immunology ,Mice, Transgenic ,Biology ,Virus Replication ,medicine.disease_cause ,Microbiology ,Cell Line ,DEAD-box RNA Helicases ,Mice ,03 medical and health sciences ,Downregulation and upregulation ,Ubiquitin ,Virology ,medicine ,Animals ,Humans ,Viral Regulatory and Accessory Proteins ,Gene ,030304 developmental biology ,Cell Nucleus ,Regulation of gene expression ,0303 health sciences ,Host Microbial Interactions ,030306 microbiology ,virus diseases ,Hep G2 Cells ,Hepatitis B ,RNA Helicase A ,digestive system diseases ,Neoplasm Proteins ,Up-Regulation ,Nuclear Pore Complex Proteins ,HBx ,HEK293 Cells ,Gene Expression Regulation ,Viral replication ,DNA, Viral ,Trans-Activators ,biology.protein - Abstract
Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver diseases. During the HBV life cycle, HBV hijacks various host factors to assist viral replication. In this research, we find that the HBV regulatory protein X (HBx) can induce the upregulation of DExH-box RNA helicase 9 (DHX9) expression by repressing proteasome-dependent degradation mediated by MDM2. Furthermore, we demonstrate that DHX9 contributes to viral DNA replication in dependence on its helicase activity and nuclear localization. In addition, the promotion of viral DNA replication by DHX9 is dependent on its interaction with Nup98. Our findings reveal that HBx-mediated DHX9 upregulation is essential for HBV DNA replication.
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- 2019
37. NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma
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Ji-Hua Ren, Ailong Huang, Sheng-Tao Cheng, Fang Ren, Qing Wang, Yi-Ping Qin, Hong-Zhong Zhou, Juan Chen, Hai-Bo Yu, Han-Qing Zeng, and Ding Yuan
- Subjects
Proteasome Endopeptidase Complex ,Carcinoma, Hepatocellular ,Hepatocellular carcinoma ,lcsh:Medicine ,X-Linked Inhibitor of Apoptosis Protein ,Apoptosis ,Inhibitor of apoptosis ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,XIAP ,0302 clinical medicine ,Cell Line, Tumor ,MG132 ,NAD(P)H Dehydrogenase (Quinone) ,SIRT6 ,Humans ,Sirtuins ,Phosphorylation ,lcsh:QH573-671 ,Molecular Biology ,Protein kinase B ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Protein Stability ,lcsh:Cytology ,Cell growth ,Research ,Liver Neoplasms ,lcsh:R ,Cell Biology ,Up-Regulation ,Proteasome ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,NQO1 ,Signal transduction ,Signal Transduction - Abstract
Background Our previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated. Methods Expression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model. Results We found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially. Conclusions Collectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.
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- 2019
38. Overexpression of ubiquitin-conjugating enzyme E2 L3 in hepatocellular carcinoma potentiates apoptosis evasion by inhibiting the GSK3β/p65 pathway
- Author
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Zhenzhen Zhang, Juan Zhang, Yu-Jiao Zhou, Sheng-Tao Cheng, Juan Chen, Ji-Hua Ren, Hong-Mei Xu, Na-Na Tao, Betty Yuen Kwan Law, Vincent Kam Wai Wong, Weixian Chen, and Hong-Zhong Zhou
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Carcinoma, Hepatocellular ,Mice, Nude ,Apoptosis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Nude mouse ,Downregulation and upregulation ,In vivo ,Puma ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Phosphorylation ,neoplasms ,Cell Proliferation ,Mice, Inbred BALB C ,Glycogen Synthase Kinase 3 beta ,biology ,Chemistry ,Cell growth ,Liver Neoplasms ,Transcription Factor RelA ,medicine.disease ,biology.organism_classification ,digestive system diseases ,Up-Regulation ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Ubiquitin-Conjugating Enzymes ,Cancer research ,Signal Transduction - Abstract
UBE2L3 is a ubiquitin-conjugating protein belonging to the E2 family that consists of 153 amino acid residues. In this study, we found that UBE2L3 was generally upregulated in clinical HCC samples compared to non-tumour samples and that there was a strong association between high UBE2L3 expression and tumour size, clinical grade and prognosis in HCC patients. UBE2L3 depletion inhibited the proliferation and induced the apoptosis of HCC cells. At the molecular level, we observed that UBE2L3 depletion enhanced the protein stability of GSK3β, thus promoting the expression and activation of GSK3β. Subsequently, activated GSK3β phosphorylated p65 and promoted its nuclear translocation to increase the expression of target genes, including PUMA, Bax, Bim, Bad, and Bid. In vivo, knockout of UBE2L3 in HCC cells inhibited tumour growth in orthotopic liver injection nude mouse models. Moreover, inhibition of p65 or GSK3β significantly restored the effects induced by UBE2L3 knockout in HCC. Together, this study reveals the stimulatory effect of UBE2L3 on HCC cell proliferation, suggesting that UBE2L3 may be an important pro-tumorigenic factor in liver carcinogenesis and a potential therapeutic target of HCC.
