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Rao H, An X, Qu X, Yu J, Xie J, Ke J, Liu Z, You L, Qiu Z, Tian L, Du W, Li W, Jia J, Liu D, Li S. SGLT2i delays c-Myc-induced HCC progression via targeting mTOR. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167805. [PMID: 40113049 DOI: 10.1016/j.bbadis.2025.167805] [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: 11/27/2024] [Revised: 02/23/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) stands as a primary malignant liver tumor characterized by metabolic reprogramming. The oncogene c-Myc exerts substantial influence by driving the transcription of numerous genes. Empagliflozin (EMPA), a sodium-glucose cotransporter-2 inhibitor (SGLT2i), is widely used in the treatment of type 2 diabetes and has recently attracted attention for its potential anti-cancer effects. This study aims to unravel the complex interplay among c-Myc, EMPA, and the mammalian target of rapamycin (mTOR) in HCC development and progression. METHODS HCC induction in mice utilized high-pressure hydrodynamic transfection of the c-Myc plasmid. QPCR and immunohistochemistry experiments were performed to detect the expression of SGLT2 in HCC tissues. In vivo experiments were conducted to corroborate the upregulation of SGLT2 following c-Myc transfection. In invo and vitro investigations were conducted to evaluate the anti-cancer effects of two SGLT2i: EMPA and canagliflozin (CANA). Network pharmacology, molecular docking analyses, CETSA experiments, and additional western blot experiments were used to reveal EMPA's interaction inhibition with mTOR. RESULTS The study identified an increase in SGLT2 expression in HCC tissues as a result of c-Myc overexpression. In vitro experiments confirmed the upregulation of SGLT2 following c-Myc transfection. Notably, the administration of SGLT2i effectively curtailed liver cancer progression, and reduced hepatic fat accumulation in mice. EMPA exhibited significant suppression of cell proliferation in c-Myc-transfected cells. In vitro experiments unveiled EMPA's interaction and with inhibition the activation of mTOR. CONCLUSION Our study highlights EMPA's potential as a therapeutic agent in delaying the development and progression of HCC.
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Affiliation(s)
- Huiling Rao
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Medical Engineering, The First Affiliated Hospital of Army Medical University, Chongqing 400000, People's Republic of China
| | - Xiaotong An
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Xinyang Qu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Juan Yu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Department of Anesthesiology, People's Hospital of Yunxi County of Hubei Province, Yunxi 442600, People's Republic of China
| | - Jin Xie
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jing Ke
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhixin Liu
- Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Lei You
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Zhenpeng Qiu
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China
| | - Lin Tian
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Weixing Du
- Department of Pathology, Renming Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Wanrong Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China
| | - Jie Jia
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Danwen Liu
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
| | - Shan Li
- School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, People's Republic of China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan 442000, People's Republic of China.
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Azadegan C, Santoro J, Whetstine JR. CONNECTING THE DOTS: EPIGENETIC REGULATION OF EXTRACHROMOSOMAL AND INHERITED DNA AMPLIFICATIONS. J Biol Chem 2025:108454. [PMID: 40154613 DOI: 10.1016/j.jbc.2025.108454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/20/2025] [Accepted: 03/22/2025] [Indexed: 04/01/2025] Open
Abstract
DNA amplification has intrigued scientists for decades. Since its discovery, significant progress has been made in understanding the mechanisms promoting DNA amplification and their associated function(s). While DNA copy gains were once thought to be regulated purely by stochastic processes, recent findings have revealed the important role of epigenetic modifications in driving these amplifications and their integration into the genome. Furthermore, advances in genomic technology have enabled detailed characterization of these genomic events in terms of size, structure, formation, and regulation. This review highlights how our understanding of DNA amplifications has evolved over time, tracing its trajectory from initial discovery to the contemporary landscape. We describe how recent discoveries have started to uncover how these genomic events occur by controlled biological processes rather than stochastic mechanisms, presenting opportunities for therapeutic modulation.
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Affiliation(s)
- Chloe Azadegan
- Drexel University, College of Medicine, Philadelphia, PA, 19111; Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia PA, 19111
| | - John Santoro
- Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia PA, 19111
| | - Johnathan R Whetstine
- Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia PA, 19111.
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Lu Y, Zhang Y, Li W, Jiang H, Wang J, Guo X. Tumor Cell-Expressed Herpesvirus Entry Mediator Regulates Proliferation and Adaptive Immunity in Ovarian Cancer. Immun Inflamm Dis 2025; 13:e70175. [PMID: 40105652 PMCID: PMC11921469 DOI: 10.1002/iid3.70175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Ovarian cancer (OvCa) is a prevalent gynecological malignancy with an increasing incidence and high mortality rate. Although the role of the herpesvirus entry mediator (HVEM), encoded by the TNFRSF14 gene, is currently considered pivotal in various types of cancer, the regulation of tumor cell-expressed HVEM in OvCa remains inadequately understood. METHODS Specimens were used to detect HVEM expression via quantitative RT-PCR and flow cytometry. The proliferation of the murine OvCa cell line ID8 was determined using the Cell Counting Kit-8, colony formation, and EdU staining assays. The immune constituents within the ascites fluid and spleen of tumor-bearing mice were analyzed by flow cytometry. Bioinformatics analysis was performed to explore cytokines, chemokines, and signaling pathways regulated by HVEM, and differential expression levels were confirmed via quantitative RT-PCR and western blot analysis. RESULTS Herein, we identified a significant upregulation of HVEM in OvCa tissues compared with that in benign tissues and observed dominant expression of HVEM in CD45⁻EpCAM⁺ subsets in OvCa specimens. Tumor cell-expressed HVEM was found to promote OvCa cell proliferation by partly activating spliced X-box-binding protein 1 (XBP1s)-c-Myc signaling. In mouse models, knockdown of Tnfrsf14 in ID8 cells alleviated OvCa progression and specifically affected the frequency and function of T cells in the ascites fluid and spleen. In addition, tumor cell-expressed HVEM altered chemokine expression (CXCL1/9/10/11 and CCL2/4/5) and STAT signal activation (STAT5 and STAT6) in ID8 cells. CONCLUSION This study investigated the effects of HVEM on OvCa and validated its potential as a therapeutic marker for treating OvCa.
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Affiliation(s)
- Yun Lu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yijun Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wenxuan Li
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Haonan Jiang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiapo Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoqing Guo
- Department of Gynecological Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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Huang YC, Yuan TM, Liu BH, Liang RY, Liu KL, Chuang SM. GCIP and SIRT6 cooperatively suppress ITGAV gene expression by modulating c-myc transcription ability. J Biol Chem 2025; 301:108314. [PMID: 39955062 PMCID: PMC11930424 DOI: 10.1016/j.jbc.2025.108314] [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: 06/11/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 02/17/2025] Open
Abstract
Grap2 and CyclinD1 interacting protein (GCIP) has been suggested to function as a tumor suppressor and acts as a transcriptional regulator that negatively controls cancer cell growth, invasion, and migration. Knockdown of GCIP reportedly enhances cancer cell migration and invasion, but no previous study has examined the mechanism(s) by which GCIP suppresses migration/invasion in cancer cells. Here, we report that cDNA microarray-based expression profiling of A549 cells without and with knockdown of GCIP reveals that the expression levels of ITGAV and ICAM-1 are negatively regulated by GCIP. In vitro co-immunoprecipitation and in vivo proximity ligation assays reveal that GCIP interacts with c-Myc. Sequence analyses reveal the presence of two c-Myc regulatory motifs (E-boxes) within the ITGAV promoter. Luciferase reporter and ChIP assays indicate that GCIP represses ITGAV transcription by interacting with c-Myc on the E-box binding sites of the ITGAV promoter region. Furthermore, GCIP interacts with SIRT6 in vitro and in vivo and cooperates with SIRT6, thereby linking its activity, to negatively regulate transcription at the E-box by modulating c-Myc transcription ability. Taken together, these findings contribute to our understanding of GCIP in tumorigenesis and identify a previously unrecognized function of GCIP: It can interact with c-Myc and SIRT6 at E-box binding sites of the ITGAV promoter region. Our data collectively reveal a regulatory network involving GCIP, SIRT6, c-Myc, and ITGAV, and suggest that the SIRT6-GCIP complex negatively regulates the oncogenic function of c-Myc in cell proliferation and migration.
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Affiliation(s)
- Yi-Ching Huang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Tien-Ming Yuan
- Department of Surgery, Feng Yuan Hospital, Ministry of Health and Welfare, Taichung, Taiwan; Department of Dental Technology and Materials Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Bang-Hung Liu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ruei-Yue Liang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Kai-Li Liu
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Show-Mei Chuang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Department of Law, National Chung Hsing University, Taichung, Taiwan.
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Xu W, Li L, Cao Z, Ye J, Gu X. Circadian Rhythms and Lung Cancer in the Context of Aging: A Review of Current Evidence. Aging Dis 2025:AD.2024.1188. [PMID: 39812541 DOI: 10.14336/ad.2024.1188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025] Open
Abstract
Circadian rhythm is the internal homeostatic physiological clock that regulates the 24-hour sleep/wake cycle. This biological clock helps to adapt to environmental changes such as light, dark, temperature, and behaviors. Aging, on the other hand, is a process of physiological changes that results in a progressive decline in cells, tissues, and other vital systems of the body. Both aging and the circadian clock are highly interlinked phenomena with a bidirectional relationship. The process of aging leads to circadian disruptions while dysfunctional circadian rhythms promote age-related complications. Both processes involve diverse physiological, molecular, and cellular changes such as modifications in the DNA repair mechanisms, mechanisms, ROS generation, apoptosis, and cell proliferation. This review aims to examine the role of aging and circadian rhythms in the context of lung cancer. This will also review the existing literature on the role of circadian disruptions in the process of aging and vice versa. Various molecular pathways and genes such as BMAL1, SIRT1, HLF, and PER1 and their implications in aging, circadian rhythms, and lung cancer will also be discussed.
