|
1
|
Xu M, Warner C, Duan X, Cheng Z, Jeyarajan AJ, Li W, Wang Y, Shao T, Salloum S, Chen PJ, Yu X, Chung RT, Lin W. HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-β1-dependent pathway. J Hepatol 2024; 80:868-881. [PMID: 38311121 PMCID: PMC11102332 DOI: 10.1016/j.jhep.2024.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 12/05/2023] [Accepted: 01/25/2024] [Indexed: 02/06/2024]
Abstract
BACKGROUND & AIMS Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-β1 signaling. METHODS The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. RESULTS We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-β1 (TGF-β1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-β1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-β1-induced fibrogenesis. CONCLUSIONS Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-β1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. IMPACT AND IMPLICATIONS HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-β1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.
Collapse
Affiliation(s)
- Min Xu
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Charlotte Warner
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Xiaoqiong Duan
- Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Chengdu, Sichuan 610052, China; Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhimeng Cheng
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Andre J Jeyarajan
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Wenting Li
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Tropical Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, China
| | - Yongtao Wang
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Tuo Shao
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Shadi Salloum
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Pei-Jer Chen
- Graduate Institute of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 10002, Taiwan
| | - Xu Yu
- The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02129, USA
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| | - Wenyu Lin
- Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| |
Collapse
|
|
2
|
Incrocci R, Monroy Del Toro R, Devitt G, Salimian M, Braich K, Swanson-Mungerson M. Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) Enhances ATP Production in B Cell Tumors through mTOR and HIF-1α. Int J Mol Sci 2024; 25:3944. [PMID: 38612754 PMCID: PMC11012313 DOI: 10.3390/ijms25073944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/26/2024] [Accepted: 03/30/2024] [Indexed: 04/14/2024] Open
Abstract
Epstein-Barr Virus (EBV) exists in a latent state in 90% of the world's population and is linked to numerous cancers, such as Burkitt's Lymphoma, Hodgkin's, and non-Hodgkin's Lymphoma. One EBV latency protein, latency membrane protein 2A (LMP2A), is expressed in multiple latency phenotypes. LMP2A signaling has been extensively studied and one target of LMP2A is the mammalian target of rapamycin (mTOR). Since mTOR has been linked to reprogramming tumor metabolism and increasing levels of hypoxia-inducible factor 1 α (HIF-1α), we hypothesized that LMP2A would increase HIF-1α levels to enhance ATP generation in B lymphoma cell lines. Our data indicate that LMP2A increases ATP generation in multiple Burkitt lymphoma cell lines that were dependent on HIF-1α. Subsequent studies indicate that the addition of the mTOR inhibitor, rapamycin, blocked the LMP2A-dependent increase in HIF-1α. Further studies demonstrate that LMP2A does not increase HIF-1α levels by increasing HIF-1α RNA or STAT3 activation. In contrast, LMP2A and mTOR-dependent increase in HIF-1α required mTOR-dependent phosphorylation of p70 S6 Kinase and 4E-BP1. These findings implicate the importance of LMP2A in promoting B cell lymphoma survival by increasing ATP generation and identifying potential pharmaceutical targets to treat EBV-associated tumors.
Collapse
Affiliation(s)
- Ryan Incrocci
- Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Downers Grove, IL 60515, USA
| | - Rosalinda Monroy Del Toro
- Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Downers Grove, IL 60515, USA
| | - Grace Devitt
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (G.D.); (M.S.)
| | - Melody Salimian
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (G.D.); (M.S.)
| | - Kamaljit Braich
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (G.D.); (M.S.)
| | - Michelle Swanson-Mungerson
- Department of Microbiology and Immunology, College of Graduate Studies, Midwestern University, Downers Grove, IL 60515, USA
- Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, USA; (G.D.); (M.S.)
| |
Collapse
|
|
3
|
Chen H, Cao D, Han N, Zhang M, Jiang W, Wang X, Zeng Q, Tang H. Hepatitis B Virus-Encoded MicroRNA (HBV-miR-3) Inhibits FIH-1 Expression to Promote Tumor Angiogenesis in HBV-Related Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:2337-2353. [PMID: 38163053 PMCID: PMC10757782 DOI: 10.2147/jhc.s436926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 12/08/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1). Results By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3'-UTR of FIH-1 mRNA by luciferase activity assay. Conclusion HBV-miR-3 was related to HCC patients' overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC.
Collapse
Affiliation(s)
- Han Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Dan Cao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Mingming Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Xin Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Qinmin Zeng
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China
| |
Collapse
|
|
4
|
Sadri M, Najafi A, Rahimi A, Behranvand N, Hossein Kazemi M, Khorramdelazad H, Falak R. Hypoxia effects on oncolytic virotherapy in Cancer: Friend or Foe? Int Immunopharmacol 2023; 122:110470. [PMID: 37433246 DOI: 10.1016/j.intimp.2023.110470] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/06/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023]
Abstract
Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods.
Collapse
Affiliation(s)
- Maryam Sadri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Najafi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nafiseh Behranvand
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
5
|
Davis DA, Shrestha P, Yarchoan R. Hypoxia and hypoxia-inducible factors in Kaposi sarcoma-associated herpesvirus infection and disease pathogenesis. J Med Virol 2023; 95:e29071. [PMID: 37665216 PMCID: PMC10502919 DOI: 10.1002/jmv.29071] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/05/2023]
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi sarcoma and several other tumors and hyperproliferative diseases seen predominantly in human immunodeficiency virus-infected and other immunocompromised persons. There is an increasing body of evidence showing that hypoxia and hypoxia-inducible factors (HIFs) play important roles in the biology of KSHV and in the pathogenesis of KSHV-induced diseases. Hypoxia and HIFs can induce lytic activation of KSHV and KSHV can in turn lead to a hypoxic-like state in infected cells. In this review, we describe the complex interactions between KSHV biology, the cellular responses to hypoxia, and the pathogenesis of KSHV-induced diseases. We also describe how interference with HIFs can lead to decreased tumor growth and/or death of infected cells and KSHV-induced tumors. Finally, we show how these observations may lead to novel strategies for the treatment of KSHV-induced diseases.
Collapse
Affiliation(s)
- David A Davis
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Prabha Shrestha
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| |
Collapse
|
|
6
|
Araldi RP, Delvalle DA, da Costa VR, Alievi AL, Teixeira MR, Dias Pinto JR, Kerkis I. Exosomes as a Nano-Carrier for Chemotherapeutics: A New Era of Oncology. Cells 2023; 12:2144. [PMID: 37681875 PMCID: PMC10486723 DOI: 10.3390/cells12172144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
Despite the considerable advancements in oncology, cancer remains one of the leading causes of death worldwide. Drug resistance mechanisms acquired by cancer cells and inefficient drug delivery limit the therapeutic efficacy of available chemotherapeutics drugs. However, studies have demonstrated that nano-drug carriers (NDCs) can overcome these limitations. In this sense, exosomes emerge as potential candidates for NDCs. This is because exosomes have better organotropism, homing capacity, cellular uptake, and cargo release ability than synthetic NDCs. In addition, exosomes can serve as NDCs for both hydrophilic and hydrophobic chemotherapeutic drugs. Thus, this review aimed to summarize the latest advances in cell-free therapy, describing how the exosomes can contribute to each step of the carcinogenesis process and discussing how these nanosized vesicles could be explored as nano-drug carriers for chemotherapeutics.
Collapse
Affiliation(s)
- Rodrigo Pinheiro Araldi
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
- BioDecision Analytics Ltd.a., São Paulo 13271-650, SP, Brazil;
| | - Denis Adrián Delvalle
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Vitor Rodrigues da Costa
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Structural and Functional Biology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Anderson Lucas Alievi
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Endocrinology and Metabology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | - Michelli Ramires Teixeira
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
- Endocrinology and Metabology Post-Graduation Program, Paulista School of Medicine, São Paulo Federal University (EPM-UNIFESP), São Paulo 04023-062, SP, Brazil
| | | | - Irina Kerkis
- Genetics Laboratory, Butantan Institute, São Paulo 05503-900, SP, Brazil; (D.A.D.); (V.R.d.C.); (A.L.A.); (M.R.T.)
| |
Collapse
|
|
7
|
Khan I, Harshithkumar R, More A, Mukherjee A. Human Papilloma Virus: An Unraveled Enigma of Universal Burden of Malignancies. Pathogens 2023; 12:pathogens12040564. [PMID: 37111450 PMCID: PMC10146077 DOI: 10.3390/pathogens12040564] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 03/28/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
HPV, or Human Papilloma Virus, has been the primary causative agent of genital warts and cervical cancer worldwide. It is a sexually transmitted infection mainly affecting women of reproductive age group, also infecting men and high-risk group individuals globally, resulting in high mortality. In recent years, HPV has also been found to be the major culprit behind anogenital cancers in both gender and oropharyngeal and colorectal cancers. Few studies have reported the incidence of HPV in breast cancers as well. For a few decades, the burden of HPV-associated malignancies has been increasing at an alarming rate due to a lack of adequate awareness, famine vaccine coverage and hesitancy. The effectiveness of currently available vaccines has been limited to prophylactic efficacy and does not prevent malignancies associated with post-exposure persistent infection. This review focuses on the current burden of HPV-associated malignancies, their causes and strategies to combat the growing prevalence of the cancers. With the advent of new technologies associated with treatment pertaining to therapeutic interventions and employing effective vaccine coverage, the burden of this disease may be reduced in the population.
Collapse
Affiliation(s)
- Ishrat Khan
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India
| | - R Harshithkumar
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India
| | - Ashwini More
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India
| | - Anupam Mukherjee
- Division of Virology, ICMR-National AIDS Research Institute, Pune 411026, India
| |
Collapse
|
|
8
|
Nunn AVW, Guy GW, Brysch W, Bell JD. Understanding Long COVID; Mitochondrial Health and Adaptation-Old Pathways, New Problems. Biomedicines 2022; 10:3113. [PMID: 36551869 PMCID: PMC9775339 DOI: 10.3390/biomedicines10123113] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 12/04/2022] Open
Abstract
Many people infected with the SARS-CoV-2 suffer long-term symptoms, such as "brain fog", fatigue and clotting problems. Explanations for "long COVID" include immune imbalance, incomplete viral clearance and potentially, mitochondrial dysfunction. As conditions with sub-optimal mitochondrial function are associated with initial severity of the disease, their prior health could be key in resistance to long COVID and recovery. The SARs virus redirects host metabolism towards replication; in response, the host can metabolically react to control the virus. Resolution is normally achieved after viral clearance as the initial stress activates a hormetic negative feedback mechanism. It is therefore possible that, in some individuals with prior sub-optimal mitochondrial function, the virus can "tip" the host into a chronic inflammatory cycle. This might explain the main symptoms, including platelet dysfunction. Long COVID could thus be described as a virally induced chronic and self-perpetuating metabolically imbalanced non-resolving state characterised by mitochondrial dysfunction, where reactive oxygen species continually drive inflammation and a shift towards glycolysis. This would suggest that a sufferer's metabolism needs to be "tipped" back using a stimulus, such as physical activity, calorie restriction, or chemical compounds that mimic these by enhancing mitochondrial function, perhaps in combination with inhibitors that quell the inflammatory response.
