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1
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Jiang Q, Braun DA, Clauser KR, Ramesh V, Shirole NH, Duke-Cohan JE, Nabilsi N, Kramer NJ, Forman C, Lippincott IE, Klaeger S, Phulphagar KM, Chea V, Kim N, Vanasse AP, Saad E, Parsons T, Carr-Reynolds M, Carulli I, Pinjusic K, Jiang Y, Li R, Syamala S, Rachimi S, Verzani EK, Stevens JD, Lane WJ, Camp SY, Meli K, Pappalardi MB, Herbert ZT, Qiu X, Cejas P, Long HW, Shukla SA, Van Allen EM, Choueiri TK, Churchman LS, Abelin JG, Gurer C, MacBeath G, Childs RW, Carr SA, Keskin DB, Wu CJ, Kaelin WG. HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy. Cell 2025:S0092-8674(25)00156-4. [PMID: 40023154 DOI: 10.1016/j.cell.2025.01.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 11/14/2024] [Accepted: 01/31/2025] [Indexed: 03/04/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
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Affiliation(s)
- Qinqin Jiang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - David A Braun
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA
| | - Karl R Clauser
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Vijyendra Ramesh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Nitin H Shirole
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Joseph E Duke-Cohan
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | | | - Nicholas J Kramer
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Cleo Forman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Isabelle E Lippincott
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Susan Klaeger
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Kshiti M Phulphagar
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Vipheaviny Chea
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nawoo Kim
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Allison P Vanasse
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Eddy Saad
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | | | - Isabel Carulli
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Katarina Pinjusic
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Yijia Jiang
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Rong Li
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Sudeepa Syamala
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Suzanna Rachimi
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Eva K Verzani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Jonathan D Stevens
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - William J Lane
- Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - Sabrina Y Camp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Kevin Meli
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | | | - Zachary T Herbert
- Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Xintao Qiu
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Paloma Cejas
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Henry W Long
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Sachet A Shukla
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Eliezer M Van Allen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Toni K Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
| | - L Stirling Churchman
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Jennifer G Abelin
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | | | | | - Richard W Childs
- Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Steven A Carr
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
| | - Derin B Keskin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Computer Science, Metropolitan College, Boston University, Boston, MA 02215, USA; Section for Bioinformatics, Department of Health Technology, Technical University of Denmark 2800 Lyngby, Denmark.
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
| | - William G Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
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2
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Beliveau BJ, Akilesh S. A guide to studying 3D genome structure and dynamics in the kidney. Nat Rev Nephrol 2025; 21:97-114. [PMID: 39406927 DOI: 10.1038/s41581-024-00894-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2024] [Indexed: 10/19/2024]
Abstract
The human genome is tightly packed into the 3D environment of the cell nucleus. Rapidly evolving and sophisticated methods of mapping 3D genome architecture have shed light on fundamental principles of genome organization and gene regulation. The genome is physically organized on different scales, from individual genes to entire chromosomes. Nuclear landmarks such as the nuclear envelope and nucleoli have important roles in compartmentalizing the genome within the nucleus. Genome activity (for example, gene transcription) is also functionally partitioned within this 3D organization. Rather than being static, the 3D organization of the genome is tightly regulated over various time scales. These dynamic changes in genome structure over time represent the fourth dimension of the genome. Innovative methods have been used to map the dynamic regulation of genome structure during important cellular processes including organism development, responses to stimuli, cell division and senescence. Furthermore, disruptions to the 4D genome have been linked to various diseases, including of the kidney. As tools and approaches to studying the 4D genome become more readily available, future studies that apply these methods to study kidney biology will provide insights into kidney function in health and disease.
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Affiliation(s)
- Brian J Beliveau
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
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3
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Yang Y, Dong S, You B, Zhou C. Dual roles of human endogenous retroviruses in cancer progression and antitumor immune response. Biochim Biophys Acta Rev Cancer 2024; 1879:189201. [PMID: 39427821 DOI: 10.1016/j.bbcan.2024.189201] [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: 09/04/2024] [Revised: 10/13/2024] [Accepted: 10/16/2024] [Indexed: 10/22/2024]
Abstract
Human endogenous retroviruses (HERVs) are a class of transposable elements formed by the integration of ancient retroviruses into the germline genome. They are inherited in a Mendelian manner and approximately constitute 8 % of the human genome. HERVs were considered as "junk DNA" for decades, but increasing evidence suggests that they play significant roles in pathological inflammation, neural differentiation, and oncogenesis. Specifically, HERVs expression has been implicated in several oncogenic processes and the formation of the tumor microenvironment. Indeed, the dual roles of HERVs in cancer, serving as both promoters of oncogenesis and forerunners of the innate antitumor immune response, remain a subject of debate. In this review, we will discuss how HERVs participate in cancer progression and how they are regulated. Our aim is to provide a comprehensive understanding of the fundamental properties and potential function of HERVs in propagating oncogenesis and activating the antitumor immune response. We hope that updated knowledge will reshape our understanding of the critical roles played by HERVs in human evolution and cancer progression.
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Affiliation(s)
- Yang Yang
- Clinical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu, China.
| | - Surong Dong
- Clinical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu, China
| | - Benshuai You
- Clinical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu, China.
| | - Chenglin Zhou
- Clinical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, Jiangsu, China.
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4
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da Silva AL, Guedes BLM, Santos SN, Correa GF, Nardy A, Nali LHDS, Bachi ALL, Romano CM. Beyond pathogens: the intriguing genetic legacy of endogenous retroviruses in host physiology. Front Cell Infect Microbiol 2024; 14:1379962. [PMID: 38655281 PMCID: PMC11035796 DOI: 10.3389/fcimb.2024.1379962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
The notion that viruses played a crucial role in the evolution of life is not a new concept. However, more recent insights suggest that this perception might be even more expansive, highlighting the ongoing impact of viruses on host evolution. Endogenous retroviruses (ERVs) are considered genomic remnants of ancient viral infections acquired throughout vertebrate evolution. Their exogenous counterparts once infected the host's germline cells, eventually leading to the permanent endogenization of their respective proviruses. The success of ERV colonization is evident so that it constitutes 8% of the human genome. Emerging genomic studies indicate that endogenous retroviruses are not merely remnants of past infections but rather play a corollary role, despite not fully understood, in host genetic regulation. This review presents some evidence supporting the crucial role of endogenous retroviruses in regulating host genetics. We explore the involvement of human ERVs (HERVs) in key physiological processes, from their precise and orchestrated activities during cellular differentiation and pluripotency to their contributions to aging and cellular senescence. Additionally, we discuss the costs associated with hosting a substantial amount of preserved viral genetic material.