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Affiliation(s)
- Wenhui Xu
- Department of Respiration, The Second Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing, Jiangsu, China
| | - Lei Li
- Department of Respiration, The Second Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing, Jiangsu, China
| | - Zhendong Cao
- Department of Respiration, The Second Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing, Jiangsu, China
| | - Jinghong Ye
- Department of Respiration, The Second Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (Jiangsu Second Hospital of Traditional Chinese Medicine), Nanjing, Jiangsu, China
| | - Xuyu Gu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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Solares S, León J, García-Gutiérrez L. The Functional Interaction Between Epstein-Barr Virus and MYC in the Pathogenesis of Burkitt Lymphoma. Cancers (Basel) 2024; 16:4212. [PMID: 39766110 PMCID: PMC11674381 DOI: 10.3390/cancers16244212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 12/13/2024] [Accepted: 12/14/2024] [Indexed: 01/11/2025] Open
Abstract
The Epstein-Barr virus (EBV) is associated with a wide range of diseases, malignant and non-malignant. EBV was, in fact, the first virus described with cell transformation capacity, discovered by Epstein in 1964 in lymphoma samples from African children. Since then, EBV has been associated with several human tumors including nasopharyngeal carcinoma, gastric carcinoma, T-cell lymphoma, Hodgkin lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma among others. The molecular hallmark of Burkitt lymphoma (BL) is a chromosomal translocation that involves the MYC gene and immunoglobulin loci, resulting in the deregulated expression of MYC, an oncogenic transcription factor that appears deregulated in about half of human tumors. The role of MYC in lymphoma is well established, as MYC overexpression drives B cell proliferation through multiple mechanisms, foremost, the stimulation of the cell cycle. Indeed, MYC is found overexpressed or deregulated in several non-Hodgkin lymphomas. Most endemic and many sporadic BLs are associated with EBV infection. While some mechanisms by which EBV can contribute to BL have been reported, the mechanism that links MYC translocation and EBV infection in BL is still under debate. Here, we review the main EBV-associated diseases, with a special focus on BL, and we discuss the interaction of EBV and MYC translocation during B cell malignant transformation in BL.
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Affiliation(s)
| | | | - Lucía García-Gutiérrez
- Instituto de Biomedicina y Biotecnología de Cantabria, Departamento de Biología Molecular, Universidad de Cantabria-CSIC, Albert Einstein 22, 39011 Cantabria, Spain; (S.S.); (J.L.)
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Nada H, Choi Y, Kim S, Jeong KS, Meanwell NA, Lee K. New insights into protein-protein interaction modulators in drug discovery and therapeutic advance. Signal Transduct Target Ther 2024; 9:341. [PMID: 39638817 PMCID: PMC11621763 DOI: 10.1038/s41392-024-02036-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 09/09/2024] [Accepted: 10/23/2024] [Indexed: 12/07/2024] Open
Abstract
Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered to be undruggable targets have become increasingly feasible due to the progress that has been made over the last two decades and the rapid technological advances. This work explores the influence of technological innovations on PPI research and development. Additionally, the diverse strategies for discovering, modulating, and characterizing PPIs and their corresponding modulators are examined with the aim of presenting a streamlined pipeline for advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in PPI modulator discovery and development, we aim to illustrate the efficacy of various strategies for identifying, optimizing, and overcoming challenges associated with PPI modulator design. The valuable lessons and insights gained from the identification, optimization, and approval of PPI modulators are discussed with the aim of demonstrating that PPI modulators have transitioned beyond early-stage drug discovery and now represent a prime opportunity with significant potential. The selected examples of PPI modulators encompass those developed for cancer, inflammation and immunomodulation, as well as antiviral applications. This perspective aims to establish a foundation for the effective targeting and modulation of PPIs using PPI modulators and pave the way for future drug development.
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Affiliation(s)
- Hossam Nada
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
- Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, USA
| | - Yongseok Choi
- College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Sungdo Kim
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
| | - Kwon Su Jeong
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea
| | - Nicholas A Meanwell
- Baruch S. Blumberg Institute, Doylestown, PA, USA
- School of Pharmacy, University of Michigan, Ann Arbor, MI, USA
- Ernest Mario School of Pharmacy, Rutgers University New Brunswick, New Brunswick, NJ, USA
| | - Kyeong Lee
- BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.
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Yan XY, Kang YY, Zhang ZY, Huang P, Yang C, Naranmandura H. Therapeutic approaches targeting oncogenic proteins in myeloid leukemia: challenges and perspectives. Expert Opin Ther Targets 2024; 28:1131-1148. [PMID: 39679536 DOI: 10.1080/14728222.2024.2443577] [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: 12/30/2023] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION Leukemia is typically categorized into myeloid leukemia and lymphoblastic leukemia based on the origins of leukemic cells. Myeloid leukemia is a group of clonal malignancies characterized by the presence of increased immature myeloid cells in both the bone marrow and peripheral blood. Of note, the aberrant expression of specific proteins or the generation of fusion proteins due to chromosomal abnormalities are well established drivers in various forms of myeloid leukemia. Therefore, these oncoproteins represent promising targets for drug development. AREAS COVERED In this review, we comprehensively discussed the pathogenesis of typical leukemia oncoproteins and the current landscape of small molecule drugs targeting these oncogenic proteins. Additionally, we elucidated novel strategies, including proteolysis-targeting chimeras (PROTACs), hyperthermia, and genomic editing, which specifically degrade oncogenic proteins in myeloid malignancies. EXPERT OPINION Although small molecule drugs have significantly improved the prognosis of oncoprotein-driven myeloid leukemia patients, drug resistance due to the mutations in oncoproteins is still a great challenge in the clinic. New approaches such as PROTACs, hyperthermia, and genomic editing are considered promising approaches for the treatment of oncoprotein-driven leukemia, especially for drug-resistant mutants.
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Affiliation(s)
- Xing Yi Yan
- Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuan Yuan Kang
- Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Ze Yan Zhang
- Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Ping Huang
- Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Chang Yang
- Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
| | - Hua Naranmandura
- Department of Hematology of First Affiliated Hospital, and Department of Public Health, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Arshi A, Mahmoudi E, Raeisi F, Dehghan Tezerjani M, Bahramian E, Ahmed Y, Peng C. Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review. Front Immunol 2024; 15:1446937. [PMID: 39257589 PMCID: PMC11384988 DOI: 10.3389/fimmu.2024.1446937] [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: 06/10/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024] Open
Abstract
Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.
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Affiliation(s)
- Asghar Arshi
- Department of Biology, York University, Toronto, ON, Canada
| | - Esmaeil Mahmoudi
- Young Researchers and Elite Club, Islamic Azad University, Shahrekord, Iran
| | | | - Masoud Dehghan Tezerjani
- Department of bioinformatics, School of Advanced Medical Technologies, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Elham Bahramian
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Yeasin Ahmed
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, United States
| | - Chun Peng
- Department of Biology, York University, Toronto, ON, Canada
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Casacuberta-Serra S, González-Larreategui Í, Capitán-Leo D, Soucek L. MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer. Signal Transduct Target Ther 2024; 9:205. [PMID: 39164274 PMCID: PMC11336233 DOI: 10.1038/s41392-024-01907-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 06/05/2024] [Accepted: 06/24/2024] [Indexed: 08/22/2024] Open
Abstract
RAS and MYC rank amongst the most commonly altered oncogenes in cancer, with RAS being the most frequently mutated and MYC the most amplified. The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon, profoundly influencing tumor development. Together and individually, these two oncogenes regulate most, if not all, hallmarks of cancer, including cell death escape, replicative immortality, tumor-associated angiogenesis, cell invasion and metastasis, metabolic adaptation, and immune evasion. Due to their frequent alteration and role in tumorigenesis, MYC and RAS emerge as highly appealing targets in cancer therapy. However, due to their complex nature, both oncogenes have been long considered "undruggable" and, until recently, no drugs directly targeting them had reached the clinic. This review aims to shed light on their complex partnership, with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer. Within this review, we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials, along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance. This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC "undruggability", hinting at a new era in their therapeutic targeting.
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Affiliation(s)
| | - Íñigo González-Larreategui
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain
| | - Daniel Capitán-Leo
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain
| | - Laura Soucek
- Peptomyc S.L., Barcelona, Spain.
- Models of cancer therapies Laboratory, Vall d'Hebron Institute of Oncology, Cellex Centre, Hospital University Vall d'Hebron Campus, Barcelona, Spain.
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
- Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain.