- Published
- 2019
39. SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3‐9 homolog 1 and SET domain containing 1A histone methyltransferases
- Author
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Fang Ren, Wenlu Zhang, Hai-Bo Yu, Hua Tang, Xiang Liu, Weixian Chen, Ailong Huang, Li Zhou, Vincent Kam Wai Wong, Yong-Feng Yang, Xue-Fei Cai, Betty Yuen Kwan Law, Yuan Hu, Hong-Zhong Zhou, Sheng-Tao Cheng, Ji-Hua Ren, Juan Chen, Na-Na Tao, Rui Gong, Quanxin Long, Yi Liu, Ying Huang, Jieli Hu, Lin He, and Qiu-Xia Yang
- Subjects
0301 basic medicine ,Hepatitis B virus ,DNA, Complementary ,RNA polymerase II ,Real-Time Polymerase Chain Reaction ,Virus Replication ,medicine.disease_cause ,Sensitivity and Specificity ,Epigenesis, Genetic ,03 medical and health sciences ,Transcription (biology) ,Sirtuin 3 ,medicine ,Humans ,Hepatology ,biology ,cccDNA ,Hepatitis B ,Chromatin ,Cell biology ,PR-SET Domains ,030104 developmental biology ,Histone ,Histone methyltransferase ,DNA, Viral ,Histone Methyltransferases ,biology.protein ,Histone deacetylase - Abstract
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Maintenance of the covalently closed circular DNA (cccDNA), which serves as a template for HBV RNA transcription, is responsible for the failure of eradicating chronic HBV during current antiviral therapy. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications. In this study, we identified silent mating type information regulation 2 homolog 3 (SIRT3) as a host factor restricting HBV transcription and replication by screening seven members of the sirtuin family, which is the class III histone deacetylase. Ectopic SIRT3 expression significantly reduced total HBV RNAs, 3.5-kb RNA, as well as replicative intermediate DNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, gene silencing of SIRT3 promoted HBV transcription and replication. A mechanistic study found that nuclear SIRT3 was recruited to the HBV cccDNA, where it deacetylated histone 3 lysine 9. Importantly, occupancy of SIRT3 on cccDNA could increase the recruitment of histone methyltransferase suppressor of variegation 3-9 homolog 1 to cccDNA and decrease recruitment of SET domain containing 1A, leading to a marked increase of trimethyl-histone H3 (Lys9) and a decrease of trimethyl-histone H3 (Lys4) on cccDNA. Moreover, SIRT3-mediated HBV cccDNA transcriptional repression involved decreased binding of host RNA polymerase II and transcription factor Yin Yang 1 to cccDNA. Finally, hepatitis B viral X protein could relieve SIRT3-mediated cccDNA transcriptional repression by inhibiting both SIRT3 expression and its recruitment to cccDNA. Conclusion SIRT3 is a host factor epigenetically restricting HBV cccDNA transcription by acting cooperatively with histone methyltransferase; these data provide a rationale for the use of SIRT3 activators in the prevention or treatment of HBV infection. (Hepatology 2018).