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Affiliation(s)
- Amanda Lopes da Silva
- Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Bruno Luiz Miranda Guedes
- Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Samuel Nascimento Santos
- UNISA Research Center, Universidade Santo Amaro, Post-Graduation in Health Sciences, São Paulo, Brazil
| | - Giovanna Francisco Correa
- Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Ariane Nardy
- UNISA Research Center, Universidade Santo Amaro, Post-Graduation in Health Sciences, São Paulo, Brazil
| | | | - Andre Luis Lacerda Bachi
- UNISA Research Center, Universidade Santo Amaro, Post-Graduation in Health Sciences, São Paulo, Brazil
| | - Camila Malta Romano
- Instituto de Medicina Tropical de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
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Hossain MJ, Nyame P, Monde K. Species-Specific Transcription Factors Associated with Long Terminal Repeat Promoters of Endogenous Retroviruses: A Comprehensive Review. Biomolecules 2024; 14:280. [PMID: 38540701 PMCID: PMC10968565 DOI: 10.3390/biom14030280] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/19/2024] [Accepted: 02/24/2024] [Indexed: 11/11/2024] Open
Abstract
Endogenous retroviruses (ERVs) became a part of the eukaryotic genome through endogenization millions of years ago. Moreover, they have lost their innate capability of virulence or replication. Nevertheless, in eukaryotic cells, they actively engage in various activities that may be advantageous or disadvantageous to the cells. The mechanisms by which transcription is triggered and implicated in cellular processes are complex. Owing to the diversity in the expression of transcription factors (TFs) in cells and the TF-binding motifs of viruses, the comprehensibility of ERV initiation and its impact on cellular functions are unclear. Currently, several factors are known to be related to their initiation. TFs that bind to the viral long-terminal repeat (LTR) are critical initiators. This review discusses the TFs shown to actively associate with ERV stimulation across species such as humans, mice, pigs, monkeys, zebrafish, Drosophila, and yeast. A comprehensive summary of the expression of previously reported TFs may aid in identifying similarities between animal species and endogenous viruses. Moreover, an in-depth understanding of ERV expression will assist in elucidating their physiological roles in eukaryotic cell development and in clarifying their relationship with endogenous retrovirus-associated diseases.
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Affiliation(s)
| | | | - Kazuaki Monde
- Department of Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (M.J.H.); (P.N.)
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6
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Haug S, Muthusamy S, Li Y, Stewart G, Li X, Treppner M, Köttgen A, Akilesh S. Multi-omic analysis of human kidney tissue identified medulla-specific gene expression patterns. Kidney Int 2024; 105:293-311. [PMID: 37995909 PMCID: PMC10843743 DOI: 10.1016/j.kint.2023.10.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 09/21/2023] [Accepted: 10/23/2023] [Indexed: 11/25/2023]
Abstract
The kidney medulla is a specialized region with important homeostatic functions. It has been implicated in genetic and developmental disorders along with ischemic and drug-induced injuries. Despite its role in kidney function and disease, the medulla's baseline gene expression and epigenomic signatures have not been well described in the adult human kidney. Here we generated and analyzed gene expression (RNA-seq), chromatin accessibility (ATAC-seq), chromatin conformation (Hi-C) and spatial transcriptomic data from the adult human kidney cortex and medulla. Tissue samples were obtained from macroscopically dissected cortex and medulla of tumor-adjacent normal material in nephrectomy specimens from five male patients. We used these carefully annotated specimens to reassign incorrectly labeled samples in the larger public Genotype-Tissue Expression (GTEx) Project, and to extract meaningful medullary gene expression signatures. Using integrated analysis of gene expression, chromatin accessibility and conformation profiles, we found insights into medulla development and function and then validated this by spatial transcriptomics and immunohistochemistry. Thus, our datasets provide a valuable resource for functional annotation of variants from genome-wide association studies and are freely accessible through an epigenome browser portal.
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Affiliation(s)
- Stefan Haug
- Institute of Genetic Epidemiology, Medical Center-University of Freiburg, Freiburg, Germany
| | - Selvaraj Muthusamy
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Yong Li
- Institute of Genetic Epidemiology, Medical Center-University of Freiburg, Freiburg, Germany
| | - Galen Stewart
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Xianwu Li
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Martin Treppner
- Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Medical Center-University of Freiburg, Freiburg, Germany.
| | - Shreeram Akilesh
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
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7
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Caliskan A, Arga KY. A Differential Transcriptional Regulome Approach to Unpack Cancer Biology: Insights on Renal Cell Carcinoma Subtypes. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2023; 27:536-545. [PMID: 37943533 DOI: 10.1089/omi.2023.0167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
Cancer research calls for new approaches that account for the regulatory complexities of biology. We present, in this study, the differential transcriptional regulome (DIFFREG) approach for the identification and prioritization of key transcriptional regulators and apply it to the case of renal cell carcinoma (RCC) biology. Of note, RCC has a poor prognosis and the biomarker and drug discovery studies to date have tended to focus on gene expression independent from mutations and/or post-translational modifications. DIFFREG focuses on the differential regulation between transcription factors (TFs) and their target genes rather than differential gene expression and integrates transcriptome profiling with the human transcriptional regulatory network to analyze differential gene regulation between healthy and RCC cases. In this study, RNA-seq tissue samples (n = 1020) from the Cancer Genome Atlas (TCGA), including healthy and tumor subjects, were integrated with a comprehensive human TF-gene interactome dataset (1122603 interactions between 1289 TFs and 25177 genes). Comparative analysis of DIFFREG profiles, consisting of perturbed TF-gene interactions, from three common subtypes (clear cell RCC, papillary RCC and chromophobe RCC) revealed subtype-specific alterations, supporting the hypothesis that these signatures in the transcriptional regulome profiles may be considered potential biomarkers that may play an important role in elucidating the molecular mechanisms of RCC development and translating knowledge about the genetic basis of RCC into the clinic. In addition, these indicators may help oncologists make the best decisions for diagnosis and prognosis management.