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Xue Z, Tian L, Zheng H, Zhang Y, Song J. Cyanidin inhibits glioma stem cells proliferation through the Wnt signaling pathway. Int J Neurosci 2024; 134:858-865. [PMID: 36458565 DOI: 10.1080/00207454.2022.2154669] [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: 12/29/2021] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 12/05/2022]
Abstract
BACKGROUND Cyanidin has a protective effect on the nervous system and has been reported to treat tumor effectively. However, its impact on glioma stem cells (GSC) is unknown. METHODS Using seven GSC lines, the anti-tumor effect of cyanidin is tested. The effect of cyanidin on the cell viability in each cell line is evaluated. Wnt signaling pathway-related genes are checked after treatment of cyanidin. Cytoplasmic/nuclear β-catenin protein levels post cyanidin treatment is detected. Protein levels of c-Myc after cyanidin treatment are determined. Twist1 and Snail1 protein levels after cyanidin treatment are checked as well. RESULTS Cyanidin significantly reduces the cell viability of all GSCs, and exhibited the most substantial effect in GBM2 but no apparent effect in 293T cells. It can regulate the Wnt signaling pathway of all GSC lines. In the GBM2, GBM7, G166, and G179 cell lines, there is upregulation of WNT1 and MYC genes, while in the G144 and GliNS2 cell line, these two genes are down-regulated after cyanidin treatment. Cytoplasmic and nuclear protein levels of β-catenin in all cell lines are down-regulated. Cyanidin treatment significantly decreases the protein level for c-Myc in the GBM2 cell line compared with untreated cells, not in G144 or GliNS2 cells. Furthermore, cyanidin strongly reduces the expression of Twist1 and Snail1 in GBM2, G179, and G144 cell lines, while the GliNS2 cells show an opposite change in the cytoplasm and no change in nuclear. CONCLUSION Cyanidin exerts an anti-tumor effect in glioma stem cell lines, probably through the Wnt signaling pathway.
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Affiliation(s)
- Zicheng Xue
- Department of Pharmacy, Maternity and Child Health Care of Zaozhuang, Zaozhuang City, Shandong Province, China
| | - Lei Tian
- Department of Pharmacy, People's Hospital of Shizhong District, Zaozhuang City, Shandong Province, China
| | - Hui Zheng
- Zaozhuang Vocational College of Science and Technology, Shandong Province, China
| | - Yucai Zhang
- Department of Pharmacy, Maternity and Child Health Care of Zaozhuang, Zaozhuang City, Shandong Province, China
| | - Junying Song
- Department of Pharmacy, Maternity and Child Health Care of Zaozhuang, Zaozhuang City, Shandong Province, China
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12
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Ghasemi N, Azizi H. Exploring Myc puzzle: Insights into cancer, stem cell biology, and PPI networks. Gene 2024; 916:148447. [PMID: 38583818 DOI: 10.1016/j.gene.2024.148447] [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: 10/05/2023] [Revised: 03/13/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024]
Abstract
"The grand orchestrator," "Universal Amplifier," "double-edged sword," and "Undruggable" are just some of the Myc oncogene so-called names. It has been around 40 years since the discovery of the Myc, and it remains in the mainstream of cancer treatment drugs. Myc is part of basic helix-loop-helix leucine zipper (bHLH-LZ) superfamily proteins, and its dysregulation can be seen in many malignant human tumors. It dysregulates critical pathways in cells that are connected to each other, such as proliferation, growth, cell cycle, and cell adhesion, impacts miRNAs action, intercellular metabolism, DNA replication, differentiation, microenvironment regulation, angiogenesis, and metastasis. Myc, surprisingly, is used in stem cell research too. Its family includes three members, MYC, MYCN, and MYCL, and each dysfunction was observed in different cancer types. This review aims to introduce Myc and its function in the body. Besides, Myc deregulatory mechanisms in cancer cells, their intricate aspects will be discussed. We will look at promising drugs and Myc-based therapies. Finally, Myc and its role in stemness, Myc pathways based on PPI network analysis, and future insights will be explained.
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Affiliation(s)
- Nima Ghasemi
- Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran
| | - Hossein Azizi
- Faculty of Biotechnology, Amol University of Special Modern Technologies, Amol, Iran.
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13
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Esain-Garcia I, Kirchner A, Melidis L, Tavares RDCA, Dhir S, Simeone A, Yu Z, Madden SK, Hermann R, Tannahill D, Balasubramanian S. G-quadruplex DNA structure is a positive regulator of MYC transcription. Proc Natl Acad Sci U S A 2024; 121:e2320240121. [PMID: 38315865 PMCID: PMC10873556 DOI: 10.1073/pnas.2320240121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
DNA structure can regulate genome function. Four-stranded DNA G-quadruplex (G4) structures have been implicated in transcriptional regulation; however, previous studies have not directly addressed the role of an individual G4 within its endogenous cellular context. Using CRISPR to genetically abrogate endogenous G4 structure folding, we directly interrogate the G4 found within the upstream regulatory region of the critical human MYC oncogene. G4 loss leads to suppression of MYC transcription from the P1 promoter that is mediated by the deposition of a de novo nucleosome alongside alterations in RNA polymerase recruitment. We also show that replacement of the endogenous MYC G4 with a different G4 structure from the KRAS oncogene restores G4 folding and MYC transcription. Moreover, we demonstrate that the MYC G4 structure itself, rather than its sequence, recruits transcription factors and histone modifiers. Overall, our work establishes that G4 structures are important features of transcriptional regulation that coordinate recruitment of key chromatin proteins and the transcriptional machinery through interactions with DNA secondary structure, rather than primary sequence.
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Affiliation(s)
- Isabel Esain-Garcia
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Angie Kirchner
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Larry Melidis
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | | | - Somdutta Dhir
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Angela Simeone
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Zutao Yu
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Sarah K. Madden
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - Regina Hermann
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
| | - David Tannahill
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
| | - Shankar Balasubramanian
- Cancer Research UK Cambridge Institute, University of Cambridge, CambridgeCB2 0RE, United Kingdom
- Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, United Kingdom
- School of Clinical Medicine, University of Cambridge, CambridgeCB2 0SP, United Kingdom
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14
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Malik S, Pradeep SP, Kumar V, Xiao Y, Deng Y, Fan R, Vasquez JC, Singh V, Bahal R. Antitumor efficacy of a sequence-specific DNA-targeted γPNA-based c-Myc inhibitor. Cell Rep Med 2024; 5:101354. [PMID: 38183981 PMCID: PMC10829792 DOI: 10.1016/j.xcrm.2023.101354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 09/21/2023] [Accepted: 12/11/2023] [Indexed: 01/08/2024]
Abstract
Targeting oncogenes at the genomic DNA level can open new avenues for precision medicine. Significant efforts are ongoing to target oncogenes using RNA-targeted and protein-targeted platforms, but no progress has been made to target genomic DNA for cancer therapy. Here, we introduce a gamma peptide nucleic acid (γPNA)-based genomic DNA-targeted platform to silence oncogenes in vivo. γPNAs efficiently invade the mixed sequences of genomic DNA with high affinity and specificity. As a proof of concept, we establish that γPNA can inhibit c-Myc transcription in multiple cell lines. We evaluate the in vivo efficacy and safety of genomic DNA targeting in three pre-clinical models. We also establish that anti-transcription γPNA in combination with histone deacetylase inhibitors and chemotherapeutic drugs results in robust antitumor activity in cell-line- and patient-derived xenografts. Overall, this strategy offers a unique therapeutic platform to target genomic DNA to inhibit oncogenes for cancer therapy.
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Affiliation(s)
- Shipra Malik
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Sai Pallavi Pradeep
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Vikas Kumar
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Yong Xiao
- Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA; Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Yanxiang Deng
- Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center and Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA
| | - Rong Fan
- Department of Biomedical Engineering, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center and Yale Cancer Center, Yale School of Medicine, New Haven, CT 06520, USA; Human and Translational Immunology, Yale School of Medicine, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Juan C Vasquez
- Department of Pediatrics, Yale School of Medicine, New Haven, CT 06520, USA
| | - Vijender Singh
- Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA
| | - Raman Bahal
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.
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15
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Canoy RJ, Shmakova A, Karpukhina A, Lomov N, Tiukacheva E, Kozhevnikova Y, André F, Germini D, Vassetzky Y. Specificity of cancer-related chromosomal translocations is linked to proximity after the DNA double-strand break and subsequent selection. NAR Cancer 2023; 5:zcad049. [PMID: 37750169 PMCID: PMC10518054 DOI: 10.1093/narcan/zcad049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 08/01/2023] [Accepted: 09/14/2023] [Indexed: 09/27/2023] Open
Abstract
Most cancer-related chromosomal translocations appear to be cell type specific. It is currently unknown why different chromosomal translocations occur in different cells. This can be due to either the occurrence of particular translocations in specific cell types or adaptive survival advantage conferred by translocations only in specific cells. We experimentally addressed this question by double-strand break (DSB) induction at MYC, IGH, AML and ETO loci in the same cell to generate chromosomal translocations in different cell lineages. Our results show that any translocation can potentially arise in any cell type. We have analyzed different factors that could affect the frequency of the translocations, and only the spatial proximity between gene loci after the DSB induction correlated with the resulting translocation frequency, supporting the 'breakage-first' model. Furthermore, upon long-term culture of cells with the generated chromosomal translocations, only oncogenic MYC-IGH and AML-ETO translocations persisted over a 60-day period. Overall, the results suggest that chromosomal translocation can be generated after DSB induction in any type of cell, but whether the cell with the translocation would persist in a cell population depends on the cell type-specific selective survival advantage that the chromosomal translocation confers to the cell.