- Published
- 2018
40. Interleukin-35 stimulates hepatitis B virus transcription and replication by targeting transcription factor HNF4α
- Author
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Ji-Hua Ren, Hai-Bo Yu, Lin He, Na-Na Tao, Fang Ren, Juan Chen, Xiang Chen, and Rui Gong
- Subjects
Male ,0301 basic medicine ,Hepatitis B virus ,HBsAg ,Mice, Transgenic ,Biology ,Virus Replication ,medicine.disease_cause ,Mice ,03 medical and health sciences ,Transcription (biology) ,Virology ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Hepatitis B e Antigens ,RNA, Messenger ,Promoter Regions, Genetic ,Transcription factor ,Hepatitis B Surface Antigens ,Interleukins ,virus diseases ,Promoter ,Hep G2 Cells ,Hepatitis B ,Recombinant Proteins ,digestive system diseases ,Up-Regulation ,Mice, Inbred C57BL ,Hepatocyte nuclear factors ,030104 developmental biology ,Gene Expression Regulation ,Hepatocyte Nuclear Factor 4 ,HBeAg ,Signal Transduction - Abstract
Hepatitis B virus (HBV) infection is a major health problem worldwide. Interleukin-35 (IL-35) is a definite immunosuppressive cytokine belonging to the IL-12 family. Nevertheless, the role of IL-35 in HBV replication remains elusive. In this study, we found that the level of HBV DNA replicative intermediates detected by qPCR and Southern blotting analysis was significantly increased by rhIL-35 in a dose-dependent manner. Moreover, HBV 3.5 kb mRNA levels were up-regulated by rhIL-35. The HBV core protein level as well as the HBsAg and HBeAg secretion levels were also increased by rhIL-35. Moreover, a mechanistic study demonstrated that IL-35 promoted HBV replication by enhancing the HBV core promoter activity. Importantly, hepatocyte nuclear factor 4α (HNF4α) was probably the target of IL-35. Mutation of the HNF4α-binding site on HBV core promoter or silencing HNF4α abolished the enhancement of HBV replication induced by IL-35. Finally, rhIL-35 was able to increase HBV replication in HBV transgenic mice. Taken together, our findings demonstrated that IL-35 has a novel role in HBV replication.
- Published
- 2018
41. HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis
- Author
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Juan Chen, Xue-Fei Cai, Ji-Hua Ren, Sheng-Tao Cheng, and Hui Jiang
- Subjects
0301 basic medicine ,Hepatitis B virus ,Carcinogenesis ,Biophysics ,Virus Replication ,SIRT2 ,Biochemistry ,03 medical and health sciences ,Sirtuin 2 ,Downregulation and upregulation ,Transcription (biology) ,Cell Line, Tumor ,Humans ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Messenger RNA ,biology ,Liver Neoplasms ,virus diseases ,Cell Biology ,Hepatitis B ,Hbv replication ,digestive system diseases ,HBx ,030104 developmental biology ,Sirtuin ,biology.protein ,Cancer research ,Histone deacetylase - Abstract
Sirtuin 2 (SIRT2) is a class III histone deacetylase that has been implicated to promote HCC development. However, the functional role of SIRT2 in HBV is still unclear. In this study, we found that HBV could upregulate SIRT2 expression. Additionally, HBx could activate SIRT2 promoter to upregulate the mRNA and protein level of SIRT2. Furthermore, we found that SIRT2 could facilitate HBV transcription and replication. Finally, we demonstrated that upregulation of SIRT2 by HBx promoted hepatocarcinogenesis. In summary, our findings revealed a novel function of SIRT2 in HBV and HBV-mediated HCC. First, SIRT2 could promote HBV replication. And then HBx-elevated SIRT2 could enhance the transformation of HBV-mediated HCC. Those findings highlight the potential role of SIRT2 in HBV and HBV-mediated HCC by interaction with HBx.