Collapse
Affiliation(s)
- Alistair V. W. Nunn
- Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London W1W 6UW, UK
| | - Geoffrey W. Guy
- The Guy Foundation, Chedington Court, Beaminster, Dorset DT8 3HY, UK
| | | | - Jimmy D. Bell
- Research Centre for Optimal Health, Department of Life Sciences, University of Westminster, London W1W 6UW, UK
| |
Collapse
|
|
9
|
Mullen PJ, Christofk HR. The Metabolic Relationship Between Viral Infection and Cancer. ANNUAL REVIEW OF CANCER BIOLOGY 2022. [DOI: 10.1146/annurev-cancerbio-070120-090423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Viruses are fundamental tools in cancer research. They were used to discover the first oncogenes in the 1970s, and they are now being modified for use as antitumor therapeutics. Key to both of these oncogenic and oncolytic properties is the ability of viruses to rewire host cell metabolism. In this review, we describe how viral oncogenes alter metabolism to increase the synthesis of macromolecules necessary for both viral replication and tumor growth. We then describe how understanding the specific metabolic requirements of virus-infected cells can help guide strategies to improve the efficacy of oncolytic viruses, and we highlight immunometabolism and tumor microenvironment research that could also increase the therapeutic benefits of oncolytic viruses. We also describe how studies describing the therapeutic effects of dietary nutrient restriction in cancer can suggest new avenues for research into antiviral therapeutics.
Collapse
Affiliation(s)
- Peter J. Mullen
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Heather R. Christofk
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California, USA
- Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, California, USA
| |
Collapse
|
|
10
|
Onisiforou A, Spyrou GM. Identification of viral-mediated pathogenic mechanisms in neurodegenerative diseases using network-based approaches. Brief Bioinform 2021; 22:bbab141. [PMID: 34237135 PMCID: PMC8574625 DOI: 10.1093/bib/bbab141] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/01/2021] [Accepted: 03/23/2021] [Indexed: 12/18/2022] Open
Abstract
During the course of a viral infection, virus-host protein-protein interactions (PPIs) play a critical role in allowing viruses to replicate and survive within the host. These interspecies molecular interactions can lead to viral-mediated perturbations of the human interactome causing the generation of various complex diseases. Evidences suggest that viral-mediated perturbations are a possible pathogenic etiology in several neurodegenerative diseases (NDs). These diseases are characterized by chronic progressive degeneration of neurons, and current therapeutic approaches provide only mild symptomatic relief; therefore, there is unmet need for the discovery of novel therapeutic interventions. In this paper, we initially review databases and tools that can be utilized to investigate viral-mediated perturbations in complex NDs using network-based analysis by examining the interaction between the ND-related PPI disease networks and the virus-host PPI network. Afterwards, we present our theoretical-driven integrative network-based bioinformatics approach that accounts for pathogen-genes-disease-related PPIs with the aim to identify viral-mediated pathogenic mechanisms focusing in multiple sclerosis (MS) disease. We identified seven high centrality nodes that can act as disease communicator nodes and exert systemic effects in the MS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways network. In addition, we identified 12 KEGG pathways, 5 Reactome pathways and 52 Gene Ontology Immune System Processes by which 80 viral proteins from eight viral species might exert viral-mediated pathogenic mechanisms in MS. Finally, our analysis highlighted the Th17 differentiation pathway, a disease communicator node and part of the 12 underlined KEGG pathways, as a key viral-mediated pathogenic mechanism and a possible therapeutic target for MS disease.
Collapse
Affiliation(s)
- Anna Onisiforou
- Department of Bioinformatics, Cyprus Institute of Neurology & Genetics, and the Cyprus School of Molecular Medicine, Cyprus
| | - George M Spyrou
- Department of Bioinformatics, Cyprus Institute of Neurology & Genetics, and professor at the Cyprus School of Molecular Medicine, Cyprus
| |
Collapse
|
|
11
|
Kumar Singh R, Pei Y, Bose D, Lamplugh ZL, Sun K, Yuan Y, Lieberman P, You J, Robertson ES. KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia. eLife 2021; 10:57436. [PMID: 34279223 PMCID: PMC8315796 DOI: 10.7554/elife.57436] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 07/17/2021] [Indexed: 12/13/2022] Open
Abstract
The cellular adaptive response to hypoxia, mediated by high HIF1α levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposi’s sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1α in normoxia, can also restrict transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1α cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1α levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1α levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.
Collapse
Affiliation(s)
- Rajnish Kumar Singh
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.,Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Yonggang Pei
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Dipayan Bose
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Zachary L Lamplugh
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Kunfeng Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Yan Yuan
- Department of Microbiology, Levy Building, School of Dental Medicine, University of Pennsylvania, Philadelphia, United States
| | - Paul Lieberman
- Program in Gene Regulation, The Wistar Institute, Philadelphia, United States
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| | - Erle S Robertson
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
| |
Collapse
|
|
12
|
Immunometabolism Modulation in Therapy. Biomedicines 2021; 9:biomedicines9070798. [PMID: 34356862 PMCID: PMC8301471 DOI: 10.3390/biomedicines9070798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
The study of cancer biology should be based around a comprehensive vision of the entire tumor ecosystem, considering the functional, bioenergetic and metabolic state of tumor cells and those of their microenvironment, and placing particular importance on immune system cells. Enhanced understanding of the molecular bases that give rise to alterations of pathways related to tumor development can open up new therapeutic intervention opportunities, such as metabolic regulation applied to immunotherapy. This review outlines the role of various oncometabolites and immunometabolites, such as TCA intermediates, in shaping pro/anti-inflammatory activity of immune cells such as MDSCs, T lymphocytes, TAMs and DCs in cancer. We also discuss the extraordinary plasticity of the immune response and its implication in immunotherapy efficacy, and highlight different therapeutic intervention possibilities based on controlling the balanced systems of specific metabolites with antagonistic functions.
Collapse
|
|
13
|
Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
Collapse
|
|
14
|
Liu PJ, Balfe P, McKeating JA, Schilling M. Oxygen Sensing and Viral Replication: Implications for Tropism and Pathogenesis. Viruses 2020; 12:E1213. [PMID: 33113858 PMCID: PMC7693908 DOI: 10.3390/v12111213] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022] Open
Abstract
The ability to detect and respond to varying oxygen tension is an essential prerequisite to life. Several mechanisms regulate the cellular response to oxygen including the prolyl hydroxylase domain (PHD)/factor inhibiting HIF (FIH)-hypoxia inducible factor (HIF) pathway, cysteamine (2-aminoethanethiol) dioxygenase (ADO) system, and the lysine-specific demethylases (KDM) 5A and KDM6A. Using a systems-based approach we discuss the literature on oxygen sensing pathways in the context of virus replication in different tissues that experience variable oxygen tension. Current information supports a model where the PHD-HIF pathway enhances the replication of viruses infecting tissues under low oxygen, however, the reverse is true for viruses with a selective tropism for higher oxygen environments. Differences in oxygen tension and associated HIF signaling may play an important role in viral tropism and pathogenesis. Thus, pharmaceutical agents that modulate HIF activity could provide novel treatment options for viral infections and associated pathological conditions.
Collapse
|
|
15
|
Herbein G, Nehme Z. Polyploid Giant Cancer Cells, a Hallmark of Oncoviruses and a New Therapeutic Challenge. Front Oncol 2020; 10:567116. [PMID: 33154944 PMCID: PMC7591763 DOI: 10.3389/fonc.2020.567116] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/11/2020] [Indexed: 12/19/2022] Open
Abstract
Tumors are renowned as intricate systems that harbor heterogeneous cancer cells with distinctly diverse molecular signatures, sizes and genomic contents. Among those various genomic clonal populations within the complex tumoral architecture are the polyploid giant cancer cells (PGCC). Although described for over a century, PGCC are increasingly being recognized for their prominent role in tumorigenesis, metastasis, therapy resistance and tumor repopulation after therapy. A shared characteristic among all tumors triggered by oncoviruses is the presence of polyploidy. Those include Human Papillomaviruses (HPV), Epstein Barr Virus (EBV), Hepatitis B and C viruses (HBV and HCV, respectively), Human T-cell lymphotropic virus-1 (HTLV-1), Kaposi's sarcoma herpesvirus (KSHV) and Merkel polyomavirus (MCPyV). Distinct viral proteins, for instance Tax for HTLV-1 or HBx for HBV have demonstrated their etiologic role in favoring the appearance of PGCC. Different intriguing biological mechanisms employed by oncogenic viruses, in addition to viruses with high oncogenic potential such as human cytomegalovirus, could support the generation of PGCC, including induction of endoreplication, inactivation of tumor suppressors, development of hypoxia, activation of cellular senescence and others. Interestingly, chemoresistance and radioresistance have been reported in the context of oncovirus-induced cancers, for example KSHV and EBV-associated lymphomas and high-risk HPV-related cervical cancer. This points toward a potential linkage between the previously mentioned players and highlights PGCC as keystone cancer cells in virally-induced tumors. Subsequently, although new therapeutic approaches are actively needed to fight PGCC, attention should also be drawn to reveal the relationship between PGCC and oncoviruses, with the ultimate goal of establishing effective therapeutic platforms for treatment of virus-associated cancers. This review discusses the presence of PGCCs in tumors induced by oncoviruses, biological mechanisms potentially favoring their appearance, as well as their consequent implication at the clinical and therapeutic level.
Collapse
Affiliation(s)
- Georges Herbein
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Department of Virology, CHRU Besancon, Besançon, France
| | - Zeina Nehme
- Pathogens & Inflammation/EPILAB Laboratory, EA 4266, University of Franche-Comté, Université Bourgogne Franche-Comté (UBFC), Besançon, France.,Faculty of Sciences, Lebanese University, Beirut, Lebanon
| |
Collapse
|
|
16
|
Yousaf I, Kaeppler J, Frost S, Seymour LW, Jacobus EJ. Attenuation of the Hypoxia Inducible Factor Pathway after Oncolytic Adenovirus Infection Coincides with Decreased Vessel Perfusion. Cancers (Basel) 2020; 12:E851. [PMID: 32244697 PMCID: PMC7225929 DOI: 10.3390/cancers12040851] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 03/25/2020] [Accepted: 03/30/2020] [Indexed: 12/30/2022] Open
Abstract
The interplay between oncolytic virus infection and tumour hypoxia is particularly unexplored in vivo, although hypoxia is present in virtually all solid carcinomas. In this study, oncolytic adenovirus infection foci were found within pimonidazole-reactive, oxygen-poor areas in a colorectal xenograft tumour, where the expression of VEGF, a target gene of the hypoxia-inducible factor (HIF), was attenuated. We hypothesised that adenovirus infection interferes with the HIF-signalling axis in the hypoxic tumour niche, possibly modifying the local vascular supply. In vitro, enadenotucirev (EnAd), adenovirus 11p and adenovirus 5 decreased the protein expression of HIF-1α only during the late phase of the viral life cycle by transcriptional down-regulation and not post-translational regulation. The decreasing HIF levels resulted in the down-regulation of angiogenic factors such as VEGF, coinciding with reduced endothelial tube formation but also increased T-cell activation in conditioned media transfer experiments. Using intravital microscopy, a decreased perfused vessel volume was observed in infected tumour nodules upon systemic delivery of EnAd, encoding the oxygen-independent fluorescent reporter UnaG to a tumour xenograft grown under an abdominal window chamber. We conclude that the attenuation of the HIF pathway upon adenoviral infection may contribute to anti-vascular and immunostimulatory effects in the periphery of established infection foci in vivo.