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Affiliation(s)
- Aysegul Caliskan
- Department of Bioengineering, Marmara University, Istanbul, Turkey
- Department of Pharmacy, Faculty of Pharmacy, Istinye University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, Istanbul, Turkey
- Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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8
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Kashima S, Braun DA. The Changing Landscape of Immunotherapy for Advanced Renal Cancer. Urol Clin North Am 2023; 50:335-349. [PMID: 36948676 DOI: 10.1016/j.ucl.2023.01.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
The management of advanced renal cell carcinoma has advanced tremendously over the past decade, but most patients still do not receive durable clinical benefit from current therapies. Renal cellcarcinoma is an immunogenic tumor, historically with conventional cytokine therapies, such as interleukin-2 and interferon-α, and contemporarily with the introduction of immune checkpoint inhibitors. Now the central therapeutic strategy in renal cell carcinoma is combination therapies including immunecheckpoint inhibitors. In this Review, we look back on the historical changes in systemic therapy for advanced renal cell carcinoma, and focus on the latest developments and prospects in this field.
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Affiliation(s)
- Soki Kashima
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, 300 George Street, Suite 6400, New Haven, CT, USA; Department of Urology, Akita University, Graduate School of Medicine, Akita, Japan
| | - David A Braun
- Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, 300 George Street, Suite 6400, New Haven, CT, USA.
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9
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Nassar AH, Abou Alaiwi S, Baca SC, Adib E, Corona RI, Seo JH, Fonseca MAS, Spisak S, El Zarif T, Tisza V, Braun DA, Du H, He M, Flaifel A, Alchoueiry M, Denize T, Matar SG, Acosta A, Shukla S, Hou Y, Steinharter J, Bouchard G, Berchuck JE, O'Connor E, Bell C, Nuzzo PV, Mary Lee GS, Signoretti S, Hirsch MS, Pomerantz M, Henske E, Gusev A, Lawrenson K, Choueiri TK, Kwiatkowski DJ, Freedman ML. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma. Nat Commun 2023; 14:346. [PMID: 36681680 PMCID: PMC9867739 DOI: 10.1038/s41467-023-35833-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/04/2023] [Indexed: 01/22/2023] Open
Abstract
While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.
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Affiliation(s)
- Amin H Nassar
- Department of Hematology/Oncology, Yale New Haven Hospital, New Haven, CT, 06510, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Sarah Abou Alaiwi
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Sylvan C Baca
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Elio Adib
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Rosario I Corona
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Center for Bioinformatics and Functional Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ji-Heui Seo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Marcos A S Fonseca
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- The Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA
| | - Talal El Zarif
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Viktoria Tisza
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- The Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA
| | - David A Braun
- Department of Hematology/Oncology, Yale New Haven Hospital, New Haven, CT, 06510, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- The Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA
| | - Heng Du
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Monica He
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Abdallah Flaifel
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Michel Alchoueiry
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Thomas Denize
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Sayed G Matar
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Andres Acosta
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Sachet Shukla
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yue Hou
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA
| | - John Steinharter
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Gabrielle Bouchard
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Jacob E Berchuck
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Edward O'Connor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Connor Bell
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Pier Vitale Nuzzo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Gwo-Shu Mary Lee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Michelle S Hirsch
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA
| | - Mark Pomerantz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Elizabeth Henske
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Alexander Gusev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- McGraw/Patterson Center for Population Sciences, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
| | - Kate Lawrenson
- Women's Cancer Research Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Center for Bioinformatics and Functional Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Toni K Choueiri
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
| | - David J Kwiatkowski
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
| | - Matthew L Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- The Eli and Edythe L. Broad Institute, Cambridge, MA, 02142, USA.
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10
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Umeki Y, Ogawa N, Uegaki Y, Saga K, Kaneda Y, Nimura K. DNA barcoding and gene expression recording reveal the presence of cancer cells with unique properties during tumor progression. Cell Mol Life Sci 2023; 80:17. [PMID: 36564568 PMCID: PMC9789022 DOI: 10.1007/s00018-022-04640-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/02/2022] [Accepted: 11/19/2022] [Indexed: 12/25/2022]
Abstract
Tumors comprise diverse cancer cell populations with specific capabilities for adaptation to the tumor microenvironment, resistance to anticancer treatments, and metastatic dissemination. However, whether these populations are pre-existing in cancer cells or stochastically appear during tumor growth remains unclear. Here, we show the heterogeneous behaviors of cancer cells regarding response to anticancer drug treatments, formation of lung metastases, and expression of transcription factors related to cancer stem-like cells using a DNA barcoding and gene expression recording system. B16F10 cells maintained clonal diversity after treatment with HVJ-E, a UV-irradiated Sendai virus, and the anticancer drug dacarbazine. PBS treatment of the primary tumor and intravenous injection of B16F10 cells resulted in metastases formed from clones of multiple cell lineages. Conversely, BL6 and 4T1 cells developed spontaneous lung metastases by a small number of clones. Notably, an identical clone of 4T1 cells developed lung metastases in different mice, suggesting the existence of cells with high metastatic potential. Cas9-based transcription recording analysis in a human prostate cancer cell line revealed that specific cells express POU5F1 in response to an anticancer drug and sphere formation. Our findings provide insights into the diversity of cancer cells during tumor progression.