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Affiliation(s)
- Reynand Jay Canoy
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
- Institute of Human Genetics, National Institutes of Health, University of the Philippines Manila, 1000 Manila, The Philippines
| | - Anna Shmakova
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
- Laboratory of Molecular Endocrinology, Institute of Experimental Cardiology, Federal State Budgetary Organization ‘National Cardiology Research Center’ of the Ministry of Health of the Russian Federation, 127994 Moscow, Russia
- Koltzov Institute of Developmental Biology, 117334 Moscow, Russia
| | - Anna Karpukhina
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
- Koltzov Institute of Developmental Biology, 117334 Moscow, Russia
| | - Nikolai Lomov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Eugenia Tiukacheva
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
- Koltzov Institute of Developmental Biology, 117334 Moscow, Russia
| | - Yana Kozhevnikova
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
| | - Franck André
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
| | - Diego Germini
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
| | - Yegor Vassetzky
- UMR 9018, CNRS, Univ. Paris-Sud, Université Paris Saclay, Institut Gustave Roussy, F-94805 Villejuif, France
- Koltzov Institute of Developmental Biology, 117334 Moscow, Russia
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16
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Zhou M, Boulos JC, Omer EA, Klauck SM, Efferth T. Modes of Action of a Novel c-MYC Inhibiting 1,2,4-Oxadiazole Derivative in Leukemia and Breast Cancer Cells. Molecules 2023; 28:5658. [PMID: 37570631 PMCID: PMC10419799 DOI: 10.3390/molecules28155658] [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: 06/16/2023] [Revised: 07/19/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
The c-MYC oncogene regulates multiple cellular activities and is a potent driver of many highly aggressive human cancers, such as leukemia and triple-negative breast cancer. The oxadiazole class of compounds has gained increasing interest for its anticancer activities. The aim of this study was to investigate the molecular modes of action of a 1,2,4-oxadiazole derivative (ZINC15675948) as a c-MYC inhibitor. ZINC15675948 displayed profound cytotoxicity at the nanomolar range in CCRF-CEM leukemia and MDA-MB-231-pcDNA3 breast cancer cells. Multidrug-resistant sublines thereof (i.e., CEM/ADR5000 and MDA-MB-231-BCRP) were moderately cross-resistant to this compound (<10-fold). Molecular docking and microscale thermophoresis revealed a strong binding of ZINC15675948 to c-MYC by interacting close to the c-MYC/MAX interface. A c-MYC reporter assay demonstrated that ZINC15675948 inhibited c-MYC activity. Western blotting and qRT-PCR showed that c-MYC expression was downregulated by ZINC15675948. Applying microarray hybridization and signaling pathway analyses, ZINC15675948 affected signaling routes downstream of c-MYC in both leukemia and breast cancer cells as demonstrated by the induction of DNA damage using single cell gel electrophoresis (alkaline comet assay) and induction of apoptosis using flow cytometry. ZINC15675948 also caused G2/M phase and S phase arrest in CCRF-CEM cells and MDA-MB-231-pcDNA3 cells, respectively, accompanied by the downregulation of CDK1 and p-CDK2 expression using western blotting. Autophagy induction was observed in CCRF-CEM cells but not MDA-MB-231-pcDNA3 cells. Furthermore, microarray-based mRNA expression profiling indicated that ZINC15675948 may target c-MYC-regulated ubiquitination, since the novel ubiquitin ligase (ELL2) was upregulated in the absence of c-MYC expression. We propose that ZINC15675948 is a promising natural product-derived compound targeting c-MYC in c-MYC-driven cancers through DNA damage, cell cycle arrest, and apoptosis.
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Affiliation(s)
- Min Zhou
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Joelle C. Boulos
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Ejlal A. Omer
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128 Mainz, Germany
| | - Sabine M. Klauck
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Disease (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University-Mainz, Staudinger Weg 5, 55128 Mainz, Germany
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17
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Fuchs S, Danßmann C, Klironomos F, Winkler A, Fallmann J, Kruetzfeldt LM, Szymansky A, Naderi J, Bernhart SH, Grunewald L, Helmsauer K, Rodriguez-Fos E, Kirchner M, Mertins P, Astrahantseff K, Suenkel C, Toedling J, Meggetto F, Remke M, Stadler PF, Hundsdoerfer P, Deubzer HE, Künkele A, Lang P, Fuchs J, Henssen AG, Eggert A, Rajewsky N, Hertwig F, Schulte JH. Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN. Nat Commun 2023; 14:3936. [PMID: 37402719 DOI: 10.1038/s41467-023-38747-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 05/12/2023] [Indexed: 07/06/2023] Open
Abstract
Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.
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Affiliation(s)
- Steffen Fuchs
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany.
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany.
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany.
- CRCT, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, 31037, Toulouse, France.
- Laboratoire d'Excellence Toulouse Cancer-TOUCAN, 31037, Toulouse, France.
| | - Clara Danßmann
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Filippos Klironomos
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Annika Winkler
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Jörg Fallmann
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107, Leipzig, Germany
| | - Louisa-Marie Kruetzfeldt
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Annabell Szymansky
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Julian Naderi
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany
| | - Stephan H Bernhart
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107, Leipzig, Germany
| | - Laura Grunewald
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Konstantin Helmsauer
- Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125, Berlin, Germany
| | - Elias Rodriguez-Fos
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125, Berlin, Germany
| | - Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany
| | - Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), 13125, Berlin, Germany
| | - Kathy Astrahantseff
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
| | - Christin Suenkel
- Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Straße 28, 10115, Berlin, Germany
- Lonza Drug Product Services, 4057, Basel, Switzerland
| | - Joern Toedling
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Fabienne Meggetto
- CRCT, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, 31037, Toulouse, France
- Laboratoire d'Excellence Toulouse Cancer-TOUCAN, 31037, Toulouse, France
| | - Marc Remke
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, 40225, Düsseldorf, Germany
- The German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, 40225, Düsseldorf, Germany
- Institute of Neuropathology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf, 40225, Düsseldorf, Germany
| | - Peter F Stadler
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107, Leipzig, Germany
| | - Patrick Hundsdoerfer
- Department of Pediatric Oncology, Helios Klinikum Berlin-Buch, 13125, Berlin, Germany
| | - Hedwig E Deubzer
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany
- Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125, Berlin, Germany
| | - Annette Künkele
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Peter Lang
- Department I - General Pediatrics, Hematology/Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Jörg Fuchs
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany
| | - Anton G Henssen
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, 13125, Berlin, Germany
| | - Angelika Eggert
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany
| | - Nikolaus Rajewsky
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Hannoversche Straße 28, 10115, Berlin, Germany
| | - Falk Hertwig
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Johannes H Schulte
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, 13353, Berlin, Germany.
- The German Cancer Consortium (DKTK), Partner Site Berlin, 10117, Berlin, Germany.
- The German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178, Berlin, Germany.
- Department I - General Pediatrics, Hematology/Oncology, University Children's Hospital, Eberhard Karls University Tuebingen, 72076, Tuebingen, Germany.
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18
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D’Avola A, Kluckova K, Finch AJ, Riches JC. Spotlight on New Therapeutic Opportunities for MYC-Driven Cancers. Onco Targets Ther 2023; 16:371-383. [PMID: 37309471 PMCID: PMC10257908 DOI: 10.2147/ott.s366627] [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: 03/04/2023] [Accepted: 06/02/2023] [Indexed: 06/14/2023] Open
Abstract
MYC can be considered to be one of the most pressing and important targets for the development of novel anti-cancer therapies. This is due to its frequent dysregulation in tumors and due to the wide-ranging impact this dysregulation has on gene expression and cellular behavior. As a result, there have been numerous attempts to target MYC over the last few decades, both directly and indirectly, with mixed results. This article reviews the biology of MYC in the context of cancers and drug development. It discusses strategies aimed at targeting MYC directly, including those aimed at reducing its expression and blocking its function. In addition, the impact of MYC dysregulation on cellular biology is outlined, and how understanding this can underpin the development of approaches aimed at molecules and pathways regulated by MYC. In particular, the review focuses on the role that MYC plays in the regulation of metabolism, and the therapeutic avenues offered by inhibiting the metabolic pathways that are essential for the survival of MYC-transformed cells.
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Affiliation(s)
- Annalisa D’Avola
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Katarina Kluckova
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Andrew J Finch
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - John C Riches
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
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19
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High levels of Myc expression are required for the robust proliferation of hepatocytes, but not for the sustained weak proliferation. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166644. [PMID: 36681356 DOI: 10.1016/j.bbadis.2023.166644] [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: 08/10/2022] [Revised: 12/22/2022] [Accepted: 01/12/2023] [Indexed: 01/20/2023]
Abstract
In contrast to the robust proliferation exhibited following acute liver injury, hepatocytes exhibit long-lasting proliferative activity in chronic liver injury. The mechanistic differences between these distinct modes of proliferation are unclear. Hepatocytes exhibited robust proliferation that peaked at 2 days following partial hepatectomy in mice, but this proliferation was completely inhibited by hepatocyte-specific expression of MadMyc, a Myc-suppressing chimeric protein. However, Myc suppression induced weak but continuous hepatocyte proliferation, thereby resulting in full restoration of liver mass despite an initial delay. Late-occurring proliferation was accompanied by prolonged suppression of proline dehydrogenase (PRODH) expression, and forced PRODH overexpression inhibited hepatocyte proliferation. In hepatocytes in chronic liver injury, Myc was not activated but PRODH expression was suppressed in regenerating hepatocytes. In liver tumors, PRODH expression was often suppressed, especially in the highly proliferative tumors with distinct Myc expression. Our results indicate that the robust proliferation of hepatocytes following acute liver injury requires high levels Myc expression and that there is a compensatory Myc-independent mode of hepatocyte proliferation with the regulation of proline metabolism, which might be relevant to liver regeneration in chronic injury.