- Published
- 2018
42. Deacetylation of Ku70 by SIRT6 attenuates Bax-mediated apoptosis in hepatocellular carcinoma
- Author
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Long-Kuan Ran, Bo Liu, Juan Chen, Ji-Hua Ren, Hua Tang, Na-Na Tao, Ailong Huang, and Hong-Zhong Zhou
- Subjects
0301 basic medicine ,SIRT6 ,Carcinoma, Hepatocellular ,Blotting, Western ,Biophysics ,Gene Expression ,Apoptosis ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Sirtuins ,Gene silencing ,Ku Autoantigen ,Molecular Biology ,bcl-2-Associated X Protein ,Ku70 ,Reverse Transcriptase Polymerase Chain Reaction ,Lysine ,Liver Neoplasms ,Acetylation ,Cell Biology ,medicine.disease ,Mitochondria ,Protein Transport ,Cytosol ,030104 developmental biology ,Microscopy, Fluorescence ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Mutation ,Cancer research ,RNA Interference ,Histone deacetylase ,Protein Binding - Abstract
SIRT6 is a class III histone deacetylase that has been implicated in HCC development. We previously reported that SIRT6 potentiated apoptosis evasion in hepatocellular carcinoma by inhibiting both Bax expression and mitochondrial translocalization. However, the mechanism underlying SIRT6-mediated inhibition of Bax mitochondrial localization remains elusive. In this study, we found that although SIRT6 had no effect on the expression level of Ku70, SIRT6 could interact with Ku70 and deacetylate it. The increased acetylation of Ku70 in SIRT6-depleted cells disrupt its interaction with Bax, which finally resulted in Bax mitochondrial translocalization. Furthermore, lysine K542 on Ku70 was the target for deacetylation by SIRT6. Ku70K542Q mutation abolished suppression of association between Ku70 and Bax and caused redistribution of Bax to the cytosol in SIRT6-depleted cells. Finally, Ku70K542Q mutation could reversed the inhibition of growth and apoptosis promotion mediated by SIRT6 silencing. Together, our findings revealed SIRT6 could block the mitochondrial translocation of Bax and decrease the apoptotic ratio of HCC cells by deacetylation of Ku70. SIRT6 may serve as a promising target for developing targeted therapies for HCC in the future.
- Published
- 2017
43. Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production
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Xiaojiong Jia, Juan Chen, Shan Zhong, Hai-Bo Yu, Wenlu Zhang, Fang Ren, Sheng-Tao Cheng, Xiao Yang, Zhong-Wen Hu, Hong-Yan Xu, Betty Yuen Kwan Law, Ji-Hua Ren, Xue-Fei Cai, Ailong Huang, Fang-Long Yao, Hui Jiang, Jieli Hu, Hong-Zhong Zhou, and Vincent Kam Wai Wong
- Subjects
0301 basic medicine ,HBsAg ,Hepatitis B virus ,Research paper ,Transcription, Genetic ,lcsh:Medicine ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Virus Replication ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Hepatitis B surface antigen (HBsAg) ,medicine ,Anti-HBV drugs ,Animals ,Humans ,Viremia ,Seroconversion ,Promoter Regions, Genetic ,lcsh:R5-920 ,Hepatitis B Surface Antigens ,Nucleoside analogue ,lcsh:R ,virus diseases ,Promoter ,General Medicine ,cccDNA ,Hep G2 Cells ,Virology ,In vitro ,digestive system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,6-Aminonicotinamide ,6-Aminonicotinamide (6-AN) ,030220 oncology & carcinogenesis ,lcsh:Medicine (General) ,Biomarkers ,medicine.drug - Abstract
Background: Hepatitis B surface antigen (HBsAg) is one of the important clinical indexes for hepatitis B virus (HBV) infection diagnosis and sustained seroconversion of HBsAg is an indicator for functional cure. However, the level of HBsAg could not be reduced by interferons and nucleoside analogs effectively. Therefore, identification of a new drug targeting HBsAg is urgently needed.Methods: In this study, 6-AN was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of 6-AN on HBV was examined in HepAD38, HepG2-NTCP and PHHs cells. In addition, the antivirus effect of 6-AN was also identified in mouse model.Findings: 6-AN treatment resulted in a significant decrease of HBsAg and other viral markers both in vitro and in vivo. Furthermore, we found that 6-AN inhibited the activities of HBV SpI, SpII and core promoter by decreasing transcription factor PPARα, subsequently reduced HBV RNAs transcription and HBsAg production.Interpretation: We have identified a novel small molecule to inhibit HBV core DNA, HBV RNAs, HBsAg production, as well as cccDNA to a minor degree both in vitro and in vivo. This study may shed light on the development of a novel class of anti-HBV agent. Keywords: Hepatitis B virus, Hepatitis B surface antigen (HBsAg), 6-Aminonicotinamide (6-AN), Anti-HBV drugs