Collapse
Affiliation(s)
- Iris Yousaf
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (I.Y.); (S.F.)
| | - Jakob Kaeppler
- Mechanisms of Metastasis Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;
| | - Sally Frost
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (I.Y.); (S.F.)
| | - Len W. Seymour
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (I.Y.); (S.F.)
| | - Egon J. Jacobus
- Anticancer Viruses and Cancer Vaccines Research Group, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; (I.Y.); (S.F.)
| |
Collapse
|
|
17
|
Martano M, Altamura G, Power K, Restucci B, Carella F, Borzacchiello G, Maiolino P. Evaluation of Hypoxia-Inducible Factor-1 Alpha (HIF-1α) in Equine Sarcoid: An Immunohistochemical and Biochemical Study. Pathogens 2020; 9:E58. [PMID: 31947661 PMCID: PMC7168668 DOI: 10.3390/pathogens9010058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND equine sarcoids are the most frequent skin tumors in equidae worldwide. It is well known that delta bovine papillomaviruses are their causative agents. We have recently shown the presence in equine sarcoids of abnormal vessel structures, which could cause a hypoxic condition. The aim of this study was to analyze the expression of hypoxia-inducible factor-1 alpha (HIF-1α) in a subset of BPV positive equine sarcoids and explore the relationship with vascular endothelial growth factor (VEGF) expression. RESULTS 80% of equine sarcoids showed strong cytoplasmic staining in >60% of neoplastic fibroblasts, while 20% of samples showed a moderate cytoplasmic staining in 40-60% of neoplastic fibroblasts for HIF-1α. Results of Western blotting (WB) were consistent with immunohistochemistry (IHC). Moreover, a positive correlation between HIF-1α and VEGF expression (r = 0.60, p < 0.01) was observed. CONCLUSION we have shown that HIF-1α was strongly expressed in equine sarcoid. The upregulation of HIF-1α has been described in numerous tumors and can be modulated by many proteins encoded by transforming viruses. Thus, it is also possible that BPV could have a relevant role in HIF-1α pathway regulation, contributing to the development of equine sarcoids by promoting HIF-1α/VEGF mediated tumor angiogenesis.
Collapse
Affiliation(s)
- Manuela Martano
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Gennaro Altamura
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Karen Power
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Brunella Restucci
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Francesca Carella
- Department of Biology, University of Naples Federico II, MSA, 80126 Naples, Italy;
| | - Giuseppe Borzacchiello
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| | - Paola Maiolino
- Department of Veterinary Medicine and Animal Productions, Naples University “Federico II”, Via F. Delpino 1, 80137 Naples, Italy; (G.A.); (K.P.); (B.R.); (G.B.); (P.M.)
| |
Collapse
|
|
18
|
Benej M, Danchenko M, Oveckova I, Cervenak F, Tomaska L, Grossmannova K, Polcicova K, Golias T, Tomaskova J. Quantitative Proteomics Reveal Peroxiredoxin Perturbation Upon Persistent Lymphocytic Choriomeningitis Virus Infection in Human Cells. Front Microbiol 2019; 10:2438. [PMID: 31708904 PMCID: PMC6823195 DOI: 10.3389/fmicb.2019.02438] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 10/10/2019] [Indexed: 12/14/2022] Open
Abstract
Experimental data indicate that during persistent infection, lymphocytic choriomeningitis virus (LCMV) may both directly or indirectly modulate regulatory cellular processes and alter cellular functions that are not critical for survival, but are essential for cell homeostasis. In order to shed more light on these processes, two-dimensional differential in-gel electrophoresis (2D-DIGE) and MALDI-TOF tandem mass spectrometry were used to determine the proteome response of the HeLa cell line to persistent LCMV infection. Quantitative analysis revealed 24 differentially abundant proteins. Functional analysis showed that LCMV-responsive proteins were primarily involved in metabolism, stress, and the defense response. Among identified proteins, we discovered significant changes for peroxiredoxins, a family of antioxidant enzymes. Decreased amount of these antioxidant proteins correlated with elevation of reactive oxygen species (ROS) in infected cells. Increased levels of ROS were accompanied by changes in the pattern of telomere restriction fragments (TRFs) in infected cells and mediated activation of hypoxia-inducible transcription factor-1 (HIF-1) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. Moreover, treatment with antioxidants resulted in reduced levels of viral nucleoprotein, indicating a connection between ROS-dependent signaling and viral replication.
Collapse
Affiliation(s)
- Martin Benej
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Maksym Danchenko
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ingrid Oveckova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Filip Cervenak
- Faculty of Natural Sciences, Department of Genetics, Comenius University in Bratislava, Bratislava, Slovakia
| | - Lubomir Tomaska
- Faculty of Natural Sciences, Department of Genetics, Comenius University in Bratislava, Bratislava, Slovakia
| | - Katarina Grossmannova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Katarina Polcicova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Tereza Golias
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jana Tomaskova
- Biomedical Research Center, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia
| |
Collapse
|
|
19
|
Singh RK, Lamplugh ZL, Lang F, Yuan Y, Lieberman P, You J, Robertson ES. KSHV-encoded LANA protects the cellular replication machinery from hypoxia induced degradation. PLoS Pathog 2019; 15:e1008025. [PMID: 31479497 PMCID: PMC6743784 DOI: 10.1371/journal.ppat.1008025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 09/13/2019] [Accepted: 08/08/2019] [Indexed: 01/15/2023] Open
Abstract
Kaposi’s sarcoma associated herpesvirus (KSHV), like all herpesviruses maintains lifelong persistence with its host genome in latently infected cells with only a small fraction of cells showing signatures of productive lytic replication. Modulation of cellular signaling pathways by KSHV-encoded latent antigens, and microRNAs, as well as some level of spontaneous reactivation are important requirements for establishment of viral-associated diseases. Hypoxia, a prominent characteristic of the microenvironment of cancers, can exert specific effects on cell cycle control, and DNA replication through HIF1α-dependent pathways. Furthermore, hypoxia can induce lytic replication of KSHV. The mechanism by which KSHV-encoded RNAs and antigens regulate cellular and viral replication in the hypoxic microenvironment has yet to be fully elucidated. We investigated replication-associated events in the isogenic background of KSHV positive and negative cells grown under normoxic or hypoxic conditions and discovered an indispensable role of KSHV for sustained cellular and viral replication, through protection of critical components of the replication machinery from degradation at different stages of the process. These include proteins involved in origin recognition, pre-initiation, initiation and elongation of replicating genomes. Our results demonstrate that KSHV-encoded LANA inhibits hypoxia-mediated degradation of these proteins to sustain continued replication of both host and KSHV DNA. The present study provides a new dimension to our understanding of the role of KSHV in survival and growth of viral infected cells growing under hypoxic conditions and suggests potential new strategies for targeted treatment of KSHV-associated cancer. Hypoxia induces cell cycle arrest and DNA replication to minimize energy and macromolecular demands on the ATP stores of cells in this microenvironment. A select set of proteins functions as transcriptional activators in hypoxia. However, transcriptional and translational pathways are negatively regulated in response to hypoxia. This preserves ATP until the cell encounters more favorable conditions. In contrast, the genome of cancer cells replicates spontaneously under hypoxic conditions, and KSHV undergoes enhanced lytic replication. This unique feature by which KSHV genome is reactivated to induce lytic replication is important to elucidate the molecular mechanism by which cells can bypass hypoxia-mediated arrest of DNA replication in cancer cells. Here we provide data which shows that KSHV can manipulate the DNA replication machinery to support replication in hypoxia. We observed that KSHV can stabilize proteins involved in the pre-initiation, initiation and elongation steps of DNA replication. Specifically, KSHV-encoded LANA was responsible for this stabilization, and maintenance of endogenous HIF1α levels was required for stabilization of these proteins in hypoxia. Expression of LANA in KSHV negative cells confers protection of these replication proteins from hypoxia-dependent degradation, and knock-down of LANA or HIF1α showed a dramatic reduction in KSHV-dependent stabilization of replication-associated proteins in hypoxia. These data suggest a role for KSHV-encoded LANA in replication of infected cells, and provides a mechanism for sustained replication of both cellular and viral DNA in hypoxia.
Collapse
Affiliation(s)
- Rajnish Kumar Singh
- Department of Otorhinolaryngology-Head and Neck surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Zachary L. Lamplugh
- Department of Otorhinolaryngology-Head and Neck surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Fengchao Lang
- Department of Otorhinolaryngology-Head and Neck surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Yan Yuan
- Department of Microbiology, Levy Building, School of Dental Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Paul Lieberman
- Program in Gene Regulation, The Wistar Institute, Philadelphia, United States of America
| | - Jianxin You
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
| | - Erle S. Robertson
- Department of Otorhinolaryngology-Head and Neck surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America
- * E-mail:
| |
Collapse
|
|
20
|
Hepatitis C Virus Downregulates Ubiquitin-Conjugating Enzyme E2S Expression To Prevent Proteasomal Degradation of NS5A, Leading to Host Cells More Sensitive to DNA Damage. J Virol 2019; 93:JVI.01240-18. [PMID: 30381483 DOI: 10.1128/jvi.01240-18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/17/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) infection may cause chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV exploits cellular machineries to establish persistent infection. We demonstrate here that ubiquitin-conjugating enzyme E2S (UBE2S), a member of the ubiquitin-conjugating enzyme family (E2s), was downregulated by endoplasmic reticulum stress caused by HCV in Huh7 cells. UBE2S interacted with domain I of HCV NS5A and degraded NS5A protein through the Lys11-linked proteasome-dependent pathway. Overexpression of UBE2S suppressed viral propagation, while depletion of UBE2S expression increased viral infectivity. Enzymatically inactive UBE2S C95A mutant exerted no antiviral activity, suggesting that ubiquitin-conjugating enzymatic activity was required for the suppressive role of UBE2S. Chromatin ubiquitination plays a crucial role in the DNA damage response. We showed that the levels of UBE2S and Lys11 chains bound to the chromatin were markedly decreased in the context of HCV replication, rendering HCV-infected cells more sensitive to DNA damage. These data suggest that HCV counteracts antiviral activity of UBE2S to optimize viral propagation and may contribute to HCV-induced liver pathogenesis.IMPORTANCE Protein homeostasis is essential to normal cell function. HCV infection disturbs the protein homeostasis in the host cells. Therefore, host cells exert an anti-HCV activity in order to maintain normal cellular metabolism. We showed that UBE2S interacted with HCV NS5A and degraded NS5A protein through the Lys11-linked proteasome-dependent pathway. However, HCV has evolved to overcome host antiviral activity. We demonstrated that the UBE2S expression level was suppressed in HCV-infected cells. Since UBE2S is an ubiquitin-conjugating enzyme and this enzyme activity is involved in DNA damage repair, HCV-infected cells are more sensitive to DNA damage, and thus UBE2S may contribute to viral oncogenesis.