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20
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Alanzi M, Abu-Tineh M, Szabados L, Sharaf Eldean MZ, Alatasi S, Taha RY, Elkourashy SA. Polatuzumab Vedotin in a Patient with Refractory Burkitt Lymphoma, a Case Report. Onco Targets Ther 2023; 16:133-139. [PMID: 36852093 PMCID: PMC9961566 DOI: 10.2147/ott.s394193] [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: 10/26/2022] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Although Burkitt lymphoma is considered a curable disease due to the progress made in choosing the most effective first-line therapy, relapsed or refractory Burkitt lymphoma (BL) has a very poor outcome. There is a lack of data supporting the treatment regimens. We report a 48-year-old male with stage II Burkitt's lymphoma with no response to the first line of high-intensity chemotherapy. However, treatment with polatuzumab vedotin led to complete clinical remission for more than one year.
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Affiliation(s)
- Meshaal Alanzi
- Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Mohammad Abu-Tineh
- Department of Medical Oncology/Hematology, National Center for Cancer Care and Research, Doha, Qatar
| | - Lajos Szabados
- Department of Nuclear Medicine, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
| | | | - Sali Alatasi
- Department of Pathology, Hamad Medical Corporation, Doha, Qatar
| | - Ruba Y Taha
- Department of Medical Oncology/Hematology, National Center for Cancer Care and Research, Doha, Qatar
| | - Sarah A Elkourashy
- Department of Medical Oncology/Hematology, National Center for Cancer Care and Research, Doha, Qatar.,Weill Cornell Medicine University, Doha, Qatar
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21
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Terletsky A, Akhmerova LG. Malignant human thyroid neoplasms associated with blood parasitic (haemosporidian) infection. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2023. [DOI: 10.15789/2220-7619-mht-1948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Investigation of archival cytological material obtained by cytologists during fine-needle aspiration biopsy in follicular, papillary, and medullary human thyroid cancers revealed haemosporidian (blood parasitic) infection. Haemosporidian infection was detected as exo- and intraerythrocytic stages of development in thyrocytes schizogony. The exoerythrocytic stage of development is represented as microschizonts in a thyroid needle biopsy specimen. Probably, blood parasitic infection is the common etiology for these pathologies. All biopsy material in medical laboratories was stained with RomanowskyGiemsa stain. To clarify the localization of nuclei (DNA) of thyrocytes and nuclei (DNA) of haemosporidian infection in cytological material following investigation of the entire set of smears, a selective series of original archival smears was stained (restained) with a Feulgen/Schiff reagent. Staining of smears with RomanowskyGiemsa stain is an adsorption method that enables re-use of the same smears for staining with a Feulgen/Schiff reagent where the fuchsin dye, after DNA hydrolysis by hydrochloric acid, is incorporated into DNA and stains it in redviolet (crimsonlilac) color. An intentionally unstained protoplasm of blood parasitic infection was present as a light band around erythrocyte nuclei. In follicular thyroid cancer, Feulgen staining of thyrocytes revealed nuclear DNA and parasitic DNA (haemosporidium nuclei) as point inclusions and rings and diffusely distributed in the thyrocyte cytoplasm. The thyrocyte cytoplasm and nuclei were vacuolated, with thyrocyte nuclei being deformed, flattened, and displaced to the cell periphery. The erythrocytes, which were initially stained with eosin (orange color), contained haemosporidian nuclei (DNA). In some cases, endoglobular inclusions in thyrocytes and erythrocytes were of the same size. In papillary thyroid cancer, we were able to localize the nuclear DNA of thyrocytes and the parasitic DNA as point inclusions and diffusely distributed in the thyrocyte cytoplasm. Two or more polymorphic nuclei may eccentrically occur in the hyperplastic cytoplasm. Haemosporidian microschizonts occurred circumnuclearly in thyrocytes and as an exoerythrocytic stage in the blood. The erythrocyte cytoplasm contained redviolet polymorphic haemosporidian nuclei (DNA). In medullary thyroid cancer, the hyperplastic cytoplasm of thyrocytes contained eccentrically located nuclei (DNA) of thyrocytes and small haemosporidian nuclei (DNA), which may occupy the whole thyrocyte. There were thyrocytes with vacuolated cytoplasm and pronounced nuclear polymorphism. The size of hyperplastic nuclei was several times larger than that of normal thyrocyte nuclei. The color of stained cytoplasmic and nuclear vacuoles of thyrocytes was less redviolet compared with that of surrounding tissues, which probably indicates the presence of parasitic DNA in them. The haemosporidian nuclear material in erythrocytes is represented by polymorphic nuclei, which may indicate the simultaneous presence of different pathogen species and/or generations in the blood. Intracellular parasitism of haemosporidian infection in thyrocytes (schizogony) associated with three thyroid cancers leads to pronounced cytoplasmic hyperplasia, cytoplasmic vacuolization, and nuclear vacuolization of the thyrocyte, followed by impaired secretory function. Multinucleated thyrocytes with incomplete cytokinesis appear. The absence of lytic death of the affected thyrocytes indicates that the contagium is able to control apoptosis and influence physiological functions of the cell. There is deformation of the nuclei, which leads to a decrease in their size, their flattening and displacement to the cell periphery, with high risk of DNA mutations and deletions in affected cells, reaching a neoplastic level.
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Abstract
C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells' metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not "undruggable" and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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23
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Rankin AW, Siegele B, Gross TG. Discordance between detection of MYC rearrangement by immunohistochemistry versus fluorescent in situ hybridization in Burkitt lymphoma. Pediatr Blood Cancer 2022; 69:e29804. [PMID: 35670760 DOI: 10.1002/pbc.29804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/14/2022] [Indexed: 11/12/2022]
Affiliation(s)
- Alexander W Rankin
- Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado, Aurora, Colorado, USA
| | - Bradford Siegele
- Department of Pathology, Children's Hospital Colorado, University of Colorado, Aurora, Colorado, USA
| | - Thomas G Gross
- Center for Cancer and Blood Disorders, Children's Hospital Colorado, University of Colorado, Aurora, Colorado, USA
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Zhang Q, Feng W, Wang Q, Wang J, Chai L, Chen Y, Wang Y, Liu J, Li M, Xie X. PPARγ activation inhibits PDGF-induced pulmonary artery smooth muscle cell proliferation and migration by modulating TERT. Biomed Pharmacother 2022; 152:113233. [PMID: 35689861 DOI: 10.1016/j.biopha.2022.113233] [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: 04/04/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 12/01/2022] Open
Abstract
Vascular remodeling is a significant feature of pulmonary artery hypertension (PAH), and is characterized by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Telomerase reverse transcriptase (TERT), as a determining factor for controlling telomerase activity, has been proven to be associated with cell proliferation. This study aims to explore whether TERT mediates the proliferation and migration of PASMCs and the underlying molecular mechanism. Primary PASMCs from Sprague-Dawley (SD) rats were used in this experiment. Cell proliferation and migration were evaluated by Cell Counting Kit-8, EdU incorporation assay and transwell assay, respectively. Telomerase activity was assessed with a rat TE ELISA kit. Small interfering RNA (siRNA) transfection was conducted to silence c-MYC expression. The protein levels of p-Akt, c-MYC, PPARγ and TERT were determined through western blotting. Our work demonstrates that PDGF upregulated TERT expression and telomerase activation by activating Akt and upregulating of c-MYC in PASMCs. Inhibition of Akt with LY294002, knockdown of c-MYC by siRNA or suppression of telomerase activity with BIBR1532 repressed PDGF-induced PASMC proliferation and migration. Furthermore, activation of peroxisome proliferator-activated receptor γ (PPARγ) with pioglitazone suppressed PDGF-induced TERT expression and telomerase activation, leading to inhibition of PASMC proliferation and migration.