- Published
- 2019
44. Decellularized human liver scaffold‐based three‐dimensional culture system facilitate hepatitis B virus infection
- Author
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Zhang Mingman, Ji-Hua Ren, Xin Chen, Ailong Huang, HongMei Xu, Ruiqiu Zhao, L. Frenguelli, Fang Ren, Juan Chen, Giuseppe Mazza, Walid Al-Akkad, Zhang Zhenzhen, and QuanBo Liu
- Subjects
Liver Cirrhosis ,Hepatitis B virus ,HBsAg ,Materials science ,Cell Survival ,0206 medical engineering ,Biomedical Engineering ,Organic Anion Transporters, Sodium-Dependent ,02 engineering and technology ,medicine.disease_cause ,Tissue Culture Techniques ,Biomaterials ,3D cell culture ,medicine ,Humans ,Decellularization ,Symporters ,Tissue Scaffolds ,Metals and Alloys ,Hep G2 Cells ,cccDNA ,Entecavir ,Hepatitis B ,021001 nanoscience & nanotechnology ,020601 biomedical engineering ,Virology ,digestive system diseases ,In vitro ,Phenotype ,Liver ,Cell culture ,Hepatocytes ,Ceramics and Composites ,0210 nano-technology ,medicine.drug - Abstract
Hepatitis B virus (HBV) study is hampered by lacking of idea cell model which support effective HBV infection and meanwhile recapitulate hepatocyte biology function in vivo. In this study, we developed decellularized human liver scaffolds for cell culture and further applied for HBV infection. As a result, primary human hepatocytes (PHHs) engrafted into liver scaffolds and maintained differentiation with stable albumin secretion and liver-specific gene expression. Comparing to mono-layer cell culture, scaffold-based three-dimensional (3D) culture system significantly augment HBV DNA (including cccDNA), RNA level as well as HBsAg secretion. Moreover, HepG2-NTCP cells cultured on 3D system exhibited higher infection efficiency and longer infection period in vitro. In addition, HBV DNA level was suppressed when anti-HBV medicine Entecavir (ETV) introduced into HepG2-NTCP 3D system. Herein, we evaluated the potential of decellularized human liver scaffold-based in 3D cell culture and disclosed that scaffold-based 3D culture system can facilitate HBV infection in vitro. This 3D culture system could be further applied in HBV-related study. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1744-1753, 2019.
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- 2019
45. Ornithine transcarbamylase downregulation is associated with poor prognosis in hepatocellular carcinoma
- Author
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Ji-Hua Ren, Xue-Fei Cai, Zhenzhen Zhang, Juan Chen, Lin He, Sheng-Tao Cheng, Na-Na Tao, Qiu-Xia Yang, Hong-Zhong Zhou, and Fang Ren
- Subjects
0301 basic medicine ,Cancer Research ,tumor suppressor ,Cell ,Ornithine transcarbamylase ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Gene silencing ,Oncogene ,business.industry ,ornithine transcarbamylase ,Cancer ,Articles ,hepatocellular carcinoma ,Cell cycle ,medicine.disease ,Molecular medicine ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,prognosis ,business - Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortalities worldwide. The role of ornithine transcarbamylase (OTC) in HCC remains unclear. In the present study, the expression of OTC in HCC was analyzed based on datasets from the Gene Expression Omnibus database of the National Center for Biotechnology Information and further confirmed by immunohistochemistry, western blotting analysis and reverse transcription-quantitative polymerase chain reaction assays on clinical samples and cell lines. Furthermore, the associations between OTC expression and clinicopathological parameters as well as clinical outcome, including the overall and disease-free survival rates were analyzed. Finally, the effect of OTC on HCC cells was measured using proliferation, bromodeoxyuridine and colony-formation assays. Lower OTC expression was observed in HCC cells and tissues compared with primary human hepatocytes. Further investigation demonstrated that low expression of OTC in HCC was associated with larger tumor size and advanced grade. A Kaplan-Meier analysis revealed that patients with lower levels of OTC exhibited shorter overall and disease-free survival times. Notably, OTC silencing with RNA interference facilitated cell proliferation in HCC SK-Hep-1 and Huh-7 cells. However, overexpression of OTC led to inhibition of cell proliferation. In conclusion, the present study identified a novel role of OTC in HCC development, providing a potential novel therapeutic target for this disease.