Collapse
|
|
21
|
Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1. PLoS Pathog 2018; 14:e1007394. [PMID: 30395643 PMCID: PMC6237423 DOI: 10.1371/journal.ppat.1007394] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 11/15/2018] [Accepted: 10/09/2018] [Indexed: 12/20/2022] Open
Abstract
Latent membrane protein 1 (LMP1) is the major transforming protein of Epstein-Barr virus (EBV) and is critical for EBV-induced B-cell transformation in vitro. Poly(ADP-ribose) polymerase 1 (PARP1) regulates accessibility of chromatin, alters functions of transcriptional activators and repressors, and has been directly implicated in transcriptional activation. Previously we showed that LMP1 activates PARP1 and increases Poly(ADP-ribos)ylation (PARylation) through PARP1. Therefore, to identify targets of LMP1 that are regulated through PARP1, LMP1 was ectopically expressed in an EBV-negative Burkitt’s lymphoma cell line. These LMP1-expressing cells were then treated with the PARP inhibitor olaparib and prepared for RNA sequencing. The LMP1/PARP targets identified through this RNA-seq experiment are largely involved in metabolism and signaling. Interestingly, Ingenuity Pathway Analysis of RNA-seq data suggests that hypoxia-inducible factor 1-alpha (HIF-1α) is an LMP1 target mediated through PARP1. PARP1 is acting as a coactivator of HIF-1α-dependent gene expression in B cells, and this co-activation is enhanced by LMP1-mediated activation of PARP1. HIF-1α forms a PARylated complex with PARP1 and both HIF-1α and PARP1 are present at promoter regions of HIF-1α downstream targets, leading to accumulation of positive histone marks at these regions. Complex formation, PARylation and binding of PARP1 and HIF-1α at promoter regions of HIF-1α downstream targets can all be attenuated by PARP1 inhibition, subsequently leading to a buildup of repressive histone marks and loss of positive histone marks. In addition, LMP1 switches cells to a glycolytic ‘Warburg’ metabolism, preferentially using aerobic glycolysis over mitochondrial respiration. Finally, LMP1+ cells are more sensitive to PARP1 inhibition and, therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies. Epstein-Barr virus (EBV) is one of the most ubiquitous human viruses, with over 90% of adults worldwide harboring lifelong latent EBV infection in a small fraction of their B-lymphocytes. EBV is known to cause lymphoproliferative disorders and is associated with several other types of cancer, including Hodgkin's lymphoma, Burkitt's lymphoma and Nasopharyngeal carcinoma. However, in most cases, the approach to EBV-positive lymphomas does not differ from EBV-negative lymphomas of the same histology. Latent membrane protein 1 (LMP1) is the major transforming protein of EBV and is critical for EBV-induced B-cell transformation in vitro. LMP1 activates several epigenetic regulators to modify host gene expression, including the chromatin-modifying enzyme Poly(ADP-ribose) polymerase 1, or PARP1. In the current study we have determined that LMP1 can activate PARP1 to increase hypoxia-inducible factor 1-alpha (HIF-1α)-dependent gene expression, leading to a change in host cell metabolism indicative of a ‘Warburg effect’ (aerobic glycolysis). This subsequently provides a proliferative advantage to LMP1-expressing cells. The LMP1-induced increase in HIF-1α-dependent gene expression, alteration of cellular metabolism, and accelerated cellular proliferation, can be offset with the PARP inhibitor olaparib. Therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies.
Collapse
|
|
22
|
Araldi RP, Sant’Ana TA, Módolo DG, de Melo TC, Spadacci-Morena DD, de Cassia Stocco R, Cerutti JM, de Souza EB. The human papillomavirus (HPV)-related cancer biology: An overview. Biomed Pharmacother 2018; 106:1537-1556. [DOI: 10.1016/j.biopha.2018.06.149] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 06/24/2018] [Accepted: 06/27/2018] [Indexed: 02/07/2023] Open
|
|
23
|
Kunanopparat A, Issara-Amphorn J, Leelahavanichkul A, Sanpavat A, Patumraj S, Tangkijvanich P, Palaga T, Hirankarn N. Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication. World J Gastroenterol 2018; 24:3861-3870. [PMID: 30228780 PMCID: PMC6141339 DOI: 10.3748/wjg.v24.i34.3861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 07/05/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo.
METHODS We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively.
RESULTS Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours.
CONCLUSION This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.
Collapse
Affiliation(s)
- Areerat Kunanopparat
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Jiraphorn Issara-Amphorn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Suthiluk Patumraj
- Center of Excellence for Microcirculation, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Pisit Tangkijvanich
- Research Unit of Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Tanapat Palaga
- Department of Microbiology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nattiya Hirankarn
- Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| |
Collapse
|
|
24
|
Yu L, Chen X, Wang L, Chen S. Oncogenic virus-induced aerobic glycolysis and tumorigenesis. J Cancer 2018; 9:3699-3706. [PMID: 30405839 PMCID: PMC6216013 DOI: 10.7150/jca.27279] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/15/2018] [Indexed: 12/17/2022] Open
Abstract
Enhanced glycolysis under normoxic conditions is known as aerobic glycolysis or the Warburg effect and is a hallmark of many tumors. Viral infection may also induce aerobic glycolysis as it is required for replication and survival. Tumor viruses inducing aerobic glycolysis and lactate production during latent infection suggest a potential role of virus-induced glycolysis in tumorigenesis. Virus or virus-encoded proteins regulate glucose uptake and lactate export, increase the activity of glycolytic enzymes, and modulate glucose metabolic signals. Accumulating evidence suggests that virus-induced glycolysis may facilitate cell growth, transformation, migration, and invasion, but its significance in tumorigenesis remains unclear. We summarize the effects of oncogenic viruses on the metabolic shift to aerobic glycolysis and discuss the possible association of this metabolic reprogramming with tumor development and progression.
Collapse
Affiliation(s)
- Li Yu
- Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Xun Chen
- Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, People's Republic of China
| | - Liantang Wang
- Department of Pathology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Shangwu Chen
- Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China
| |
Collapse
|
|
25
|
Piccaluga PP, Weber A, Ambrosio MR, Ahmed Y, Leoncini L. Epstein-Barr Virus-Induced Metabolic Rearrangements in Human B-Cell Lymphomas. Front Microbiol 2018; 9:1233. [PMID: 29937761 PMCID: PMC6002739 DOI: 10.3389/fmicb.2018.01233] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 05/22/2018] [Indexed: 12/16/2022] Open
Abstract
Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect). More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein–Barr virus (EBV) was the first virus linked with cancer in humans when Burkitt lymphoma (BL) was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas.
Collapse
Affiliation(s)
- Pier P Piccaluga
- Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy.,Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.,Department of Pathology, Jomo Kenyatta University of Agriculture and Technology, Juja, Kenya
| | - Alessandra Weber
- Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy
| | - Maria R Ambrosio
- Section of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Yonis Ahmed
- Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Lorenzo Leoncini
- Section of Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy
| |
Collapse
|
|
26
|
Metabolic reprogramming of Kaposi's sarcoma associated herpes virus infected B-cells in hypoxia. PLoS Pathog 2018; 14:e1007062. [PMID: 29746587 PMCID: PMC5963815 DOI: 10.1371/journal.ppat.1007062] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/22/2018] [Accepted: 04/27/2018] [Indexed: 12/26/2022] Open
Abstract
Kaposi’s sarcoma associated herpesvirus (KSHV) infection stabilizes hypoxia inducible factors (HIFs). The interaction between KSHV encoded factors and HIFs plays a critical role in KSHV latency, reactivation and associated disease phenotypes. Besides modulation of large-scale signaling, KSHV infection also reprograms the metabolic activity of infected cells. However, the mechanism and cellular pathways modulated during these changes are poorly understood. We performed comparative RNA sequencing analysis on cells with stabilized hypoxia inducible factor 1 alpha (HIF1α) of KSHV negative or positive background to identify changes in global and metabolic gene expression. Our results show that hypoxia induces glucose dependency of KSHV positive cells with high glucose uptake and high lactate release. We identified the KSHV-encoded vGPCR, as a novel target of HIF1α and one of the main viral antigens of this metabolic reprogramming. Bioinformatics analysis of vGPCR promoter identified 9 distinct hypoxia responsive elements which were activated by HIF1α in-vitro. Expression of vGPCR alone was sufficient for induction of changes in the metabolic phenotype similar to those induced by KSHV under hypoxic conditions. Silencing of HIF1α rescued the hypoxia associated phenotype of KSHV positive cells. Analysis of the host transcriptome identified several common targets of hypoxia as well as KSHV encoded factors and other synergistically activated genes belonging to cellular pathways. These include those involved in carbohydrate, lipid and amino acids metabolism. Further DNA methyltranferases, DNMT3A and DNMT3B were found to be regulated by either KSHV, hypoxia, or both synergistically at the transcript and protein levels. This study showed distinct and common, as well as synergistic effects of HIF1α and KSHV-encoded proteins on metabolic reprogramming of KSHV-infected cells in the hypoxia. Hypoxia inducible factors (HIFs) play a critical role in survival and growth of cancerous cells, in addition to modulating cellular metabolism. Kaposi’s sarcoma associated herpesvirus (KSHV) infection stabilizes HIFs. Several factors encoded by KSHV are known to interact with up or downstream targets of HIFs. However, the process by which KSHV infection leads to stabilized HIF1α and modulation of the cellular metabolism is not understood. Comparative RNA sequencing analysis on cells with stabilized hypoxia inducible factor 1 alpha (HIF1α), of KSHV negative or positive cells led to identification of changes in global and metabolic gene expression. Our results show that hypoxia induces glucose dependency of KSHV positive cells with high glucose uptake and high lactate release. KSHV-encoded vGPCR was identified as a novel target of HIF1α regulation and a major viral antigen involved in metabolic reprogramming. Silencing of HIF1α rescued the hypoxia associated phenotype of KSHV positive cells. Analysis of the host transcriptome identified several common targets of hypoxia and KSHV-encoded factors, as well as other synergistically activated genes belonging to cellular metabolic pathways. This study showed unique, common and the synergistic effects of both HIF1α and KSHV-encoded proteins on metabolic reprogramming of KSHV-infected cells in hypoxia.