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Affiliation(s)
- Qianqian Zhang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Wei Feng
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Qingting Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Jian Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Limin Chai
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Yuqian Chen
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Yan Wang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Jin Liu
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Manxiang Li
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Xinming Xie
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
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25
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Simultaneous Analysis of the p16 Gene and Protein in Canine Lymphoma Cells and Their Correlation with pRb Phosphorylation. Vet Sci 2022; 9:vetsci9080393. [PMID: 36006308 PMCID: PMC9416461 DOI: 10.3390/vetsci9080393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Lymphoma is one of the most frequently diagnosed malignancies in dogs. The most common epigenetic alteration is gene methylation. Methylation of the p16 gene leads to decreased expression of its protein. The p16 protein inhibits the activity of cyclin-dependent kinase, as a negative control of the cell cycle to prevent phosphorylation of the retinoblastoma (pRb) protein. The methylation of the p16 gene has been reported in canine lymphomas, however, p16 protein expression has not been examined in previous studies. In this study, the gene and protein expression of p16, and phosphorylation of pRb, were examined simultaneously in canine lymphoma/leukemia cell lines treated with or without a demethylation drug in vitro. We identified the hypermethylation of the p16 gene, the decreased expression of p16 protein and the hyperphosphorylation of pRb in four out of eight cell lines. Furthermore, we revealed that the expression of the p16 protein was more stable than that of the p16 gene and more closely related to the phosphorylation of pRb. In conclusion, the p16 protein expression is suggested as a promising biomarker for canine lymphoma cells, and the p16–pRb pathway could be a target for the better treatment of canine lymphomas. Abstract Cyclin-dependent kinase inhibitor p16 (CDKN2A) primarily functions as a negative regulator of the retinoblastoma protein (pRb) pathway to prevent pRb phosphorylation, thus playing a critical role in cell cycle arrest. In canine lymphoma cells, methylation due to inactivation of the p16 gene has been reported. However, its protein expression has not been examined in previous studies. In our in vitro study, the gene and protein expression of p16 and phosphorylated pRb were examined simultaneously in eight canine lymphoma and leukemia cell lines (17-71, CLBL-1, GL-1, CLC, CLGL-90, Ema, Nody-1, and UL-1). Methylation of the p16 gene was also explored using the demethylation drug 5-Aza-2′-deoxycytidine (5-Aza). After 5-Aza treatment, p16 gene and protein expression increased and pRb phosphorylation decreased, suggesting that both hypermethylation of the p16 gene and pRb hyperphosphorylation occurred in four out of eight cell lines (CLBL-1, CLC, Nody-1, and UL-1). Moreover, the estimation of p16’s protein expression was better than that of p16’s mRNA expression because the expression of the protein was more stable than those of the gene, and highly related to the phosphorylation of pRb. These results revealed that p16’s protein expression could be a promising biomarker for canine lymphoma cells.
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Ancos-Pintado R, Bragado-García I, Morales ML, García-Vicente R, Arroyo-Barea A, Rodríguez-García A, Martínez-López J, Linares M, Hernández-Sánchez M. High-Throughput CRISPR Screening in Hematological Neoplasms. Cancers (Basel) 2022; 14:3612. [PMID: 35892871 PMCID: PMC9329962 DOI: 10.3390/cancers14153612] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/16/2022] [Accepted: 07/20/2022] [Indexed: 02/01/2023] Open
Abstract
CRISPR is becoming an indispensable tool in biological research, revolutionizing diverse fields of medical research and biotechnology. In the last few years, several CRISPR-based genome-targeting tools have been translated for the study of hematological neoplasms. However, there is a lack of reviews focused on the wide uses of this technology in hematology. Therefore, in this review, we summarize the main CRISPR-based approaches of high throughput screenings applied to this field. Here we explain several libraries and algorithms for analysis of CRISPR screens used in hematology, accompanied by the most relevant databases. Moreover, we focus on (1) the identification of novel modulator genes of drug resistance and efficacy, which could anticipate relapses in patients and (2) new therapeutic targets and synthetic lethal interactions. We also discuss the approaches to uncover novel biomarkers of malignant transformations and immune evasion mechanisms. We explain the current literature in the most common lymphoid and myeloid neoplasms using this tool. Then, we conclude with future directions, highlighting the importance of further gene candidate validation and the integration and harmonization of the data from CRISPR screening approaches.
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Affiliation(s)
- Raquel Ancos-Pintado
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain; (I.B.-G.); (A.A.-B.)
| | - Irene Bragado-García
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain; (I.B.-G.); (A.A.-B.)
| | - María Luz Morales
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
| | - Roberto García-Vicente
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
| | - Andrés Arroyo-Barea
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain; (I.B.-G.); (A.A.-B.)
| | - Alba Rodríguez-García
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
| | - Joaquín Martínez-López
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
- Department of Medicine, Medicine School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain
| | - María Linares
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, CIBERONC, ES 28041 Madrid, Spain; (R.A.-P.); (M.L.M.); (R.G.-V.); (A.R.-G.); (J.M.-L.); (M.L.)
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain; (I.B.-G.); (A.A.-B.)
| | - María Hernández-Sánchez
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain; (I.B.-G.); (A.A.-B.)
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Sheikh IN, Elgehiny A, Ragoonanan D, Mahadeo KM, Nieto Y, Khazal S. Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective. Cancers (Basel) 2022; 14:2912. [PMID: 35740580 PMCID: PMC9221186 DOI: 10.3390/cancers14122912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/04/2022] [Accepted: 06/08/2022] [Indexed: 02/01/2023] Open
Abstract
Non-Hodgkin lymphoma (NHL) is a broad entity which comprises a number of different types of lymphomatous malignancies. In the pediatric and adolescent population, the type and prognosis of NHL varies by age and gender. In comparison to adults, pediatric and adolescent patients generally have better outcomes following treatment for primary NHL. However, relapsed/refractory (R/R) disease is associated with poorer outcomes in many types of NHL such as diffuse large B cell lymphoma and Burkitt lymphoma. Newer therapies have been approved in the use of primary NHL in the pediatric and adolescent population such as Rituximab and other therapies such as chimeric antigen receptor T-cell (CAR T-cell) therapy are under investigation for the treatment of R/R NHL. In this review, we feature the characteristics, diagnosis, and treatments of the most common NHLs in the pediatric and adolescent population and also highlight the differences that exist between pediatric and adult disease. We then detail the areas of treatment advances such as immunotherapy with CAR T-cells, brentuximab vedotin, and blinatumomab as well as cell cycle inhibitors and describe areas where further research is needed. The aim of this review is to juxtapose established research regarding pediatric and adolescent NHL with recent advancements as well as highlight treatment gaps where more investigation is needed.
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Affiliation(s)
- Irtiza N. Sheikh
- Department of Pediatrics, Pediatric Hematology Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Amr Elgehiny
- Department of Pediatrics, McGovern Medical School, The University of Texas at Houston Health Science Center, Houston, TX 77030, USA;
| | - Dristhi Ragoonanan
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Kris M. Mahadeo
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
| | - Yago Nieto
- Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Sajad Khazal
- Department of Pediatrics, CARTOX Program, Pediatric Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (D.R.); (K.M.M.)
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Soyland DJ, Thanel PF, Sievers ME, Wagner K, Vuong SM. Primary epidural sporadic Burkitt lymphoma in a 3-year-old: Case report and literature review. Surg Neurol Int 2022; 13:106. [PMID: 35399880 PMCID: PMC8986637 DOI: 10.25259/sni_1172_2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 03/16/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Burkitt lymphoma (BL) is a common tumor of childhood that usually arises in the abdomen or pelvis in its sporadic form. In a minority of cases, BL can present with CNS involvement, usually as a secondary site. Rarely, BL can arise primarily in the epidural space and present with back pain, or less commonly, acute myelopathy. This presentation is a surgical emergency and requires vigilant management. Case Description: We describe a case of pediatric BL arising primarily within the epidural space and presenting with progressive difficulty walking in a 3-year-old boy. Progression to complete inability to walk, absent lower extremity deep tendon reflexes, and new urinary incontinence prompted MRI of the spine, which showed a lesion extending from T5 to T10 and wrapping around the anterior and posterior portions of the spine with evidence of spinal cord compression. The patient underwent decompressive laminectomies from T5 to T10 and partial debulking of the posterior portions of the tumor. Microscopic examination showed a prominent “starry sky” pattern with abundant mitotic figures. Immunohistochemistry confirmed the diagnosis of BL. The patient is 10 months post-op and continues to undergo chemotherapy with partial neurologic improvement. He was free of recurrence 10 months post-operative. Conclusion: This appears to be the youngest described patient presenting with acute myelopathy in primary paraspinal BL. Management should include surgical decompression of the spinal cord followed by one of the various described chemotherapeutic regimens. Preoperative staging and neurologic function correlate with prognosis.
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Affiliation(s)
- Dallas J. Soyland
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Paul F. Thanel
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Meaghan E. Sievers
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Kayelyn Wagner
- Department of Pediatric Oncology, Sanford School of Medicine, Sioux Falls, South Dakota, United States
| | - Shawn M. Vuong
- Department of Neurosurgery, Sanford School of Medicine, Sioux Falls, South Dakota, United States
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Abstract
Epstein–Barr virus (EBV) contributes to Burkitt lymphoma and post-transplant lymphoproliferative disease (PTLD). EBV-transforming programs activate lipid metabolism to convert B cells into immortalized lymphoblastoid cell lines (LCL), a PTLD model. We found that stages of EBV transformation generate lipid reactive oxygen species (ROS) byproducts to varying degrees, and that a Burkitt-like phase of B cell outgrowth requires lipid ROS detoxification by glutathione peroxidase 4 and its cofactor glutathione. Perturbation of this redox defense in early stages of transformation or in Burkitt cells triggered ferroptosis, a programmed cell death pathway. LCLs were less dependent on this defense, a distinction tied to EBV latency programs. This highlights ferroptosis induction as a potential therapeutic approach for prevention or treatment of certain EBV+ lymphomas. Epstein–Barr virus (EBV) causes 200,000 cancers annually. Upon B cell infection, EBV induces lipid metabolism to support B cell proliferation. Yet, little is known about how latent EBV infection, or human B cell stimulation more generally, alter sensitivity to ferroptosis, a nonapoptotic form of programmed cell death driven by iron-dependent lipid peroxidation and membrane damage. To gain insights, we analyzed lipid reactive oxygen species (ROS) levels and ferroptosis vulnerability in primary human CD19+ B cells infected by EBV or stimulated by key B cell receptors. Prior to the first mitosis, EBV-infected cells were exquisitely sensitive to blockade of glutathione biosynthesis, a phenomenon not observed with B cell receptor stimulation. Subsequently, EBV-mediated Burkitt-like hyperproliferation generated elevated levels of lipid ROS, which necessitated SLC7A11-mediated cystine import and glutathione peroxidase 4 (GPX4) activity to prevent ferroptosis. By comparison, B cells were sensitized to ferroptosis induction by combinatorial CD40-ligand and interleukin-4 stimulation or anti–B cell receptor and Toll-like receptor 9 stimulation upon GPX4 inhibition but not with SLC7A11 blockade. EBV transforming B cells became progressively resistant to ferroptosis induction upon switching to the latency III program and lymphoblastoid physiology. Similarly, latency I Burkitt cells were particularly vulnerable to blockade of SLC7A11 or GPX4 or cystine withdrawal, while latency III Burkitt and lymphoblastoid cells were comparatively resistant. The selenocysteine biosynthesis kinase PSTK was newly implicated as a cellular target for ferroptosis induction including in Burkitt cells, likely due to roles in GPX4 biosynthesis. These results highlight ferroptosis as an intriguing therapeutic target for the prevention or treatment of particular EBV-driven B cell malignancies.
