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  • 1
    Online Resource
    Online Resource
    Hepatitis transactivator protein X promotes extracellular matrix modification through HIF/LOX pathway in liver cancer
    Springer Science and Business Media LLC ; 2018
    In:  Oncogenesis Vol. 7, No. 5 ( 2018-05-25)
    Details
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 7, No. 5 ( 2018-05-25)
    Abstract: Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancer, is a lethal malignancy that is tightly associated with chronic hepatitis B virus (HBV) infection. HBV encodes a viral onco-protein, transactivator protein X (HBx), which interacts with proteins of hepatocytes to promote oncogenesis. Our current study focused on the interaction of HBx with a transcription factor, hypoxia-inducible factor-1α (HIF-1α), which is stabilized by low O 2 condition (hypoxia) and is found to be frequently overexpressed in HCC intra-tumorally due to poor blood perfusion. Here, we showed that overexpression of HBx by tetracycline-inducible systems further stabilized HIF-1α under hypoxia in HBV-negative HCC cell lines. Reversely, knockdown of HBx reduced HIF-1α protein stabilization under hypoxia in HBV-positive HCC cell lines. More intriguingly, overexpression of HBx elevated the mRNA and protein expression of a family of HIF-1α target genes, the lysyl oxidase (LOX) family in HCC. The LOX family members function to cross-link collagen in the extracellular matrix (ECM) to promote cancer progression and metastasis. By analyzing the collagens under scanning electron microscope, we found that collagen fibers were significantly smaller in size when incubated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells in vitro. Transwell invasion assay further revealed that less cells were able to invade through the matrigel which was pre-treated with conditioned medium from HBx knockdown HCC cells as compared to control HCC cells. Orthotopic and subcutaneous HCC models further showed that knockdown of HBx in HCC cells reduced collagen crosslinking and stiffness in vivo and repressed HCC growth and metastasis. Taken together, our in vitro and in vivo studies showed the HBx remodeled the ECM through HIF-1α/LOX pathway to promote HCC metastasis.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    URL: Article
    DOI: 10.1038/s41389-018-0052-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2674437-5
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  • 2
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    Polo‐like kinase 4 inhibitor CFI‐400945 suppresses liver cancer through cell cycle perturbation and eliciting antitumor immunity
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Hepatology Vol. 77, No. 3 ( 2023-03), p. 729-744
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 77, No. 3 ( 2023-03), p. 729-744
    Abstract: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo‐like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. Approach and Results: An orally available PLK4 inhibitor, CFI‐400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI‐400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41–stimulator of interferon genes–interferon regulatory factor 3/7–NF‐κβ cytosolic DNA sensing pathway, thereby driving the transcription of senescence‐associated secretory phenotypes, which recruit immune cells. CFI‐400945 was evaluated in liver‐specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor‐infiltrated immune cells were analyzed. CFI‐400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4–positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI‐400945 with anti–programmed death‐1 showed a tendency to improve HCC survival. Conclusions: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing‐mediated immune response, CFI‐400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late‐stage mouse HCC.
    Type of Medium: Online Resource
    ISSN: 0270-9139
    URL: Article
    DOI: 10.1002/hep.32461
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 604603-4
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  • 3
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    Online Resource
    Histone methyltransferase G9a promotes liver cancer development by epigenetic silencing of tumor suppressor gene RARRES3
    Elsevier BV ; 2017
    In:  Journal of Hepatology Vol. 67, No. 4 ( 2017-10), p. 758-769
    Details
    In: Journal of Hepatology, Elsevier BV, Vol. 67, No. 4 ( 2017-10), p. 758-769
    Type of Medium: Online Resource
    ISSN: 0168-8278
    URL: Article
    DOI: 10.1016/j.jhep.2017.05.015
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 605953-3
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  • 4
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    Hepatocellular Carcinoma Cells Up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice
    Elsevier BV ; 2020
    In:  Gastroenterology Vol. 159, No. 2 ( 2020-08), p. 609-623
    Details
    In: Gastroenterology, Elsevier BV, Vol. 159, No. 2 ( 2020-08), p. 609-623
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1053/j.gastro.2020.03.074
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 80112-4
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  • 5
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    Abstract 2429: HIF-1α repressed glycerol-3-phosphate shuttle to reduce oxidative stress in liver cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2429-2429
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2429-2429