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Affiliation(s)
- Yuka Umeki
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Noriaki Ogawa
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Yuko Uegaki
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Kotaro Saga
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Yasufumi Kaneda
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
| | - Keisuke Nimura
- Division of Gene Therapy Science, Department of Genome Biology, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan
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11
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Zhou RT, Ni YR, Zeng FJ. The roles of long noncoding RNAs in the regulation of OCT4 expression. Stem Cell Res Ther 2022; 13:383. [PMID: 35907897 PMCID: PMC9338536 DOI: 10.1186/s13287-022-03059-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 07/19/2022] [Indexed: 12/13/2022] Open
Abstract
OCT4 is a major transcription factor that maintains the pluripotency of stem cells, including embryonic stem cells, induced pluripotent stem cells and cancer stem cells. An increasing number of long noncoding RNAs have been reported to participate in the regulation of OCT4 expression through various mechanisms, including binding with the OCT4 gene promoter to regulate local methylation; promoting chromosomal spatial folding to form an inner ring, thereby aggregating OCT4 cis-acting elements scattered in discontinuous sites of the chromosome; competitively binding microRNAs with OCT4 to upregulate OCT4 expression at the posttranscriptional level; and sharing a promoter with OCT4. Moreover, the transcription of some long noncoding RNAs is regulated by OCT4, and certain long noncoding RNAs form feedback regulatory loops with OCT4. In this review, we summarized the research progress of the long noncoding RNAs involved in the regulation of OCT4 expression.
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Affiliation(s)
- Rui-Ting Zhou
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, Hubei, China.,Yichang Central People's Hospital, Yichang, 443003, Hubei, China.,Medical College, China Three Gorges University, Yichang, 443002, Hubei, China
| | - Yi-Ran Ni
- Medical College, China Three Gorges University, Yichang, 443002, Hubei, China.,Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, 443002, Hubei, China
| | - Fan-Jun Zeng
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443003, Hubei, China. .,Yichang Central People's Hospital, Yichang, 443003, Hubei, China.
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12
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Zhang M, Zheng S, Liang JQ. Transcriptional and reverse transcriptional regulation of host genes by human endogenous retroviruses in cancers. Front Microbiol 2022; 13:946296. [PMID: 35928153 PMCID: PMC9343867 DOI: 10.3389/fmicb.2022.946296] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/29/2022] [Indexed: 11/16/2022] Open
Abstract
Human endogenous retroviruses (HERVs) originated from ancient retroviral infections of germline cells millions of years ago and have evolved as part of the host genome. HERVs not only retain the capacity as retroelements but also regulate host genes. The expansion of HERVs involves transcription by RNA polymerase II, reverse transcription, and re-integration into the host genome. Fast progress in deep sequencing and functional analysis has revealed the importance of domesticated copies of HERVs, including their regulatory sequences, transcripts, and proteins in normal cells. However, evidence also suggests the involvement of HERVs in the development and progression of many types of cancer. Here we summarize the current state of knowledge about the expression of HERVs, transcriptional regulation of host genes by HERVs, and the functions of HERVs in reverse transcription and gene editing with their reverse transcriptase.
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Affiliation(s)
- Mengwen Zhang
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Second Affiliated Hospital, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China
| | - Shu Zheng
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
- Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Second Affiliated Hospital, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Shu Zheng,
| | - Jessie Qiaoyi Liang
- Department of Medicine and Therapeutics, Faculty of Medicine, Center for Gut Microbiota Research, Li Ka Shing Institute of Health Sciences, Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Jessie Qiaoyi Liang,
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13
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Choueiri TK, Albiges L, Atkins MB, Bakouny Z, Bratslavsky G, Braun DA, Haas NB, Haanen JB, Hakimi AA, Jewett MA, Jonasch E, Kaelin WG, Kapur P, Labaki C, Lewis B, McDermott DF, Pal SK, Pels K, Poteat S, Powles T, Rathmell WK, Rini BI, Signoretti S, Tannir NM, Uzzo RG, Hammers HJ. From Basic Science to Clinical Translation in Kidney Cancer: A Report from the Second Kidney Cancer Research Summit. Clin Cancer Res 2022; 28:831-839. [PMID: 34965942 PMCID: PMC9223120 DOI: 10.1158/1078-0432.ccr-21-3238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 11/07/2021] [Accepted: 12/21/2021] [Indexed: 11/16/2022]
Abstract
The second Kidney Cancer Research Summit was held virtually in October 2020. The meeting gathered worldwide experts in the field of kidney cancer, including basic, translational, and clinical scientists as well as patient advocates. Novel studies were presented, addressing areas of unmet need related to different topics. These include novel metabolic targets, promising immunotherapeutic regimens, predictive genomic and transcriptomic biomarkers, and variant histologies of renal cell carcinoma (RCC). With the development of pioneering technologies, and an unprecedented commitment to kidney cancer research, the field has tremendously evolved. This perspective aims to summarize the different sessions of the conference, outline major advances in the understanding of RCC and discuss current challenges faced by the field.
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Affiliation(s)
- Toni K. Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Laurence Albiges
- Department of Medical Oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France
| | - Michael B. Atkins
- Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA
| | - Ziad Bakouny
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Gennady Bratslavsky
- Department of Urology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York
| | - David A. Braun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Naomi B. Haas
- Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - John B.A.G. Haanen
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - A Ari Hakimi
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael A.S. Jewett
- Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Eric Jonasch
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William G. Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Payal Kapur
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Chris Labaki
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - David F. McDermott
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
| | - Sumanta K. Pal
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Kevin Pels
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Thomas Powles
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - W. Kimryn Rathmell
- Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, TN, USA
| | - Brian I. Rini
- Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, TN, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Nizar M. Tannir
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert G. Uzzo
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Hans J. Hammers
- Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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14
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Fayzullina D, Kharwar RK, Acharya A, Buzdin A, Borisov N, Timashev P, Ulasov I, Kapomba B. FNC: An Advanced Anticancer Therapeutic or Just an Underdog? Front Oncol 2022; 12:820647. [PMID: 35223502 PMCID: PMC8867032 DOI: 10.3389/fonc.2022.820647] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 01/13/2022] [Indexed: 12/14/2022] Open
Abstract
Azvudine (FNC) is a novel cytidine analogue that has both antiviral and anticancer activities. This minireview focuses on its underlying molecular mechanisms of suppressing viral life cycle and cancer cell growth and discusses applications of this nucleoside drug for advanced therapy of tumors and malignant blood diseases. FNC inhibits positive-stand RNA viruses, like HCV, EV, SARS-COV-2, HBV, and retroviruses, including HIV, by suppressing their RNA-dependent polymerase enzymes. It may also inhibit such enzyme (reverse transcriptase) in the human retrotransposons, including human endogenous retroviruses (HERVs). As the activation of retrotransposons can be the major factor of ongoing cancer genome instability and consequently higher aggressiveness of tumors, FNC has a potential to increase the efficacy of multiple anticancer therapies. Furthermore, FNC also showed other aspects of anticancer activity by inhibiting adhesion, migration, invasion, and proliferation of malignant cells. It was also reported to be involved in cell cycle arrest and apoptosis, thereby inhibiting the progression of cancer through different pathways. To the date, the grounds of FNC effects on cancer cells are not fully understood and hence additional studies are needed for better understanding molecular mechanisms of its anticancer activities to support its medical use in oncology.