- Published
- 2019
46. Niacin Analogue, 6-Aminonicotinamide, a Novel Inhibitor of Hepatitis B Virus and HBsAg Secretion
- Author
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Fang Ren, Zhong-Wen Hu, Xiao Yang, Vincent Kam Wai Wong, Hong-Yan Xu, Ji-Hua Ren, Shan Zhong, Xiao-Jiong Jia, Hui Jiang, Jie-Li Hu, Xue-Fei Cai, Wen-Lu Zhang, Fang-Long Yao, Hai-Bo Yu, Sheng-Tao Cheng, Hong-Zhong Zhou, Ai-Long Huang, Betty Yuen Kwan Law, and Juan Chen
- Published
- 2019
47. NAD(P)H: Quinone oxidoreductase 1 overexpression in hepatocellular carcinoma potentiates apoptosis evasion through regulating stabilization of X-linked inhibitor of apoptosis protein
- Author
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Juan Chen, Hong-Zhong Zhou, Yong Chen, Fang Ren, Ji-Hua Ren, Xue-Fei Cai, Hui Jiang, Weixian Chen, Hai-Bo Yu, Wenlu Zhang, Sheng-Tao Cheng, Ni Tang, Lin He, Wan-Yu Li, Hao-Yang Cai, Yao Chen, Qiu-Xia Yang, Na-Na Tao, Ailong Huang, Vincent Kam Wai Wong, Betty Yuen Kwan Law, and Hua Tang
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Carcinoma, Hepatocellular ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Inhibitor of apoptosis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,medicine ,NAD(P)H Dehydrogenase (Quinone) ,Animals ,Humans ,Phosphorylation ,Cell Line, Transformed ,Mice, Inbred BALB C ,Cell growth ,Chemistry ,Liver Neoplasms ,medicine.disease ,digestive system diseases ,XIAP ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,NAD+ kinase ,Growth inhibition - Abstract
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an antioxidant enzyme which is associated with poor prognosis in human breast, colon, lung and liver cancers. However, the molecular mechanisms underlying the pro-tumorigenic function of NQO1 remains unclear. This study investigated the function of NQO1 in the context of hepatocellular carcinoma (HCC) development. We found that NQO1 was frequently up-regulated in human liver cancer, and its high expression level was correlated with the tumor stage and low survival rate of HCC patients. Loss-of-function of NQO1 inhibited growth in HCC cells with increased apoptosis in vitro, and suppressed orthotopic tumorigenicity in vivo. Mechanistically, high level of NQO1 in HCC cells enhanced protein stability of X-linked inhibitor of apoptosis protein (XIAP) by increasing its phosphorylation at Ser 87. Reintroduction of wile type XIAP and the phospho-mimic mutants XIAPS87D significantly reversed NQO1 knock-down/out induced growth inhibition and apoptosis. In mouse model with orthotopically implanted hepatocarcinoma, NQO1 suppression and NQO1 inhibitor suppressed tumor growth and induced apoptosis. NQO1 plays an important role in sustaining HCC cell proliferation and may thus act as a potential therapeutic target in HCC treatment.
- Published
- 2018
48. PBK overexpression promotes metastasis of hepatocellular carcinoma via activating ETV4-uPAR signaling pathway
- Author
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Li Zhou, Xiaojiong Jia, Hai-Bo Yu, Juan Chen, Fang Ren, Shan Zhong, Ji-Hua Ren, Rui Gong, Hong-Zhong Zhou, Ailong Huang, Qiu-Xia Yang, Hua Tang, Sheng-Tao Cheng, Zhong-Wen Hu, and Lin He
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Carcinoma, Hepatocellular ,Mice, Nude ,Receptors, Cell Surface ,Biology ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Neoplasm Metastasis ,RNA, Small Interfering ,neoplasms ,Mitogen-Activated Protein Kinase Kinases ,Gene knockdown ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Proto-Oncogene Proteins c-ets ,Kinase ,Liver Neoplasms ,Hep G2 Cells ,Middle Aged ,medicine.disease ,Prognosis ,Urokinase receptor ,030104 developmental biology ,Mannose-Binding Lectins ,Oncology ,Liver ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Cancer research ,Female ,RNA Interference ,Signal transduction ,Chromatin immunoprecipitation ,Signal Transduction - Abstract
Invasion and metastasis are the predominant causes of lethal outcomes in patients with hepatocellular carcinoma (HCC). However, the molecular mechanism underlying the invasive or metastatic process are still insufficiently understood. Here, we first integrated several public databases and identified a novel protein kinase, PDZ-binding kinase (PBK) that was frequently upregulated and correlated with poor prognosis in patients with HCC. Gain- or loss-of-function analysis revealed that PBK promoted migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, PBK enhanced uPAR expression by activating its promoter activity. Chromatin immunoprecipitation (ChIP) assay showed that ETV4 directly bound to the core region of uPAR promoter while PBK could enhance the binding of ETV4 to uPAR promoter. In orthotopic mouse model, PBK knockdown markedly inhibited the lung metastasis of HCC cells, while this effect was significantly restored by uPAR overexpression. Finally, there was a positive correlation between PBK and uPAR, ETV4 and uPAR in HCC clinical samples. Collectively, these findings revealed that PBK acted as a crucial kinase by promoting invasion and migration via the ETV4-uPAR signaling pathway, and it therefore could be a promising diagnostic biomarker and therapeutic target for HCC metastasis.