Collapse
|
|
27
|
Wittekindt C, Wagner S, Sharma SJ, Würdemann N, Knuth J, Reder H, Klußmann JP. [HPV - A different view on Head and Neck Cancer]. Laryngorhinootologie 2018; 97:S48-S113. [PMID: 29905354 PMCID: PMC6540966 DOI: 10.1055/s-0043-121596] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck cancer is the sixth most common cancer with over 500000 annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas (OSCC) show increased association with human papillomavirus (HPV). HPV-associated and HPV-negative OSCC are 2 different entities regarding biological characteristics, therapeutic response, and patient prognosis. In HPV OSCC, viral oncoprotein activity, as well as genetic (mutations and chromosomal aberrations) and epigenetic alterations plays a key role during carcinogenesis. Based on improved treatment response, the introduction of therapy de-intensification and targeted therapy is discussed for patients with HPV OSCC. A promising targeted therapy concept is immunotherapy. The use of checkpoint inhibitors (e.g. anti-PD1) is currently investigated. By means of liquid biopsies, biomarkers such as viral DNA or tumor mutations in the will soon be available for disease monitoring, as well as detection of treatment failure. By now, primary prophylaxis of HPV OSCC can be achieved by vaccination of girls and boys.
Collapse
Affiliation(s)
- Claus Wittekindt
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Steffen Wagner
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Shachi Jenny Sharma
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Nora Würdemann
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Jennifer Knuth
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Henrike Reder
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| | - Jens Peter Klußmann
- Klinik für HNO-Heilkunde, Kopf-/Halschirurgie, Plastische Operationen, Universitätsklinikum Gießen und Marburg GmbH, Standort Gießen
| |
Collapse
|
|
28
|
Tan Z, Huang Q, Zang J, Teng SF, Chen TR, Wei HF, Song DW, Liu TL, Yang XH, Fu CG, Hu ZQ, Zhou W, Yan WJ, Xiao JR. HIF-1α activates hypoxia-induced BCL-9 expression in human colorectal cancer cells. Oncotarget 2018; 8:25885-25896. [PMID: 27121066 PMCID: PMC5432224 DOI: 10.18632/oncotarget.8834] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 03/28/2016] [Indexed: 11/25/2022] Open
Abstract
B-cell CLL/lymphoma 9 protein (BCL-9), a multi-functional co-factor in Wnt signaling, induced carcinogenesis as well as promoting tumor progression, metastasis and chemo-resistance in colorectal cancer (CRC). However, the mechanisms for increased BCL-9 expression in CRC were not well understood. Here, we report that hypoxia, a hallmark of solid tumors, induced BCL-9 mRNA expression in human CRC cells. Analysis of BCL-9 promoter revealed two functional hypoxia-responsive elements (HRE-B and HRE-C) that can be specifically bound with and be transactivated by hypoxia inducible factors (HIF) -1α but not HIF-2α. Consistently, ectopic expression of HIF-1α but not HIF-2α transcriptionally induced BCL-9 expression levels in cells. Knockdown of endogenous HIF-1α but not HIF-2α by siRNA largely abolished the induction of HIF by hypoxia. Furthermore, there was a strong association of HIF-1α expression with BCL-9 expression in human CRC specimens. In summary, results from this study demonstrated that hypoxia induced BCL-9 expression in human CRC cells mainly through HIF-1α, which could be an important underlying mechanism for increased BCL-9 expression in CRC.
Collapse
Affiliation(s)
- Zhen Tan
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.,Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Quan Huang
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jia Zang
- Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shi-Feng Teng
- Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tian-Rui Chen
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hai-Feng Wei
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dian-Wen Song
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tie-Long Liu
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xing-Hai Yang
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chuan-Gang Fu
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zhi-Qian Hu
- Department of Colorectal Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wang Zhou
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wang-Jun Yan
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jian-Ru Xiao
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| |
Collapse
|
|
29
|
Hernández-Palomares MLE, Godoy-Lugo JA, Gómez-Jiménez S, Gámez-Alejo LA, Ortiz RM, Muñoz-Valle JF, Peregrino-Uriarte AB, Yepiz-Plascencia G, Rosas-Rodríguez JA, Soñanez-Organis JG. Regulation of lactate dehydrogenase in response to WSSV infection in the shrimp Litopenaeus vannamei. FISH & SHELLFISH IMMUNOLOGY 2018; 74:401-409. [PMID: 29337249 DOI: 10.1016/j.fsi.2018.01.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 12/17/2017] [Accepted: 01/11/2018] [Indexed: 06/07/2023]
Abstract
Lactate dehydrogenase (LDH) is key for anaerobic glycolysis. LDH is induced by the hypoxia inducible factor -1 (HIF-1). HIF-1 induces genes involved in glucose metabolism and regulates cellular oxygen homeostasis. HIF-1 is formed by a regulatory α-subunit (HIF-1α) and a constitutive β-subunit (HIF-1β). The white spot syndrome virus (WSSV) induces anaerobic glycolysis in shrimp hemocytes, associated with lactate accumulation. Although infection and lactate production are associated, the LDH role in WSSV-infected shrimp has not been examined. In this work, the effects of HIF-1 silencing on the expression of two LDH subunits (LDHvan-1 and LDHvan-2) in shrimp infected with the WSSV were studied. HIF-1α transcripts increased in gills, hepatopancreas, and muscle after WSSV infection, while HIF-1β remained constitutively expressed. The expression for both LDH subunits increased in each tissue evaluated during the WSSV infection, translating into increased enzyme activity. Glucose concentration increased in each tissue evaluated, while lactate increased in gills and hepatopancreas, but not in muscle. Silencing of HIF-1α blocked the increase of LDH expression and enzyme activity, along with glucose (all tissues) and lactate (gills and hepatopancreas) concentrations produced by WSSV infection. These results demonstrate that HIF-1 up regulates the expression of LDH subunits during WSSV infection, and that this induction contributes to substrate metabolism in energetically active tissues of infected shrimp.
Collapse
Affiliation(s)
- M L E Hernández-Palomares
- Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera a la Victoria KM. 0.6, Hermosillo, Sonora, C.P. 83304, Mexico
| | - J A Godoy-Lugo
- Universidad de Sonora, Departamento de Ciencias Químico Biológicas y Agropecuarias, Universidad de Sonora Unidad Regional Sur, Lázaro Cárdenas #100, Col. Francisco Villa, Apartado Postal 85390, Navojoa, Sonora, Mexico
| | - S Gómez-Jiménez
- Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera a la Victoria KM. 0.6, Hermosillo, Sonora, C.P. 83304, Mexico
| | - L A Gámez-Alejo
- Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera a la Victoria KM. 0.6, Hermosillo, Sonora, C.P. 83304, Mexico
| | - R M Ortiz
- School of Natural Sciences, University of California Merced, 5200 N Lake Road, Merced, CA, 95343, USA
| | - J F Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - A B Peregrino-Uriarte
- Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera a la Victoria KM. 0.6, Hermosillo, Sonora, C.P. 83304, Mexico
| | - G Yepiz-Plascencia
- Centro de Investigación en Alimentación y Desarrollo (CIAD), Carretera a la Victoria KM. 0.6, Hermosillo, Sonora, C.P. 83304, Mexico
| | - J A Rosas-Rodríguez
- Universidad de Sonora, Departamento de Ciencias Químico Biológicas y Agropecuarias, Universidad de Sonora Unidad Regional Sur, Lázaro Cárdenas #100, Col. Francisco Villa, Apartado Postal 85390, Navojoa, Sonora, Mexico
| | - J G Soñanez-Organis
- Universidad de Sonora, Departamento de Ciencias Químico Biológicas y Agropecuarias, Universidad de Sonora Unidad Regional Sur, Lázaro Cárdenas #100, Col. Francisco Villa, Apartado Postal 85390, Navojoa, Sonora, Mexico.
| |
Collapse
|
|
30
|
Li S, Yang Y, Ding X, Yang M, She S, Peng H, Xu X, Ran X, Li S, Hu P, Hu H, Zhang D, Ren H. LHBs can elevate the expression of MDR1 through HIF-1α in patients with CHB infection: a comparative proteomic study. Oncotarget 2018; 8:4549-4562. [PMID: 27999186 PMCID: PMC5354853 DOI: 10.18632/oncotarget.13941] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 12/05/2016] [Indexed: 12/18/2022] Open
Abstract
Background and Aims Hepatitis B virus (HBV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). To gain a better understanding of the pathogenesis of HBV infection, this study aimed to investigate the differentially expressed proteins (DEPs) in liver tissues from patients with chronic hepatitis B (CHB) infection. Results Seventy-one DEPs were identified. Overexpression of multi-drug resistance protein 1 (MDR1) was validated by RT-qPCR and western blot analyses. Moreover, its expression was increased at both the mRNA and protein levels in response to overexpression of HBV large surface protein (LHBs). Furthermore, screening of transcription factors suggested the possible involvement of hypoxia-inducible factor 1α (HIF-1α) in the interaction between LHBs and MDR1. The function of HIF-1α in the MDR1 activation was confirmed by EMSA and reporter gene analyses. Materials And Methods Liver samples from CHB patients and controls without HBV infection were collected and subjected to isobaric tags for relative and absolute quantitation (iTRAQ) and mass spectrometric analysis. Conclusions These results imply that LHBs, in association with HIF-1α, induces MDR1 overexpression, which may contribute to the pathogenic changes in CHB infection.
Collapse
Affiliation(s)
- Shiying Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Yixuan Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xiangchun Ding
- Department of Infectious Diseases, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, PR China
| | - Min Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Sha She
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Hong Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xiaoming Xu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xiaoping Ran
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Sanglin Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Huaidong Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Dazhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| |
Collapse
|
|
31
|
Yoshizaki T, Kondo S, Endo K, Nakanishi Y, Aga M, Kobayashi E, Hirai N, Sugimoto H, Hatano M, Ueno T, Ishikawa K, Wakisaka N. Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. Cancer Sci 2018; 109:272-278. [PMID: 29247573 PMCID: PMC5797826 DOI: 10.1111/cas.13473] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 12/11/2017] [Accepted: 12/13/2017] [Indexed: 12/12/2022] Open
Abstract
Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein‐Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre‐invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1‐expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but it still has a pivotal role during all stages of NPC development.