    Abstract: Liver cancer is the fifth most prevalent and third most common cancer globally. Hepatocellular carcinoma (HCC), arises from hepatocytes, accounts for more than 80% of liver cancer. HCC cells undergo extensive metabolic rewiring to support their uncontrolled growth. HCC cells encounter extremely high level of oxidative stress which is mostly generated in the electron transport chain. Reactive oxygen species (ROS) rapidly accumulate in the electron transport chain (ETC) during hypoxia due to inadequate electron transfer to O2 in the ETC. The glycerol phosphate (GP) shuttle plays an important role to transfer electron source (NADH) from cytoplasm to mitochondria to initiate the ETC. The GP shuttle is mediated by glycerol 3 phosphate dehydrogenase (GPD) which converts dihydroxyacetone phosphate to glycerol 3 phosphate (G3P) through the oxidation of NADH to NAD+. This contributes to ATP production in the mitochondria. Here, we reported that hypoxia-inducible factor 1 (HIF-1) acts as a transcriptional repressor instead of an activator to suppress transcription of an important ETC component of the glycerol phosphate shuttle (GPD) to reduce activity of the GP shuttle, thereby reducing oxidative stress. GPD expression was significantly reduced under hypoxic condition. Surprisingly, knockout, knockdown, or inhibition of HIF-1 restored GPD expression in hypoxia. GPD expression was significantly under-expressed in tumorous as compared to non-tumorous liver tissues in 91 HCC patients of our center by 2.67 fold. TCGA database containing 49 HCC patients echoed with our in-house data. Downregulation of GPD was associated with poor cellular differentiation and overall survival in HCC patients. Stable overexpression of GPD1 in multiple HCC cell lines increased the levels of G3P as well as NAD+, which is crucial to lactate dehydrogenase (LDHA) activity. GPD overexpression altered mitochondrial activity, ROS levels, and suppressed HCC cell proliferation. Taken together, this study showed that the HIF-1 negatively controls key component of the GP shuttle to maximize HCC growth. Citation Format: Shuo ZHANG, Robin Kit-Ho LAI, David Kung-Chun CHIU, Iris Mingjing XU, Aki Pui Wah TSE, Chun-Ming WONG, Irene Oi Lin NG, Carmen Chak Lui WONG. HIF-1α repressed glycerol-3-phosphate shuttle to reduce oxidative stress in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2429.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2429
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
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    Abstract 882: Thioredoxin system inhibition using auranofin represents a new therapeutic approach for hepatocellular carcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 882-882
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 882-882
    Abstract: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and third leading cause of cancer deaths worldwide due to late symptom presentation and ineffective treatments. Currently, tyrosine kinase inhibitors Sorafenib and Lenvatinib are the only FDA-approved first-line treatment for HCC patients. Cancer cells experience distinctly high amount of oxidative stress compared to normal cells. Reactive oxygen species (ROS) are by-products of metabolism. However, cancer cells’ metabolic activities are hyper-activated as they have greater demands for energy, thereby also resulting in greater amounts of ROS generated. Besides, oncogenes and properties of the tumor microenvironment like ER stress and hypoxia also contribute to ROS generation in cancer cells. With higher concentrations of ROS, cancer cells also have increased antioxidant production capacity to counteract ROS. NADPH is a major metabolite and antioxidant immensely generated by cancer cells. In human HCC, our group previously found the pentose phosphate pathway and folate cycle to be major metabolic pathways of NADPH production. The thioredoxin system is a ubiquitous mammalian antioxidant system that is activated by the antioxidant system-activating electron donor NADPH. Thioredoxin reductase 1 (TXNRD1) is the sole activating-enzyme of the thioredoxin system through transmission of electron from NADPH to TXN, the ROS-scavenging member of the thioredoxin system. TXNRD1 is imperative for maintenance of intracellular redox homeostasis as confirmed when NRF2 was found to be the transcription activator of TXNRD1. Overexpression of TXNRD1 was found in human HCC with significant correlations with poor clinical prognosis and patient survival. Altogether, these findings are indicative of redox balance being vital for HCC growth. Loss-of-function studies utilizing shRNA-mediated inhibition of TXNRD1 resulted in significant induction of oxidative stress which suppressed HCC growth. The resulting oxidative stress also sensitized HCC cells towards its conventional therapeutic Sorafenib. Translationally, pharmacological TXNRD1 inhibitor auranofin (AUR) also induced oxidative stress which greatly sensitized HCC cells towards Sorafenib. Synergism between AUR and Sorafenib was observed as oxidative stress accumulations dramatically induced apoptosis in vitro and suppressed tumor formation in vivo. Our investigation demonstrated oxidative stress induction through inhibition of the thioredoxin system sensitized HCC cells towards conventional therapeutics. Combination of TXNRD1 inhibitor AUR and Sorafenib represents a novel treatment regimen, with enhanced efficacy, for HCC patients. Citation Format: Derek Lee, Iris Ming-Jing Xu, David Kung-Chun Chiu, Robin Kit-Ho Lai, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong. Thioredoxin system inhibition using auranofin represents a new therapeutic approach for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 882.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-882