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Cryptic MYC insertions in Burkitt lymphoma: New data and a review of the literature. PLoS One 2022; 17:e0263980. [PMID: 35167621 PMCID: PMC8846522 DOI: 10.1371/journal.pone.0263980] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 02/01/2022] [Indexed: 12/24/2022] Open
Abstract
The occurrence of MYC-negative Burkitt lymphoma (BL) has been discussed for many years. The real frequency of the MYC insertion in MYC-negative BL is still unknown. Fine-needle aspiration biopsies of 108 consecutive patients with clinicopathologically suspected BL (suspBL) were evaluated by flow cytometry, classical cytogenetics, and fluorescence in situ hybridization (FISH). We found 12 cases (11%) without the MYC rearrangement by FISH with a MYC breakapart probe: two patients (1.9%) with cryptic MYC/IGH fusion (finally diagnosed as BL) and 10 patients (9.3%) with 11q gain/loss (finally diagnosed as Burkitt-like lymphoma with 11q aberration). The exact breakpoints of the cryptic MYC/IGH were investigated by next-generation sequencing. The MYC insertions’ breakpoints were identified in PVT1 in the first case, and 42 kb upstream of 5′MYC in the second case. To date, a molecular characterization of the MYC insertion in BL has only been reported in one case. Detailed descriptions of our MYC insertions in a routinely and consecutively diagnosed suspBL cohort will contribute to resolving the issue of MYC negativity in BL. In our opinion, the presence of the MYC insertions in BL and other lymphomas might be underestimated, because routine genetic diagnostics are usually based on FISH only, without karyotyping.
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Prochownik EV, Wang H. Normal and Neoplastic Growth Suppression by the Extended Myc Network. Cells 2022; 11:747. [PMID: 35203395 PMCID: PMC8870482 DOI: 10.3390/cells11040747] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/09/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022] Open
Abstract
Among the first discovered and most prominent cellular oncogenes is MYC, which encodes a bHLH-ZIP transcription factor (Myc) that both activates and suppresses numerous genes involved in proliferation, energy production, metabolism and translation. Myc belongs to a small group of bHLH-ZIP transcriptional regulators (the Myc Network) that includes its obligate heterodimerization partner Max and six "Mxd proteins" (Mxd1-4, Mnt and Mga), each of which heterodimerizes with Max and largely opposes Myc's functions. More recently, a second group of bHLH-ZIP proteins (the Mlx Network) has emerged that bears many parallels with the Myc Network. It is comprised of the Myc-like factors ChREBP and MondoA, which, in association with the Max-like member Mlx, regulate smaller and more functionally restricted repertoires of target genes, some of which are shared with Myc. Opposing ChREBP and MondoA are heterodimers comprised of Mlx and Mxd1, Mxd4 and Mnt, which also structurally and operationally link the two Networks. We discuss here the functions of these "Extended Myc Network" members, with particular emphasis on their roles in suppressing normal and neoplastic growth. These roles are complex due to the temporal- and tissue-restricted expression of Extended Myc Network proteins in normal cells, their regulation of both common and unique target genes and, in some cases, their functional redundancy.
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Affiliation(s)
- Edward V. Prochownik
- Division of Hematology/Oncology, The Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
- The Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
- The Hillman Cancer Center of UPMC, Pittsburgh, PA 15224, USA
- The Pittsburgh Liver Research Center, Pittsburgh, PA 15224, USA
| | - Huabo Wang
- Division of Hematology/Oncology, The Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA;
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Radiosensitizing Effect of Celastrol by Inhibiting G2/M Phase Arrest Induced by the c-myc Gene of Human SW1353 Chondrosarcoma Cells: Network and Experimental Analyses. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1948657. [PMID: 35141331 PMCID: PMC8820907 DOI: 10.1155/2022/1948657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/30/2021] [Indexed: 11/21/2022]
Abstract
Objective Studies have unveiled that the components of Tripterygium wilfordii Hook F (TWHF) such as celastrol could attenuate apoptosis and proliferation of various tumor cells. This study is focused on the radiosensitization effect and apoptotic pathways of celastrol via the inhibition of the c-myc gene and the influence of which combined with radiotherapy on the proliferation, apoptosis, invasion, and metastasis of chondrosarcoma cells. Methods A variety of bioinformatic tools were applied to explore the expression level and prognosis of the c-myc gene in different tumor cells and chondrosarcoma cells. We used pharmacology network to analyze the components, pathways, targets, molecular functions of TWHF and explore the relevant effective components over the MYC gene. Clone formation assay, CCK-8 assay, flow cytometry, and transwell migration assay were applied to detect the effects of celastrol on the expression of c-myc gene, cell apoptosis, and cell cycle. Radiation therapy was used to observe the radiosensitization effect of celastrol on chondrosarcoma. Results This study shows that the c-myc gene is overexpressed in various tumor cells and bone tumor cells to varying degrees. Celastrol can significantly inhibit the expression of the c-myc gene, induce G2/M phase arrest through regulation of G2/M phase-related proteins, and promote SW1353 cell apoptosis through the mitochondrial signaling pathway. In addition, we also found that the use of triptorubin to inhibit c-myc gene expression in combination with radiotherapy can increase the osteosarcoma cells' apoptosis rate through the mitochondrial signaling pathway significantly. Conclusions Our study validated the radiosensitization effect of celastrol through knocking down the expression of the c-myc gene to induce G2/M phase arrest and provides a new idea for the treatment of refractory or recurrent chondrosarcoma that is not sensitive to radiotherapy.
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Comparative Investigation of Gene Regulatory Processes Underlying Avian Influenza Viruses in Chicken and Duck. BIOLOGY 2022; 11:biology11020219. [PMID: 35205087 PMCID: PMC8868632 DOI: 10.3390/biology11020219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/07/2022] [Accepted: 01/25/2022] [Indexed: 11/30/2022]
Abstract
Simple Summary Avian influenza poses a great risk to gallinaceous poultry, while mallard ducks can withstand most virus strains. To date, the mechanisms underlying the susceptibility of chicken and the effective immune response of duck have not been completely understood. In this study, our aim is to investigate the transcriptional gene regulation governing the expression of important avian-influenza-induced genes and to reveal the master regulators stimulating an effective immune response after virus infection in ducks while dysfunctioning in chicken. Abstract The avian influenza virus (AIV) mainly affects birds and not only causes animals’ deaths, but also poses a great risk of zoonotically infecting humans. While ducks and wild waterfowl are seen as a natural reservoir for AIVs and can withstand most virus strains, chicken mostly succumb to infection with high pathogenic avian influenza (HPAI). To date, the mechanisms underlying the susceptibility of chicken and the effective immune response of duck have not been completely unraveled. In this study, we investigate the transcriptional gene regulation underlying disease progression in chicken and duck after AIV infection. For this purpose, we use a publicly available RNA-sequencing dataset from chicken and ducks infected with low-pathogenic avian influenza (LPAI) H5N2 and HPAI H5N1 (lung and ileum tissues, 1 and 3 days post-infection). Unlike previous studies, we performed a promoter analysis based on orthologous genes to detect important transcription factors (TFs) and their cooperation, based on which we apply a systems biology approach to identify common and species-specific master regulators. We found master regulators such as EGR1, FOS, and SP1, specifically for chicken and ETS1 and SMAD3/4, specifically for duck, which could be responsible for the duck’s effective and the chicken’s ineffective immune response.
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Peng Y, Song Y, Wang H. Systematic Elucidation of the Aneuploidy Landscape and Identification of Aneuploidy Driver Genes in Prostate Cancer. Front Cell Dev Biol 2022; 9:723466. [PMID: 35127694 PMCID: PMC8814427 DOI: 10.3389/fcell.2021.723466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
Aneuploidy is widely identified as a remarkable feature of malignancy genomes. Increasing evidences suggested aneuploidy was involved in the progression and metastasis of prostate cancer (PCa). Nevertheless, no comprehensive analysis was conducted in PCa about the effects of aneuploidy on different omics and, especially, about the driver genes of aneuploidy. Here, we validated the association of aneuploidy with the progression and prognosis of PCa and performed a systematic analysis in mutation profile, methylation profile, and gene expression profile, which detailed the molecular process aneuploidy implicated. By multi-omics analysis, we managed to identify 11 potential aneuploidy driver genes (GSTM2, HAAO, C2orf88, CYP27A1, FAXDC2, HFE, C8orf88, GSTP1, EFS, HIF3A, and WFDC2), all of which were related to the development and metastasis of PCa. Meanwhile, we also found aneuploidy and its driver genes were correlated with the immune microenvironment of PCa. Our findings could shed light on the tumorigenesis of PCa and provide a better understanding of the development and metastasis of PCa; additionally, the driver genes could be promising and actionable therapeutic targets pointing to aneuploidy.