Collapse
Affiliation(s)
- Tomokazu Yoshizaki
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Satoru Kondo
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Kazuhira Endo
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Yosuke Nakanishi
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Mitsuharu Aga
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Eiji Kobayashi
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Nobuyuki Hirai
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Hisashi Sugimoto
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Miyako Hatano
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Takayoshi Ueno
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Kazuya Ishikawa
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| | - Naohiro Wakisaka
- Department of Otolaryngology - Head and Neck Surgery, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
| |
Collapse
|
|
32
|
Liu G, Wang C, E M. [Mechanism and Prospect of Radiotherapy Combined with Apotatinib
in the Treatment of Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:847-851. [PMID: 29277185 PMCID: PMC5973393 DOI: 10.3779/j.issn.1009-3419.2017.12.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
非小细胞肺癌是危害人类生命健康的最常见的恶性肿瘤之一。大多数患者确诊时为晚期，不符合手术适应症，主要的治疗方法是放化疗联合。近年来，随着抗血管生成治疗恶性肿瘤理论的提出，阿帕替尼作为一种新型的抗肿瘤药物，与放疗联合具有协同作用。可能的机制包括使血管正常化，改善肿瘤内乏氧情况，调节促血管生成因子水平等。将阿帕替尼与放疗联合有望成为一种新的治疗策略应用于非小细胞肺癌的治疗中，提高肺癌的治疗效果。
Collapse
Affiliation(s)
- Guohui Liu
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Chunbo Wang
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Mingyan E
- Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| |
Collapse
|
|
33
|
Henke N, Ferreirós N, Geisslinger G, Ding MG, Essler S, Fuhrmann DC, Geis T, Namgaladze D, Dehne N, Brüne B. Loss of HIF-1α in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model. Oncotarget 2017; 7:25915-29. [PMID: 27015123 PMCID: PMC5041954 DOI: 10.18632/oncotarget.8297] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 03/11/2016] [Indexed: 01/04/2023] Open
Abstract
Activation of hypoxia-inducible factor (HIF) and macrophage infiltration of solid tumors independently promote tumor progression. As little is known how myeloid HIF affects tumor development, we injected the polycyclic aromatic hydrocarbon (PAH) and procarcinogen 3-methylcholanthrene (MCA; 100 μg/100 μl) subcutaneously into myeloid-specific Hif-1α and Hif-2α knockout mice (C57BL/6J) to induce fibrosarcomas (n = 16). Deletion of Hif-1α but not Hif-2α in macrophages diminished tumor outgrowth in the MCA-model. While analysis of the tumor initiation phase showed comparable inflammation after MCA-injection, metabolism of MCA was impaired in the absence of Hif-1α. An ex vivo macrophage/fibroblast coculture recapitulated reduced DNA damage after MCA-stimulation in fibroblasts of cocultures with Hif-1αLysM−/− macrophages compared to wild type macrophages. A loss of myeloid Hif-1α decreased RNA levels of arylhydrocarbon receptor (AhR)/arylhydrocarbon receptor nuclear translocator (ARNT) targets such as Cyp1a1 because of reduced Arnt but unchanged Ahr expression. Cocultures using Hif-1αLysM−/− macrophages stimulated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA; 2 μg/ml) also attenuated a DNA damage response in fibroblasts, while the DNA damage-inducing metabolite DMBA-trans-3,4-dihydrodiol remained effective in the absence of Hif-1α. In chemical-induced carcinogenesis, HIF-1α in macrophages maintains ARNT expression to facilitate PAH-biotransformation. This implies a metabolic activation of PAHs in stromal cells, i.e. myeloid-derived cells, to be crucial for tumor initiation.
Collapse
Affiliation(s)
- Nina Henke
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Nerea Ferreirós
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Martina G Ding
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Silke Essler
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Dominik C Fuhrmann
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Theresa Geis
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Dmitry Namgaladze
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Nathalie Dehne
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| |
Collapse
|
|
34
|
Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines. Oncotarget 2017; 8:89681-89691. [PMID: 29163780 PMCID: PMC5685701 DOI: 10.18632/oncotarget.20813] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 08/21/2017] [Indexed: 01/14/2023] Open
Abstract
Purpose Human papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1α expression in HNSCC. Experimental Technique HPV-positive and -negative HNSCC cells were examined for adaptive responses to hypoxia. Expression of HIF-1α, prolyl hydroxylase-domain protein 2 (PHD2) and E-cadherin was analyzed by Western blotting, immunofluorescence (IF) microscopy and migration/wound healing assays. Results HPV-positive HNSCC cells showed higher HIF-1α and PHD2 protein levels under normoxia and hypoxia. HIF-1α hydroxylation was reduced in HPV-positive HNSCC cell lines under PHD and proteasomal inhibition. In vitro wound healing assays showed impairment of migration and proliferation by HIF-1α pathway activation in HPV-negative cell lines only. In contrast, migration and proliferation in HPV-positive cell lines was impaired by HIF-1α specific siRNA. Conclusions HPV-positive HNSCC cells show activation of the HIF pathway and adaptation to HIF-1α upregulation, representing potential therapeutic targets in this emerging tumor entity.
Collapse
|
|
35
|
Cuninghame S, Jackson R, Lees SJ, Zehbe I. Two common variants of human papillomavirus type 16 E6 differentially deregulate sugar metabolism and hypoxia signalling in permissive human keratinocytes. J Gen Virol 2017; 98:2310-2319. [PMID: 28857035 DOI: 10.1099/jgv.0.000905] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Human papillomavirus type 16 (HPV16) is responsible for most cancers attributable to HPV infection and naturally occurring variants of the HPV16 E6 oncoprotein predispose individuals to varying risk for developing cancer. Population studies by us and others have demonstrated that the common Asian-American E6 (AAE6) variant is a higher risk factor for cervical cancer than the E6 of another common variant, the European prototype (EPE6). However, a complete understanding of the molecular processes fundamental to these epidemiological findings is still lacking. Our previously published functional studies of these two E6 variants showed that AAE6 had a higher immortalization and transformation potential than EPE6. Proteomic analysis revealed markedly different protein patterns between these variants, especially with respect to key cellular metabolic enzymes. Here, we tested the Warburg effect and hypoxia signalling (hallmarks of cancer development) as plausible mechanisms underlying these observations. Lactate and glucose production were enhanced in AAE6-transduced keratinocytes, likely due to raised levels of metabolic enzymes, but independent of hypoxia-inducible factor 1 alpha (HIF-1α) activity. The HIF-1α protein level and activity were elevated by AAE6 in hypoxic conditions, leading to a hypoxia-tolerant phenotype with enhanced migratory potential. The deregulation of HIF-1α was caused by the AAE6 variant's ability to augment mitogen-activated protein kinase/extracellular related kinase signalling. The present study reveals prominent underlying mechanisms of the AAE6's enhanced oncogenic potential.
Collapse
Affiliation(s)
- Sean Cuninghame
- Probe Development and Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada
| | - Robert Jackson
- Probe Development and Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada.,Biotechnology Program, Lakehead University, Thunder Bay, Ontario, Canada
| | - Simon J Lees
- Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada.,Biology Department, Lakehead University, Thunder Bay, Ontario, Canada
| | - Ingeborg Zehbe
- Biology Department, Lakehead University, Thunder Bay, Ontario, Canada.,Probe Development and Biomarker Exploration, Thunder Bay Regional Health Research Institute, Thunder Bay, Ontario, Canada.,Medical Sciences Division, Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada
| |
Collapse
|
|
36
|
microRNA-33a-5p increases radiosensitivity by inhibiting glycolysis in melanoma. Oncotarget 2017; 8:83660-83672. [PMID: 29137372 PMCID: PMC5663544 DOI: 10.18632/oncotarget.19014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 06/19/2017] [Indexed: 12/20/2022] Open
Abstract
Glycolysis was reported to have a positive correlation with radioresistance. Our previous study found that the miR-33a functioned as a tumor suppressor in malignant melanoma by targeting hypoxia-inducible factor1-alpha (HIF-1α), a gene known to promote glycolysis. However, the role of miR-33a-5p in radiosensitivity remains to be elucidated. We found that miR-33a-5p was downregulated in melanoma tissues and cells. Cell proliferation was downregulated after overexpression of miR-33a-5p in WM451 cells, accompanied by a decreased level of glycolysis. In contrast, cell proliferation was upregulated after inhibition of miR-33a-5p in WM35 cells, accompanied by increased glycolysis. Overexpression of miR-33a-5p enhanced the sensitivity of melanoma cells to X-radiation by MTT assay, while downregulation of miR-33a-5p had the opposite effects. Finally, in vivo experiments with xenografts in nude mice confirmed that high expression of miR-33a-5p in tumor cells increased radiosensitivity via inhibiting glycolysis. In conclusions, miR-33a-5p promotes radiosensitivity by negatively regulating glycolysis in melanoma.
Collapse
|
|
37
|
Kraus RJ, Yu X, Cordes BLA, Sathiamoorthi S, Iempridee T, Nawandar DM, Ma S, Romero-Masters JC, McChesney KG, Lin Z, Makielski KR, Lee DL, Lambert PF, Johannsen EC, Kenney SC, Mertz JE. Hypoxia-inducible factor-1α plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter. PLoS Pathog 2017; 13:e1006404. [PMID: 28617871 PMCID: PMC5487075 DOI: 10.1371/journal.ppat.1006404] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 06/27/2017] [Accepted: 05/08/2017] [Indexed: 12/17/2022] Open
Abstract
When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-αs). We report here that HIF-1α also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1α and lytic EBV antigens. ShRNA knockdown of HIF-1α significantly reduced deferoxamine-mediated lytic reactivation. HIF-1α directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF-1α did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1α induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF-1α and Blimp-1α, another cellular factor implicated in lytic reactivation. HIF-1α activity also accumulated along with Blimp-1α during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1α plays central roles in both EBV’s natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF-1α protein accumulation are good candidates for development of a lytic-induction therapy for treating some EBV-associated malignancies. Most adults throughout the world are infected with Epstein-Barr virus (EBV), a human herpesvirus frequently associated in a latent state with some cancers of epithelial and B-cell origin such as nasopharyngeal carcinoma and Burkitt lymphoma, respectively. To develop an oncolytic therapy for treating patients with EBV-associated cancers, we need a method to efficiently induce synthesis of lytic EBV proteins. The EBV protein encoded by its immediate-early BZLF1 gene usually mediates the switch into lytic viral infection. We show here that HIF-1α, a cellular transcription factor that accumulates in cells when deprived of normal levels of oxygen, can induce lytic EBV infection. HIF-1α mediates this switch by directly binding to a specific sequence located within the BZLF1 gene promoter, activating its expression. Importantly, we also show that deferoxamine, an FDA-approved drug that inhibits degradation of HIF-1α, can induce synthesis of lytic EBV proteins in some EBV-positive epithelial and lymphocytic cell lines. These findings indicate that HIF-1α-stabilizing drugs, administered in combination with nucleoside analogues such as ganciclovir, may be helpful as part of a lytic-induction therapy for treating some patients with EBV-positive malignancies.