- Published
- 2018
49. SIRT7 restricts HBV transcription and replication through catalyzing desuccinylation of histone H3 associated with cccDNA minichromosome.
- Author
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Hai-Bo Yu, Sheng-Tao Cheng, Fang Ren, Yong Chen, Xiao-Feng Shi, Kam Wai Wong, Vincent, Yuen Kwan Law, Betty, Ji-Hua Ren, Shan Zhong, Wei-Xian Chen, Hong-Mei Xu, Zhen-Zhen Zhang, Jie-Li Hu, Xue-Fei Cai, Yuan Hu, Wen-Lu Zhang, Quan-Xin Long, Lin He, Zhong-Wen Hu, and Hui Jiang
- Subjects
HEPATITIS B virus ,CHRONIC hepatitis B ,HEPATITIS B ,CIRCULAR DNA ,HISTONE acetylation - Abstract
Chronic hepatitis B virus (HBV) infection is a significant public health burden worldwide. HBV covalently closed circular DNA (cccDNA) organized as a minichromosome in nucleus is responsible for viral persistence and is the key obstacle for a cure of chronic hepatitis B (CHB). Recent studies suggest cccDNA transcription is epigenetically regulated by histone modifications, especially histone acetylation and methylation. In the present study, we identified transcriptionally active histone succinylation (H3K122succ) as a new histone modification on cccDNA minichromosome by using cccDNA ChIP-Seq approach. Silent mating type information regulation 2 homolog 7 (SIRT7), as an NAD+-dependent histone desuccinylase, could bind to cccDNA through interaction with HBV core protein where it catalyzed histone 3 lysine 122 (H3K122) desuccinylation. Moreover, SIRT7 acts cooperatively with histone methyltransferase, suppressor of variegation 3-9 homolog 1 (SUV39H1) and SET domain containing 2 (SETD2) to induce silencing of HBV transcription through modulation of chromatin structure. Our data improved the understanding of histone modifications of the cccDNA minichromosome, thus transcriptional silencing of cccDNA may represent a novel antiviral strategy for the prevention or treatment of HBV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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50. SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
- Author
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Na-Na Tao, Zhenzhen Zhang, Juan Chen, Ji-Hua Ren, Hua Tang, Ailong Huang, Yong Chen, Xiang Chen, Long-Kuan Ran, Ke Chen, Li Zhou, and Wan-Yu Li
- Subjects
Male ,Transcriptional Activation ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Cell Survival ,Apoptosis ,Histones ,Mice ,03 medical and health sciences ,Bcl-2-associated X protein ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Sirtuins ,RNA, Messenger ,RNA, Small Interfering ,Promoter Regions, Genetic ,Transcription factor ,Cell Proliferation ,bcl-2-Associated X Protein ,Mice, Inbred BALB C ,Gene knockdown ,Antibiotics, Antineoplastic ,biology ,Liver Neoplasms ,Cancer ,Hep G2 Cells ,medicine.disease ,Enzyme Activation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Doxorubicin ,biology.protein ,Cancer research ,RNA Interference ,Tumor Suppressor Protein p53 ,Signal transduction ,Liver cancer ,E2F1 Transcription Factor ,Protein Binding ,Signal Transduction ,Deacetylase activity - Abstract
Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC). Experimental Design: The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo. Results: SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro. At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples. Conclusions: SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. Clin Cancer Res; 22(13); 3372–82. ©2016 AACR.
- Published
- 2016
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