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Affiliation(s)
- Daria Fayzullina
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Rajesh Kumar Kharwar
- Endocrine Research Lab, Department of Zoology, Kutir Post Graduate College, Chakkey, Jaunpur, India
| | - Arbind Acharya
- Tumor Immunology Lab, Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, India
| | - Anton Buzdin
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Nicolas Borisov
- Department of Medical and Biological Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Peter Timashev
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ilya Ulasov
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Byron Kapomba
- Department of General Surgery, Parirenyatwa Group of Hospitals, Harare, Zimbabwe,*Correspondence: Byron Kapomba,
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15
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Bersanelli M, Casartelli C, Buti S, Porta C. Renal cell carcinoma and viral infections: A dangerous relationship? World J Nephrol 2022; 11:1-12. [PMID: 35117975 PMCID: PMC8790307 DOI: 10.5527/wjn.v11.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 08/10/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Virus-related cancers in humans are widely recognized, but in the case of renal cancer, the link with the world of viruses is not clearly established in humans, despite being known in animal biology. In the present review, we aimed to explore the literature on renal cell carcinoma (RCC) for a possible role of viruses in human RCC tumorigenesis and immune homeostasis, hypothesizing the contribution of viruses to the immunogenicity of this tumor. A scientific literature search was conducted using the PubMed, Web of Science, and Google Scholar databases with the keywords “virus” or “viruses” or “viral infection” matched with (“AND”) “renal cell carcinoma” or “kidney cancer” or “renal cancer” or “renal carcinoma” or “renal tumor” or “RCC”. The retrieved findings evidenced two main aspects testifying to the relationship between RCC and viruses: The presence of viruses within the tumor, especially in non-clear cell RCC cases, and RCC occurrence in cases with pre-existing chronic viral infections. Some retrieved translational and clinical data suggest the possible contribution of viruses, particularly Epstein-Barr virus, to the marked immunogenicity of sarcomatoid RCC. In addition, it was revealed the possible role of endogenous retrovirus reactivation in RCC oncogenesis, introducing new fascinating hypotheses about this tumor’s immunogenicity and likeliness of response to immune checkpoint inhibitors.
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Affiliation(s)
- Melissa Bersanelli
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy
| | - Chiara Casartelli
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
- Department of Medicine and Surgery, University of Parma, Parma 43126, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy
| | - Camillo Porta
- Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, Bari 70121, Italy
- Department of Medical Oncology, Policlinico Consorziale, Bari 70124, Italy
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16
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The Zebrafish Model to Understand Epigenetics in Renal Diseases. Int J Mol Sci 2021; 22:ijms22179152. [PMID: 34502062 PMCID: PMC8431166 DOI: 10.3390/ijms22179152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/22/2021] [Accepted: 08/23/2021] [Indexed: 11/24/2022] Open
Abstract
Epigenetic modifications are able to alter gene expression and include DNA methylation, different histone variants, and post-transcriptional modifications (PTMs), such as acetylation or phosphorylation, and through short/long RNAs, respectively. In this review, we focus on current knowledge concerning epigenetic modifications in gene regulation. We describe different forms of epigenetic modifications and explain how epigenetic changes can be detected. The relevance of epigenetics in renal diseases is highlighted with multiple examples and the use of the zebrafish model to study glomerular diseases in general and epigenetics in renal diseases in particular is discussed. We end with an outlook on how to use epigenetic modifications as a therapeutic target for different diseases. Here, the zebrafish model can be employed as a high-throughput screening tool not only to discover epigenetic alterations contributing to disease, but also to test novel substances that change epigenetic signatures in vivo. Therefore, the zebrafish model harbors the opportunity to find novel pathogenic pathways allowing a pre-selection of potential targets and compounds to be tested for renal diseases.
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17
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Pisano MP, Grandi N, Tramontano E. Human Endogenous Retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) Are Dynamically Modulated in Different Stages of Immunity. BIOLOGY 2021; 10:biology10050405. [PMID: 34062989 PMCID: PMC8147956 DOI: 10.3390/biology10050405] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/26/2021] [Accepted: 04/30/2021] [Indexed: 12/25/2022]
Abstract
Human Endogenous retroviruses (HERVs) and Mammalian Apparent LTRs Retrotransposons (MaLRs) are remnants of ancient retroviral infections that represent a large fraction of our genome. The HERV and MaLR transcriptional activity is regulated in developmental stages, adult tissues, and pathological conditions. In this work, we used a bioinformatics approach based on RNA-sequencing (RNA-seq) to study the expression and modulation of HERVs and MaLR in a scenario of activation of the immune response. We analyzed transcriptome data from subjects before and after the administration of an inactivated vaccine against the Hantaan orthohantavirus, the causative agent of Korean hemorrhagic fever, to investigate the HERV and MaLR expression and differential expression in response to the administration of the vaccine. Specifically, we described the HERV transcriptome in PBMCs and identified HERV and MaLR loci differentially expressed after the 2nd, 3rd, and 4th inactivated vaccine administrations. We found that the expression of 545 HERV and MaLR elements increased in response to the vaccine and that the activation of several individual HERV and MaLR loci is specific for each vaccine administration and correlated to different genes and immune-related pathways.
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18
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Human Endogenous Retroviruses as Biomedicine Markers. Virol Sin 2021; 36:852-858. [PMID: 33905075 DOI: 10.1007/s12250-021-00387-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 03/15/2021] [Indexed: 11/27/2022] Open
Abstract
Human endogenous retroviruses (HERVs) were formed via ancient integration of exogenous retroviruses into the human genome and are considered to be viral "fossils". The human genome is embedded with a considerable amount of HERVs, witnessing the long-term evolutionary history of the viruses and the host. Most HERVs have lost coding capability during selection but still function in terms of HERV-mediated regulation of host gene expression. In this review, we summarize the roles of HERV activation in response to viral infections and diseases, and emphasize the potential use of HERVs as biomedicine markers in the early diagnosis of diseases such as cancer, which provides a new perspective for the clinical application of HERVs.