Collapse
Affiliation(s)
- Richard J. Kraus
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Xianming Yu
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Blue-leaf A. Cordes
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Saraniya Sathiamoorthi
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Tawin Iempridee
- National Nanotechnology Center, National Science and Technology Development Agency, Thailand Science Park, Pathum Thani, Thailand
| | - Dhananjay M. Nawandar
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Shidong Ma
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - James C. Romero-Masters
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Kyle G. McChesney
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Zhen Lin
- Department of Pathology, Tulane University Health Sciences Center and Tulane Cancer Center, New Orleans, Louisiana, United States of America
| | - Kathleen R. Makielski
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Denis L. Lee
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Eric C. Johannsen
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Shannon C. Kenney
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
| | - Janet E. Mertz
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, United States of America
- * E-mail:
| |
Collapse
|
|
38
|
Lo AKF, Dawson CW, Young LS, Lo KW. The role of metabolic reprogramming in γ-herpesvirus-associated oncogenesis. Int J Cancer 2017; 141:1512-1521. [PMID: 28542909 DOI: 10.1002/ijc.30795] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/01/2017] [Accepted: 05/10/2017] [Indexed: 12/26/2022]
Abstract
The γ-herpesviruses, EBV and KSHV, are closely associated with a number of human cancers. While the signal transduction pathways exploited by γ-herpesviruses to promote cell growth, survival and transformation have been reported, recent studies have uncovered the impact of γ-herpesvirus infection on host cell metabolism. Here, we review the mechanisms used by γ-herpesviruses to induce metabolic reprogramming in host cells, focusing on their ability to modulate the activity of metabolic regulators and manipulate metabolic pathways. While γ-herpesviruses alter metabolic phenotypes as a means to support viral infection and long-term persistence, this modulation can inadvertently contribute to cancer development. Strategies that target deregulated metabolic phenotypes induced by γ-herpesviruses provide new opportunities for therapeutic intervention.
Collapse
Affiliation(s)
- Angela Kwok-Fung Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Christopher W Dawson
- Institutite of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, United Kingdom
| | - Lawrence S Young
- Warwick Medical School, University of Warwick, Coventry, United Kingdom
| | - Kwok-Wai Lo
- Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China and Li Ka Shing Institute of Health Science, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| |
Collapse
|
|
39
|
Mthembu NN, Mbita Z, Hull R, Dlamini Z. Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers. HIV AIDS-RESEARCH AND PALLIATIVE CARE 2017; 9:77-93. [PMID: 28694706 PMCID: PMC5490432 DOI: 10.2147/hiv.s124911] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer. This aberrant splicing leads to abnormal production of protein and is caused by mutations in cis-acting elements or trans-acting factors in angiogenesis-related genes. Restoring the normal regulation of alternative splicing of angiogenic genes would alter the expression of protein isoforms and may confer normal cell physiology in patients with these cancers. This review highlights the abnormalities in alternative splicing of angiogenesis-related genes and their implication in HIV/AIDS-related cancers. This allows us to gain an insight into the pathogenesis of HIV/AIDS-related cancer and in turn elucidate the therapeutic potential of alternatively spliced genes in HIV/AIDS-related malignancies.
Collapse
Affiliation(s)
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Sovenga, South Africa
| | - Rodney Hull
- Research, Innovation and Engagements, Mangosuthu University of Technology, Durban
| | - Zodwa Dlamini
- Research, Innovation and Engagements, Mangosuthu University of Technology, Durban
| |
Collapse
|
|
40
|
Araldi RP, Assaf SMR, Carvalho RFD, Carvalho MACRD, Souza JMD, Magnelli RF, Módolo DG, Roperto FP, Stocco RDC, Beçak W. Papillomaviruses: a systematic review. Genet Mol Biol 2017; 40:1-21. [PMID: 28212457 PMCID: PMC5409773 DOI: 10.1590/1678-4685-gmb-2016-0128] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 09/28/2016] [Indexed: 12/15/2022] Open
Abstract
In the last decades, a group of viruses has received great attention due to its
relationship with cancer development and its wide distribution throughout the
vertebrates: the papillomaviruses. In this article, we aim to review some of the most
relevant reports concerning the use of bovines as an experimental model for studies
related to papillomaviruses. Moreover, the obtained data contributes to the
development of strategies against the clinical consequences of bovine
papillomaviruses (BPV) that have led to drastic hazards to the herds. To overcome the
problem, the vaccines that we have been developing involve recombinant DNA
technology, aiming at prophylactic and therapeutic procedures. It is important to
point out that these strategies can be used as models for innovative procedures
against HPV, as this virus is the main causal agent of cervical cancer, the second
most fatal cancer in women.
Collapse
Affiliation(s)
- Rodrigo Pinheiro Araldi
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | | | | | | | - Jacqueline Mazzuchelli de Souza
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Roberta Fiusa Magnelli
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil.,Programa de Pós-graduação Interunidades em Biotecnologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | | | - Franco Peppino Roperto
- Dipartimento di Medicina Veterinaria e Produzioni Animali, Università degli Studi di Napoli Federico II, Napoli, Campania, Italy
| | | | - Willy Beçak
- Laboratório de Genética, Instituto Butantan, São Paulo, SP, Brazil
| |
Collapse
|
|
41
|
Xu W, Zhou W, Cheng M, Wang J, Liu Z, He S, Luo X, Huang W, Chen T, Yan W, Xiao J. Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. Sci Rep 2017; 7:40446. [PMID: 28074862 PMCID: PMC5225427 DOI: 10.1038/srep40446] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 12/07/2016] [Indexed: 12/11/2022] Open
Abstract
The Wnt/β-catenin signaling is abnormally activated in the progression of hepatocellular carcinoma (HCC). BCL9 is an essential co-activator in the Wnt/β-catenin signaling. Importantly, BCL9 is absent from tumors originating from normal cellular counterparts and overexpressed in many cancers including HCC. But the mechanism for BCL9 overexpression remains unknown. Ample evidence indicates that hypoxia inducible factors (HIFs) play a role in the development of HCC. It was found in our study that BCL9 was overexpressed in both primary HCC and bone metastasis specimens; loss of BCL9 inhibited the proliferation, migration and angiogenesis of HCC; and that that hypoxia mechanically induced the expression of BCL9. BCL9 induction under the hypoxic condition was predominantly mediated by HIF-1α but not HIF2α. In vitro evidence from xenograft models indicated that BCL9 promoter/gene knockout inhibited HCC tumor growth and angiogenesis. Notably, we found that BCL9 and HIF-1α were coordinately regulated in human HCC specimen. The above findings suggest that hypoxia may promote the expression of BCL9 and associate with the development of HCC. Specific regulation of BCL9 expression by HIF-1α may prove to be an underlying crosstalk between Wnt/β-catenin signaling and hypoxia signaling pathways.
Collapse
Affiliation(s)
- Wei Xu
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| | - Wang Zhou
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| | - Mo Cheng
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| | - Jing Wang
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.,Department of Anatomy, Xuzhou Medical University, NO. 209, Tongshan Road, Xuzhou, 221004, China
| | - Zhian Liu
- Department of Anatomy, Xuzhou Medical University, NO. 209, Tongshan Road, Xuzhou, 221004, China
| | - Shaohui He
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| | - Xiangji Luo
- Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, NO. 225, Changhai Road, Shanghai, 200438, China
| | - Wending Huang
- Department of Bone and soft tissue tumors, Fudan Cancer Center, Fudan University, NO. 270, Dong'an Road, Shanghai, 200000, China
| | - Tianrui Chen
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| | - Wangjun Yan
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China.,Department of Bone and soft tissue tumors, Fudan Cancer Center, Fudan University, NO. 270, Dong'an Road, Shanghai, 200000, China
| | - Jianru Xiao
- Department of Orthorpedic Oncology, Changzheng Hospital, Second Military Medical University, NO. 415, Fengyang Road, Shanghai, 200003, China
| |
Collapse
|
|
42
|
Viollet C, Davis DA, Tekeste SS, Reczko M, Ziegelbauer JM, Pezzella F, Ragoussis J, Yarchoan R. RNA Sequencing Reveals that Kaposi Sarcoma-Associated Herpesvirus Infection Mimics Hypoxia Gene Expression Signature. PLoS Pathog 2017; 13:e1006143. [PMID: 28046107 PMCID: PMC5234848 DOI: 10.1371/journal.ppat.1006143] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 01/13/2017] [Accepted: 12/19/2016] [Indexed: 01/09/2023] Open
Abstract
Kaposi sarcoma-associated herpesvirus (KSHV) causes several tumors and hyperproliferative disorders. Hypoxia and hypoxia-inducible factors (HIFs) activate latent and lytic KSHV genes, and several KSHV proteins increase the cellular levels of HIF. Here, we used RNA sequencing, qRT-PCR, Taqman assays, and pathway analysis to explore the miRNA and mRNA response of uninfected and KSHV-infected cells to hypoxia, to compare this with the genetic changes seen in chronic latent KSHV infection, and to explore the degree to which hypoxia and KSHV infection interact in modulating mRNA and miRNA expression. We found that the gene expression signatures for KSHV infection and hypoxia have a 34% overlap. Moreover, there were considerable similarities between the genes up-regulated by hypoxia in uninfected (SLK) and in KSHV-infected (SLKK) cells. hsa-miR-210, a HIF-target known to have pro-angiogenic and anti-apoptotic properties, was significantly up-regulated by both KSHV infection and hypoxia using Taqman assays. Interestingly, expression of KSHV-encoded miRNAs was not affected by hypoxia. These results demonstrate that KSHV harnesses a part of the hypoxic cellular response and that a substantial portion of hypoxia-induced changes in cellular gene expression are induced by KSHV infection. Therefore, targeting hypoxic pathways may be a useful way to develop therapeutic strategies for KSHV-related diseases.
Collapse
Affiliation(s)
- Coralie Viollet
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - David A. Davis
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Shewit S. Tekeste
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Martin Reczko
- Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece
| | - Joseph M. Ziegelbauer
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom
| | - Jiannis Ragoussis
- The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
- Institute of Molecular Oncology, Alexander Fleming Biomedical Sciences Research Center, Vari, Greece
- McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada
- Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| |
Collapse
|
|
43
|
Ankyrin Repeat Proteins of Orf Virus Influence the Cellular Hypoxia Response Pathway. J Virol 2016; 91:JVI.01430-16. [PMID: 27795413 DOI: 10.1128/jvi.01430-16] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 10/18/2016] [Indexed: 11/20/2022] Open
Abstract
Hypoxia-inducible factor (HIF) is a transcriptional activator with a central role in regulating cellular responses to hypoxia. It is also emerging as a major target for viral manipulation of the cellular environment. Under normoxic conditions, HIF is tightly suppressed by the activity of oxygen-dependent prolyl and asparaginyl hydroxylases. The asparaginyl hydroxylase active against HIF, factor inhibiting HIF (FIH), has also been shown to hydroxylate some ankyrin repeat (ANK) proteins. Using bioinformatic analysis, we identified the five ANK proteins of the parapoxvirus orf virus (ORFV) as potential substrates of FIH. Consistent with this prediction, coimmunoprecipitation of FIH was detected with each of the ORFV ANK proteins, and for one representative ORFV ANK protein, the interaction was shown to be dependent on the ANK domain. Immunofluorescence studies revealed colocalization of FIH and the viral ANK proteins. In addition, mass spectrometry confirmed that three of the five ORFV ANK proteins are efficiently hydroxylated by FIH in vitro While FIH levels were unaffected by ORFV infection, transient expression of each of the ORFV ANK proteins resulted in derepression of HIF-1α activity in reporter gene assays. Furthermore, ORFV-infected cells showed upregulated HIF target gene expression. Our data suggest that sequestration of FIH by ORFV ANK proteins leads to derepression of HIF activity. These findings reveal a previously unknown mechanism of viral activation of HIF that may extend to other members of the poxvirus family. IMPORTANCE The protein-protein binding motif formed from multiple repeats of the ankyrin motif is common among chordopoxviruses. However, information on the roles of these poxviral ankyrin repeat (ANK) proteins remains limited. Our data indicate that the parapoxvirus orf virus (ORFV) is able to upregulate hypoxia-inducible factor (HIF) target gene expression. This response is mediated by the viral ANK proteins, which sequester the HIF regulator FIH (factor inhibiting HIF). This is the first demonstration of any viral protein interacting directly with FIH. Our data reveal a new mechanism by which viruses reprogram HIF, a master regulator of cellular metabolism, and also show a new role for the ANK family of poxvirus proteins.