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
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  • 7
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    Online Resource
    Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma
    Springer Science and Business Media LLC ; 2017
    In:  Nature Communications Vol. 8, No. 1 ( 2017-09-11)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2017-09-11)
    Abstract: Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-017-00530-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2553671-0
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  • 8
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    Online Resource
    Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma
    American Society for Clinical Investigation ; 2017
    In:  Journal of Clinical Investigation Vol. 127, No. 5 ( 2017-4-10), p. 1856-1872
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 127, No. 5 ( 2017-4-10), p. 1856-1872
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    URL: Article
    DOI: 10.1172/JCI90253
    DOI: 10.1172/JCI90253DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2017
    detail.hit.zdb_id: 3067-3
    detail.hit.zdb_id: 2018375-6
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  • 9
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    Online Resource
    Hypoxia induces myeloid‐derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C‐C motif) ligand 26
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Hepatology Vol. 64, No. 3 ( 2016-09), p. 797-813
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 64, No. 3 ( 2016-09), p. 797-813
    Abstract: A population of stromal cells, myeloid‐derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O 2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia‐induced MDSC infiltration is dependent on hypoxia‐inducible factors. We further found that hypoxia‐inducible factors activate the transcription of chemokine (C‐C motif) ligand 26 in cancer cells to recruit chemokine (C‐X3‐C motif) receptor 1‐expressing MDSCs to the primary tumor. Knockdown of chemokine (C‐C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C‐C motif) ligand 26 production in cancer cells by the hypoxia‐inducible factor inhibitor digoxin or blockade of chemokine (C‐X3‐C motif) receptor 1 in MDSCs by chemokine (C‐X3‐C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. Conclusion : This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (H epatology 2016;64:797‐813)
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.28655
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 604603-4
    detail.hit.zdb_id: 1472120-X
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  • 10
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    RNA N6‐methyladenosine methyltransferase‐like 3 promotes liver cancer progression through YTHDF2‐dependent posttranscriptional silencing of SOCS2
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hepatology Vol. 67, No. 6 ( 2018-06), p. 2254-2270
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 67, No. 6 ( 2018-06), p. 2254-2270
    Abstract: Epigenetic alterations have contributed greatly to human carcinogenesis. Conventional epigenetic studies have predominantly focused on DNA methylation, histone modifications, and chromatin remodeling. Recently, diverse and reversible chemical modifications of RNAs have emerged as a new layer of epigenetic regulation. N6‐methyladenosine (m6A) is the most abundant chemical modification of eukaryotic messenger RNA (mRNA) and is important for the regulation of mRNA stability, splicing, and translation. Using transcriptome sequencing, we discovered that methyltransferase‐like 3 (METTL3), a major RNA N6‐adenosine methyltransferase, was significantly up‐regulated in human hepatocellular carcinoma (HCC) and multiple solid tumors. Clinically, overexpression of METTL3 is associated with poor prognosis of patients with HCC. Functionally, we proved that knockdown of METTL3 drastically reduced HCC cell proliferation, migration, and colony formation in vitro . Knockout of METTL3 remarkably suppressed HCC tumorigenicity and lung metastasis in vivo . On the other hand, using the CRISPR/dCas9‐VP64 activation system, we demonstrated that overexpression of METTL3 significantly promoted HCC growth both in vitro and in vivo . Through transcriptome sequencing, m6A sequencing, and m6A methylated RNA immuno‐precipitation quantitative reverse‐transcription polymerase chain reaction, we identified suppressor of cytokine signaling 2 (SOCS2) as a target of METTL3‐mediated m6A modification. Knockdown of METTL3 substantially abolished SOCS2 mRNA m6A modification and augmented SOCS2 mRNA expression. We also showed that m6A‐mediated SOCS2 mRNA degradation relied on the m6A reader protein YTHDF2‐dependent pathway. Conclusion : METTL3 is frequently up‐regulated in human HCC and contributes to HCC progression. METTL3 represses SOCS2 expression in HCC through an m6A‐YTHDF2‐dependent mechanism. Our findings suggest an important mechanism of epigenetic alteration in liver carcinogenesis. (H epatology 2018;67:2254‐2270).
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.29683
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 604603-4
    detail.hit.zdb_id: 1472120-X
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