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19
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Jahangiri L, Ishola T, Pucci P, Trigg RM, Pereira J, Williams JA, Cavanagh ML, Gkoutos GV, Tsaprouni L, Turner SD. The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells. Cancers (Basel) 2021; 13:cancers13061239. [PMID: 33799834 PMCID: PMC7998932 DOI: 10.3390/cancers13061239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/06/2021] [Accepted: 03/08/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Cancer stem cells (CSCs) represent a distinct cancer subpopulation that can influence the tumour microenvironment, in addition to cancer progression and relapse. A multitude of factors including CSC properties, long noncoding RNAs (lncRNAs), and autophagy play pivotal roles in maintaining CSCs. We discuss the methods of detection of CSCs and how our knowledge of regulatory and cellular processes, and their interaction with the microenvironment, may lead to more effective targeting of these cells. Autophagy and lncRNAs can regulate several cellular functions, thereby promoting stemness factors and CSC properties, hence understanding this triangle and its associated signalling networks can lead to enhanced therapy response, while paving the way for the development of novel therapeutic approaches. Abstract Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.
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Affiliation(s)
- Leila Jahangiri
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Correspondence: (L.J.); (G.V.G.)
| | - Tala Ishola
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Perla Pucci
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
| | - Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Department of Functional Genomics, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Joao Pereira
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - John A. Williams
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
| | - Megan L. Cavanagh
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Georgios V. Gkoutos
- Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK;
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2SY, UK
- Mammalian Genetics Unit, Medical Research Council Harwell Institute, Oxfordshire OX110RD, UK
- MRC Health Data Research Midlands, University of Birmingham, Birmingham B15 2TT, UK
- NIHR Experimental Cancer Medicine Centre, Birmingham B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, Birmingham B15 2TT, UK
- NIHR Biomedical Research Centre, Birmingham B15 2TT, UK
- Correspondence: (L.J.); (G.V.G.)
| | - Loukia Tsaprouni
- Department of Life Sciences, Birmingham City University, Birmingham B15 3TN, UK; (T.I.); (M.L.C.); (L.T.)
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; (P.P.); (R.M.T.); (S.D.T.)
- Central European Institute of Technology (CEITEC), Masaryk University, 625 00 Brno, Czech Republic
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20
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Xu Y, Miller CP, Warren EH, Tykodi SS. Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma. Hum Vaccin Immunother 2021; 17:1882-1896. [PMID: 33667140 PMCID: PMC8189101 DOI: 10.1080/21645515.2020.1870846] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In renal-cell carcinoma (RCC), tumor-reactive T-cell responses can occur spontaneously or in response to systemic immunotherapy with cytokines and immune checkpoint inhibitors. Cancer vaccines and engineered T-cell therapies are designed to selectively augment tumor antigen-specific CD8+ T-cell responses with the goal to elicit tumor regression and avoid toxicities associated with nonspecific immunotherapies. In this review, we provide an overview of the central role of T-cell immunity in the treatment of advanced RCC. Clinical outcomes for antigen-targeted vaccines or other T-cell-engaging therapies for RCC are summarized and evaluated, and emerging new strategies to enhance the effectiveness of antigen-specific therapy for RCC are discussed.
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Affiliation(s)
- Yuexin Xu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Chris P Miller
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Edus H Warren
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA
| | - Scott S Tykodi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA
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21
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Gao Y, Yu XF, Chen T. Human endogenous retroviruses in cancer: Expression, regulation and function. Oncol Lett 2020; 21:121. [PMID: 33552242 PMCID: PMC7798031 DOI: 10.3892/ol.2020.12382] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/27/2020] [Indexed: 12/16/2022] Open
Abstract
Human endogenous retroviruses (HERVs) are the remnants of ancient retroviruses that infected human germline cells and became integrated into the human genome millions of years ago. Although most of these sequences are incomplete and silent, several potential pathological roles of HERVs have been observed in numerous diseases, such as multiple sclerosis and rheumatoid arthritis, and especially cancer, including breast cancer and pancreatic carcinoma. The present review investigates the expression signatures and complex regulatory mechanisms of HERVs in cancer. The long terminal repeats-driven transcriptional initiation of HERVs are regulated by transcription factors (such as Sp3) and epigenetic modifications (such as DNA methylation), and are influenced by environmental factors (such as ultraviolet radiation). In addition, this review focuses on the dual opposing effects of HERVs in cancer. HERVs can suppress cancer via immune activation; however, they can also promote cancer. HERV env gene serves a prime role in promoting carcinogenesis in certain malignant tumors, including breast cancer, pancreatic cancer, germ cell tumors, leukemia and Kaposi's sarcoma. Also, HERV ENV proteins can promote cancer via immune suppression. Targeting ENV proteins is a potential future antitumor treatment modality.
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Affiliation(s)
- Yuan Gao
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zheijang 310009, P.R. China
| | - Xiao-Fang Yu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zheijang 310009, P.R. China
| | - Ting Chen
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zheijang 310009, P.R. China
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22
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Cao W, Kang R, Xiang Y, Hong J. Human Endogenous Retroviruses in Clear Cell Renal Cell Carcinoma: Biological Functions and Clinical Values. Onco Targets Ther 2020; 13:7877-7885. [PMID: 32821127 PMCID: PMC7423347 DOI: 10.2147/ott.s259534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/13/2020] [Indexed: 01/05/2023] Open
Abstract
Human endogenous retroviruses (HERVs) form an important part of the human genome, commonly losing their coding ability and exhibiting only rare expression in healthy tissues to promote the stability of the genome. However, overexpression of HERVs has been observed in various malignant tumors, including clear cell renal cell carcinoma (ccRCC), and may be closely correlated with tumorigenesis and progression. HERVs may activate the interferon (IFN) signaling pathway by a viral mimicry process to enhance antitumor immune responses. There is increasing interest in the diagnostic and prognostic value of HERVs in cancers, and they may be candidate targets for tumor immunotherapy. The review will introduce the biological functions of HERVs in ccRCC and their clinical value, especially in regard to immunotherapy.