Collapse
|
|
44
|
Devraj G, Beerlage C, Brüne B, Kempf VAJ. Hypoxia and HIF-1 activation in bacterial infections. Microbes Infect 2016; 19:144-156. [PMID: 27903434 DOI: 10.1016/j.micinf.2016.11.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 11/14/2016] [Accepted: 11/21/2016] [Indexed: 12/22/2022]
Abstract
For most of the living beings, oxygen is one of the essential elements required to sustain life. Deprivation of oxygen causes tissue hypoxia and this severely affects host cell and organ functions. Tissue hypoxia is a prominent microenvironmental condition occurring in infections and there is a body of evidence that hypoxia and inflammation are interconnected with each other. The primary key factor mediating the mammalian hypoxic response is hypoxia inducible factor (HIF)-1, which regulates oxygen homeostasis on cellular, tissue and organism level. Recent studies show that HIF-1 plays a central role in angiogenesis, cancer and cardiovascular disease but also in bacterial infections. Activation of HIF-1 depends on the nature of the pathogen and the characteristics of infections in certain hosts. Up to date, it is not completely clear whether the phenomenon of HIF-1 activation in infections has a protective or detrimental effect on the host. In this review, we give an overview of whether and how hypoxia and HIF-1 affect the course of infections.
Collapse
Affiliation(s)
- Gayatri Devraj
- Institute of Medical Microbiology and Infection Control, Goethe-University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Christiane Beerlage
- Institute of Medical Microbiology and Infection Control, Goethe-University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I - Pathobiochemistry, Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
| | - Volkhard A J Kempf
- Institute of Medical Microbiology and Infection Control, Goethe-University, Paul-Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany.
| |
Collapse
|
|
45
|
Sung WW, Chu YC, Chen PR, Liao MH, Lee JW. Positive regulation of HIF-1A expression by EBV oncoprotein LMP1 in nasopharyngeal carcinoma cells. Cancer Lett 2016; 382:21-31. [PMID: 27567526 DOI: 10.1016/j.canlet.2016.08.021] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 08/22/2016] [Accepted: 08/22/2016] [Indexed: 12/11/2022]
Abstract
Latent membrane protein 1 (LMP1) is a pivotal viral oncoprotein that contributes to the carcinogenesis of Epstein-Barr virus (EBV)-associated malignancies, including nasopharyngeal carcinoma (NPC). We investigated the regulation of hypoxia-inducible factor 1-α (HIF-1α) by LMP1. In NPC cells, we found that LMP1 significantly enhanced the HIF-1α mRNA level, and not only the protein amount as described previously. Mechanistically, the stability of the HIF-1α transcript was remarkably prolonged by LMP1 via reduced expressions of RNA-destabilizing proteins tristetraprolin (TTP) and pumilio RNA-binding family member 2 (PUM2) through C-terminal activation region 1 (CTAR1) and CTAR3 interaction with the ERK1/2 and STAT3 signaling pathways, respectively, in parallel with hindrance of PUM2 binding to the HIF-1α mRNA 3'-untranslated region (3'-UTR). On the other hand, HIF-1A promoter activity was also obviously facilitated by the LMP1 CTAR1-recruited ERK1/2/NF-κB pathway. Intriguingly, in this scenario, augmented HIF-1α further exhibited positive auto-regulation of its own gene transcription. Our results showed the first time that LMP1 directly up-regulates HIF-1A transcription and post-transcription in NPC cells, in addition to providing evidence of an increase in the HIF-1α mRNA level caused by a tumor-associated virus under normoxic conditions.
Collapse
Affiliation(s)
- Wei-Wen Sung
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Yi-Chih Chu
- Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
| | - Peir-Rong Chen
- Department of Otolaryngology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
| | - Ming-Hui Liao
- Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan.
| | - Jeng-Woei Lee
- Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan; Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan.
| |
Collapse
|
|
46
|
Araldi RP, Módolo DG, de Sá Júnior PL, Consonni SR, de Carvalho RF, Roperto FP, Beçak W, de Cassia Stocco R. Genetics and metabolic deregulation following cancer initiation: A world to explore. Biomed Pharmacother 2016; 82:449-58. [DOI: 10.1016/j.biopha.2016.05.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/16/2016] [Accepted: 05/19/2016] [Indexed: 02/08/2023] Open
|
|
47
|
CHEN YAO, CAO KE, WANG SHAOHUA, CHEN JIA, HE BIN, HE GU, CHEN YONG, PENG BIN, ZHOU JIANDA. MicroRNA-138 suppresses proliferation, invasion and glycolysis in malignant melanoma cells by targeting HIF-1α. Exp Ther Med 2016; 11:2513-2518. [PMID: 27284341 PMCID: PMC4887928 DOI: 10.3892/etm.2016.3220] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Accepted: 01/26/2016] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRs) may induce mRNA degradation or inhibit protein translation by directly binding to the 3'-untranslational region of target mRNAs. It has been reported that miR-138 is downregulated in malignant melanoma (MM) cells. However, the role of miR-138 in MM cell proliferation, invasion and energy metabolism remains unknown. These were investigated using reverse transcription-quantitative polymerase chain reaction was used to evaluate the expression of miR-138 and the mRNA expression of hypoxia-inducible factor-1α (HIF-1α), as HIF-1α serves a crucial role in glycolysis, which is important for tumor growth. In addition, western blot analysis was used to detected the protein expression of HIF-1α, while MTT and Transwell assays evaluated cell proliferation and invasion, respectively. Furthermore, glucose consumption and lactic acid production were assessed. These tests were conducted using the normal human melanocyte cell line HM and the MM cell line WM451, which was transfected variously with scramble miR mimics, miR-138 mimics, miR-138 inhibitor, non-specific small interfering (si)RNA, HIF-1α siRNA, or co-transfected with miR-138 mimics and pc-DNA3.1(+)-HIF-1α plasmid. The results showed that miR-138 was significantly downregulated in MM WM451 cells compared to a normal melanocyte cell line HM. Overexpression of miR-138 significantly inhibited the proliferation and invasion of WM451 cells. These effects were similar to those induced by the siRNA-mediated knockdown of HIF-1α, a direct target of miR-138. Further investigation found that miR-138 negatively regulated the protein expression of HIF-1α in WM451 cells. Moreover, upregulation of miR-138 notably inhibited the glycolysis level, as demonstrated by reduced glucose consumption and lactic acid production, which could be reversed by the overexpression of HIF-1α. In summary, the present study demonstrated that miR-138 is able to inhibit proliferation, invasion and glycolysis in MM cells, potentially by directly targeting HIF-1α.
Collapse
Affiliation(s)
- YAO CHEN
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
- Department of Plastic Surgery, Longgang Orthopedics Hospital of Shenzhen, Shenzhen, Guangdong 518116, P.R. China
| | - KE CAO
- Department of Oncology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - SHAOHUA WANG
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - JIA CHEN
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - BIN HE
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - GU HE
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - YONG CHEN
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - BIN PENG
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - JIANDA ZHOU
- Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| |
Collapse
|
|
48
|
CHEN YAO, ZHANG ZIQING, LUO CHENGQUN, CHEN ZIZI, ZHOU JIANDA. MicroRNA-18b inhibits the growth of malignant melanoma via inhibition of HIF-1α-mediated glycolysis. Oncol Rep 2016; 36:471-9. [DOI: 10.3892/or.2016.4824] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 02/19/2016] [Indexed: 11/06/2022] Open
|
|
49
|
Kurmyshkina OV, Belova LL, Kovchur PI, Volkova TO. [Remodeling of angiogenesis and lymphangiogenesis in cervical cancer development]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2015; 61:579-97. [PMID: 26539865 DOI: 10.18097/pbmc20156105579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Ability to stimulate angiogenesis/lymphangiogenesis is recognized as an inherent feature of cancer cells providing necessary conditions for their growth and dissemination. "Angiogenic switch" is one of the earliest consequences of malignant transformation that encompasses a great number of genes and triggers a complex set of signaling cascades in endothelial cells. The processes of tumor microvasculature development are closely connected to the steps of carcinogenesis (from benign lesions to invasive forms) and occur through multiple deviations from the norm. Analysis of expression of proangiogenic factors at successive steps of cervical cancer development (intraepithelial neoplasia, cancer in situ, microinvasive, and invasive cancer) enables to reconstruct the regulatory mechanisms of (lymph-)angiogenesis and to discriminate the most important components. This review presents detailed analysis of literature data on expression of the key regulators of angiogenesis in cervical intraepithelial neoplasia and cervical cancer. Their possible involvement in molecular mechanisms of neoplastic transformation of epithelial cells, as well as invasion and tumor metastasis is discussed. Correlation between expression of proangiogenic molecular factors and various clinicopathological parameters is considered, the potential of their use in molecular diagnostics and targeted therapy of cervical cancer is reviewed. Particular attention is paid to relatively poorly studied regulators of lymphangiogenesis and "non-VEGF dependent", or alternative, angiogenic pathways that constitute the prospect of future research in the field.
Collapse
Affiliation(s)
- O V Kurmyshkina
- Institute of High-Tech Biomedicine, Petrozavodsk State University, Petrozavodsk, Russia
| | - L L Belova
- Institute of High-Tech Biomedicine, Petrozavodsk State University, Petrozavodsk, Russia
| | - P I Kovchur
- Institute of High-Tech Biomedicine, Petrozavodsk State University, Petrozavodsk, Russia
| | - T O Volkova
- Institute of High-Tech Biomedicine, Petrozavodsk State University, Petrozavodsk, Russia
| |
Collapse
|
|
50
|
Dolcetti R. Cross-talk between Epstein-Barr virus and microenvironment in the pathogenesis of lymphomas. Semin Cancer Biol 2015; 34:58-69. [DOI: 10.1016/j.semcancer.2015.04.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 04/22/2015] [Accepted: 04/24/2015] [Indexed: 12/13/2022]
|