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Affiliation(s)
- Wenjun Cao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ran Kang
- Department of Urology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, People's Republic of China
| | - Yining Xiang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jidong Hong
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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23
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Zeng J, Feng Q, Wang Y, Xie G, Li Y, Yang Y, Feng J. Circular RNA circ_001842 plays an oncogenic role in renal cell carcinoma by disrupting microRNA-502-5p-mediated inhibition of SLC39A14. J Cell Mol Med 2020; 24:9712-9725. [PMID: 32729666 PMCID: PMC7520279 DOI: 10.1111/jcmm.15529] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 05/18/2020] [Accepted: 06/02/2020] [Indexed: 12/22/2022] Open
Abstract
Renal cell carcinoma (RCC) is a common urologic malignancy, and up to 30% of RCC patients present with locally advanced or metastatic disease at the time of initial diagnosis. Increasing evidence suggests that circular RNAs (circRNAs) serve as genomic regulatory molecules in various human cancers. Our initial in silico microarray-based analysis identified that circRNA circ_001842 was highly expressed in RCC. Such up-regulation of circ_001842 in RCC was experimentally validated in tissues and cell lines using RT-qPCR. Thereafter, we attempted to identify the role of circ_001842 in the pathogenesis of RCC. Through a series of gain- and loss-of function assays, cell biological functions were examined using colony formation assay, Transwell assay, annexin V-FITC/PI-labelled flow cytometry and scratch test. A high expression of circ_001842 in tissues was observed as associated with poor prognosis of RCC patients. circ_001842 was found to elevate SLC39A14 expression by binding to miR-502-5p, consequently resulting in augmented RCC cell proliferation, migration and invasion, as well as EMT in vitro and tumour growth in vivo. These observations imply the involvement of circ_001842 in RCC pathogenesis through a miR-502-5p-dependent SLC39A14 mechanism, suggesting circ_001842 is a potential target for RCC treatment.
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Affiliation(s)
- Jiawei Zeng
- Department of Clinical Laboratory, Mianyang Central Hospital, Mianyang, China
| | - Qian Feng
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yaodong Wang
- Department of Urology Surgery, Mianyang Central Hospital, Mianyang, China
| | - Gang Xie
- Department of Pathology, Mianyang Central Hospital, Mianyang, China
| | - Yuanmeng Li
- Department of Medical Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yuwei Yang
- Department of Clinical Laboratory, Mianyang Central Hospital, Mianyang, China
| | - Jiafu Feng
- Department of Clinical Laboratory, Mianyang Central Hospital, Mianyang, China.,Department of Medical Laboratory, Affiliated Hospital of Southwest Medical University, Luzhou, China
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24
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Vergara Bermejo A, Ragonnaud E, Daradoumis J, Holst P. Cancer Associated Endogenous Retroviruses: Ideal Immune Targets for Adenovirus-Based Immunotherapy. Int J Mol Sci 2020; 21:ijms21144843. [PMID: 32650622 PMCID: PMC7402293 DOI: 10.3390/ijms21144843] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for several cancers where the field had fallen short in providing competent therapies. Despite the improvement, broadly acting and highly effective therapies capable of eliminating or preventing human cancers with insufficient mutated antigens are still missing. Adenoviral vector-based vaccines are a successful tool in the treatment of various diseases including cancer; however, their success has been limited. In this review we discuss the potential of adenovirus as therapeutic tools and the current developments to use them against cancer. More specifically, we examine how to use them to target endogenous retroviruses (ERVs). ERVs, comprising 8% of the human genome, have been detected in several cancers, while they remain silent in healthy tissues. Their low immunogenicity together with their immunosuppressive capacity aid cancer to escape immunosurveillance. In that regard, virus-like-vaccine (VLV) technology, combining adenoviral vectors and virus-like-particles (VLPs), can be ideal to target ERVs and elicit B-cell responses, as well as CD8+ and CD4+ T-cells responses.
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Affiliation(s)
- Amaia Vergara Bermejo
- InProTher, Bioinnovation Institute, Copenhagen Bio Science Park, 2200 Copenhagen, Denmark; (E.R.); (J.D.)
- Correspondence: (A.V.B.); (P.H.)
| | - Emeline Ragonnaud
- InProTher, Bioinnovation Institute, Copenhagen Bio Science Park, 2200 Copenhagen, Denmark; (E.R.); (J.D.)
| | - Joana Daradoumis
- InProTher, Bioinnovation Institute, Copenhagen Bio Science Park, 2200 Copenhagen, Denmark; (E.R.); (J.D.)
- Center for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Peter Holst
- InProTher, Bioinnovation Institute, Copenhagen Bio Science Park, 2200 Copenhagen, Denmark; (E.R.); (J.D.)
- Center for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
- Correspondence: (A.V.B.); (P.H.)
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25
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Pisano MP, Grandi N, Tramontano E. High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development. Viruses 2020; 12:E633. [PMID: 32545287 PMCID: PMC7354619 DOI: 10.3390/v12060633] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/07/2020] [Accepted: 06/10/2020] [Indexed: 01/19/2023] Open
Abstract
Human Endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that represent a large fraction of our genome. Their transcriptional activity is finely regulated in early developmental stages and their expression is modulated in different cell types and tissues. Such activity has an impact on human physiology and pathology that is only partially understood up to date. Novel high-throughput sequencing tools have recently allowed for a great advancement in elucidating the various HERV expression patterns in different tissues as well as the mechanisms controlling their transcription, and overall, have helped in gaining better insights in an all-inclusive understanding of the impact of HERVs in biology of the host.
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Affiliation(s)
- Maria Paola Pisano
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, 09042 Cagliari, Italy; (M.P.P.); (N.G.)
| | - Nicole Grandi
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, 09042 Cagliari, Italy; (M.P.P.); (N.G.)
| | - Enzo Tramontano
- Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, 09042 Cagliari, Italy; (M.P.P.); (N.G.)
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 09042 Cagliari, Italy
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26
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Emamalipour M, Seidi K, Zununi Vahed S, Jahanban-Esfahlan A, Jaymand M, Majdi H, Amoozgar Z, Chitkushev LT, Javaheri T, Jahanban-Esfahlan R, Zare P. Horizontal Gene Transfer: From Evolutionary Flexibility to Disease Progression. Front Cell Dev Biol 2020; 8:229. [PMID: 32509768 PMCID: PMC7248198 DOI: 10.3389/fcell.2020.00229] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/17/2020] [Indexed: 12/11/2022] Open
Abstract
Flexibility in the exchange of genetic material takes place between different organisms of the same or different species. This phenomenon is known to play a key role in the genetic, physiological, and ecological performance of the host. Exchange of genetic materials can cause both beneficial and/or adverse biological consequences. Horizontal gene transfer (HGT) or lateral gene transfer (LGT) as a general mechanism leads to biodiversity and biological innovations in nature. HGT mediators are one of the genetic engineering tools used for selective introduction of desired changes in the genome for gene/cell therapy purposes. HGT, however, is crucial in development, emergence, and recurrence of various human-related diseases, such as cancer, genetic-, metabolic-, and neurodegenerative disorders and can negatively affect the therapeutic outcome by promoting resistant forms or disrupting the performance of genome editing toolkits. Because of the importance of HGT and its vital physio- and pathological roles, here the variety of HGT mechanisms are reviewed, ranging from extracellular vesicles (EVs) and nanotubes in prokaryotes to cell-free DNA and apoptotic bodies in eukaryotes. Next, we argue that HGT plays a role both in the development of useful features and in pathological states associated with emerging and recurrent forms of the disease. A better understanding of the different HGT mediators and their genome-altering effects/potentials may pave the way for the development of more effective therapeutic and diagnostic regimes.
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Affiliation(s)
- Melissa Emamalipour
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khaled Seidi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Mehdi Jaymand
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hasan Majdi
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Amoozgar
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - L T Chitkushev
- Department of Computer Science, Metropolitan College, Boston University, Boston, MA, United States.,Health Informatics Lab, Metropolitan College, Boston University, Boston, MA, United States
| | - Tahereh Javaheri
- Health Informatics Lab, Metropolitan College, Boston University, Boston, MA, United States
| | - Rana Jahanban-Esfahlan
- Department of Medical Biotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Peyman Zare
- Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, Warsaw, Poland.,Dioscuri Center of Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
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27
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Marasca F, Gasparotto E, Polimeni B, Vadalà R, Ranzani V, Bodega B. The Sophisticated Transcriptional Response Governed by Transposable Elements in Human Health and Disease. Int J Mol Sci 2020; 21:ijms21093201. [PMID: 32366056 PMCID: PMC7247572 DOI: 10.3390/ijms21093201] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/29/2020] [Accepted: 04/29/2020] [Indexed: 01/15/2023] Open
Abstract
Transposable elements (TEs), which cover ~45% of the human genome, although firstly considered as “selfish” DNA, are nowadays recognized as driving forces in eukaryotic genome evolution. This capability resides in generating a plethora of sophisticated RNA regulatory networks that influence the cell type specific transcriptome in health and disease. Indeed, TEs are transcribed and their RNAs mediate multi-layered transcriptional regulatory functions in cellular identity establishment, but also in the regulation of cellular plasticity and adaptability to environmental cues, as occurs in the immune response. Moreover, TEs transcriptional deregulation also evolved to promote pathogenesis, as in autoimmune and inflammatory diseases and cancers. Importantly, many of these findings have been achieved through the employment of Next Generation Sequencing (NGS) technologies and bioinformatic tools that are in continuous improvement to overcome the limitations of analyzing TEs sequences. However, they are highly homologous, and their annotation is still ambiguous. Here, we will review some of the most recent findings, questions and improvements to study at high resolution this intriguing portion of the human genome in health and diseases, opening the scenario to novel therapeutic opportunities.
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Affiliation(s)
- Federica Marasca
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
| | - Erica Gasparotto
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
| | - Benedetto Polimeni
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
| | - Rebecca Vadalà
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
- Translational and Molecular Medicine, DIMET, University of Milan-Bicocca, 20900 Monza, Italy
| | - Valeria Ranzani
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
| | - Beatrice Bodega
- Fondazione INGM, Istituto Nazionale di Genetica Molecolare “Enrica e Romeo Invernizzi”, 20122 Milan, Italy; (F.M.); (E.G.); (B.P.); (R.V.); (V.R.)
- Correspondence:
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28
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Avgan N, Wang JI, Fernandez-Chamorro J, Weatheritt RJ. Multilayered control of exon acquisition permits the emergence of novel forms of regulatory control. Genome Biol 2019; 20:141. [PMID: 31315652 PMCID: PMC6637531 DOI: 10.1186/s13059-019-1757-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 07/09/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The long introns of mammals are pools of evolutionary potential due to the multiplicity of sequences that permit the acquisition of novel exons. However, the permissibility of genes to this type of acquisition and its influence on the evolution of cell regulation is poorly understood. RESULTS Here, we observe that human genes are highly permissive to the inclusion of novel exonic regions permitting the emergence of novel regulatory features. Our analysis reveals the potential for novel exon acquisition to occur in over 30% of evaluated human genes. Regulatory processes including the rate of splicing efficiency and RNA polymerase II (RNAPII) elongation control this process by modulating the "window of opportunity" for spliceosomal recognition. DNA damage alters this window promoting the inclusion of repeat-derived novel exons that reduce the ribosomal engagement of cell cycle genes. Finally, we demonstrate that the inclusion of novel exons is suppressed in hematological cancer samples and can be reversed by drugs modulating the rate of RNAPII elongation. CONCLUSION Our work demonstrates that the inclusion of repeat-associated novel intronic regions is a tightly controlled process capable of expanding the regulatory capacity of cells.
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Affiliation(s)
- Nesli Avgan
- EMBL Australia, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
| | - Juli I Wang
- EMBL Australia, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia
- St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, 2010, Australia
| | | | - Robert J Weatheritt
- EMBL Australia, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
- St. Vincent's Clinical School, University of New South Wales, Sydney, NSW, 2010, Australia.
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