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Affiliation(s)
- Yun Peng
- Tianjin Institute of Urology, the 2nd Hospital of Tianjin Medical University, Tianjin, China
| | - Yuxuan Song
- Department of Urology, Peking University People’s Hospital, Beijing, China
| | - Haitao Wang
- Department of Oncology, the 2nd Hospital of Tianjin Medical University, Tianjin, China
- *Correspondence: Haitao Wang,
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Wang MQ, Li HY, Cao HW, Lang XX, Chen YS. Selective c-MYC G4 DNA recognition based on a fluorescent light-up probe with disaggregation-induced emission characteristics. J Mater Chem B 2022; 10:7772-7779. [DOI: 10.1039/d2tb01316a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
c-MYC promoter is well-known as an important oncogene, whose overexpression leads to ∼80% of all solid tumors. The four-stranded G4 present in the c-MYC promoter has been shown to play...
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The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol 2022; 19:23-36. [PMID: 34508258 PMCID: PMC9083341 DOI: 10.1038/s41571-021-00549-2] [Citation(s) in RCA: 469] [Impact Index Per Article: 156.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/28/2021] [Indexed: 02/08/2023]
Abstract
The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.
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Kos IA, Thurner L, Bittenbring JT, Christofyllakis K, Kaddu-Mulindwa D. Advances in Lymphoma Molecular Diagnostics. Diagnostics (Basel) 2021; 11:diagnostics11122174. [PMID: 34943410 PMCID: PMC8699850 DOI: 10.3390/diagnostics11122174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 11/16/2022] Open
Abstract
Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent years much scientific effort has been undertaken to identify and understand molecular changes in lymphomas, resulting in a wide range of genetic alterations that have been reported across all types of lymphomas. As many of these changes are now incorporated into the World Health Organization’s defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms, their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here, we give an overview of and discuss advances in molecular techniques in current clinical practice, as well as highlight some of them in a clinical context.
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Song Y, Du J, Lu P, Zou Q, Zeng S, Liu M, Hu X, Ma W, Lin H, Liu X, Niu F. LncRNA NFYC-AS1 promotes the development of lung adenocarcinomas through autophagy, apoptosis, and MET/c-Myc oncogenic proteins. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1621. [PMID: 34926665 PMCID: PMC8640918 DOI: 10.21037/atm-21-4995] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/09/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Nuclear transcription factor Y subunit C antisense RNA 1 (NFYC-AS1) was revealed to be a potential prognostic biomarker in lung adenocarcinoma (LAUD) by analyzing The Cancer Genome Atlas (TCGA) database. However, the function of NFYC-AS1 has not been verified in cancers, including LAUD. We plan to verify the function of NFYC-AS1 in LAUD through this study. METHODS We determined NFYC-AS1 expression in 4 LAUD cell lines, and 1 normal lung cell line (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR). small interfering RNA (siRNA) was employed to specifically knockdown NFYC-AS1 in H1299 and PC9 cell lines. Cell growth and invasion activity of LAUD cells was assessed by WST-1, colony formation and transwell assay, respectively. The effect of NFYC-AS1 expression on cell apoptosis was then assessed by flow cytometry assay. Furthermore, the expression of downstream proteins of NFYC-AS1 was investigated by Western blot. RESULTS The proliferation, migration, and invasion of cells were inhibited and apoptosis was increased after NFYC-AS1 knockdown in LAUD cells. The cells transfected with NFYC-AS1 siRNA had a higher rate of apoptosis compared with that in control cells. The apoptosis-related proteins p53 and PARP were upregulated. These suggested NFYC-AS1 could inhibit the apoptosis of LAUD cells. In terms of the expression of major autophagy proteins, p62 was downregulated while Beclin 1 was upregulated after NFYC-AS1 knockdown, which suggested that autophagy was activated. The expression of oncogenic proteins MET and c-Myc was downregulated. CONCLUSIONS In summary, the above results suggest that NFYC-AS1 may promote the proliferation of LAUD through autophagy and apoptosis.
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Affiliation(s)
- Ye Song
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Jike Du
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Pinglan Lu
- Department of Surgical Intensive Care Unit, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qingfeng Zou
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Shaoting Zeng
- Department of Anesthesiology, The Second Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Meiyuan Liu
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaoye Hu
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Wen Ma
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hanhong Lin
- Department of Biotechnology, GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Xiaoyan Liu
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Feiyu Niu
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
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Burchett JB, Knudsen-Clark AM, Altman BJ. MYC Ran Up the Clock: The Complex Interplay between MYC and the Molecular Circadian Clock in Cancer. Int J Mol Sci 2021; 22:7761. [PMID: 34299381 PMCID: PMC8305799 DOI: 10.3390/ijms22147761] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/02/2021] [Accepted: 07/14/2021] [Indexed: 12/13/2022] Open
Abstract
The MYC oncoprotein and its family members N-MYC and L-MYC are known to drive a wide variety of human cancers. Emerging evidence suggests that MYC has a bi-directional relationship with the molecular clock in cancer. The molecular clock is responsible for circadian (~24 h) rhythms in most eukaryotic cells and organisms, as a mechanism to adapt to light/dark cycles. Disruption of human circadian rhythms, such as through shift work, may serve as a risk factor for cancer, but connections with oncogenic drivers such as MYC were previously not well understood. In this review, we examine recent evidence that MYC in cancer cells can disrupt the molecular clock; and conversely, that molecular clock disruption in cancer can deregulate and elevate MYC. Since MYC and the molecular clock control many of the same processes, we then consider competition between MYC and the molecular clock in several select aspects of tumor biology, including chromatin state, global transcriptional profile, metabolic rewiring, and immune infiltrate in the tumor. Finally, we discuss how the molecular clock can be monitored or diagnosed in human tumors, and how MYC inhibition could potentially restore molecular clock function. Further study of the relationship between the molecular clock and MYC in cancer may reveal previously unsuspected vulnerabilities which could lead to new treatment strategies.
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Affiliation(s)
- Jamison B. Burchett
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Amelia M. Knudsen-Clark
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Brian J. Altman
- Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA;
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA
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Cadoni E, Magalhães PR, Emídio RM, Mendes E, Vítor J, Carvalho J, Cruz C, Victor BL, Paulo A. New (Iso)quinolinyl-pyridine-2,6-dicarboxamide G-Quadruplex Stabilizers. A Structure-Activity Relationship Study. Pharmaceuticals (Basel) 2021; 14:ph14070669. [PMID: 34358095 PMCID: PMC8308870 DOI: 10.3390/ph14070669] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 12/15/2022] Open
Abstract
G-quadruplex (G4)-interactive small molecules have a wide range of potential applications, not only as drugs, but also as sensors of quadruplex structures. The purpose of this work is the synthesis of analogues of the bis-methylquinolinium-pyridine-2,6-dicarboxamide G4 ligand 360A, to identify relevant structure-activity relationships to apply to the design of other G4-interactive small molecules bearing bis-quinoline or bis-isoquinoline moieties. Thermal denaturation experiments revealed that non-methylated derivatives with a relative 1,4 position between the amide linker and the nitrogen of the quinoline ring are moderate G4 stabilizers, with a preference for the hybrid h-Telo G4, a 21-nt sequence present in human telomeres. Insertion of a positive charge upon methylation of quinoline/isoquinoline nitrogen increases compounds' ability to selectively stabilize G4s compared to duplex DNA, with a preference for parallel structures. Among these, compounds having a relative 1,3-position between the charged methylquinolinium/isoquinolinium nitrogen and the amide linker are the best G4 stabilizers. More interestingly, these ligands showed different capacities to selectively block DNA polymerization in a PCR-stop assay and to induce G4 conformation switches of hybrid h-Telo G4. Molecular dynamic simulations with the parallel G4 formed by a 21-nt sequence present in k-RAS gene promoter, showed that the relative spatial orientation of the two methylated quinoline/isoquinoline rings determines the ligands mode and strength of binding to G4s.
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Affiliation(s)
- Enrico Cadoni
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (E.C.); (E.M.)
| | - Pedro R. Magalhães
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal; (P.R.M.); (R.M.E.); (B.L.V.)
| | - Rita M. Emídio
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal; (P.R.M.); (R.M.E.); (B.L.V.)
| | - Eduarda Mendes
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (E.C.); (E.M.)
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
| | - Jorge Vítor
- Department of Pharmacy, Pharmacology and Health Technologies, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;
| | - Josué Carvalho
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; (J.C.); (C.C.)
| | - Carla Cruz
- CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; (J.C.); (C.C.)
| | - Bruno L. Victor
- Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal; (P.R.M.); (R.M.E.); (B.L.V.)
| | - Alexandra Paulo
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (E.C.); (E.M.)
- Department of Pharmaceutical Sciences and Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
- Correspondence:
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Ye M, Huang W, Liu R, Kong Y, Liu Y, Chen X, Xu J. Synergistic Activity of the HSP90 Inhibitor Ganetespib With Lapatinib Reverses Acquired Lapatinib Resistance in HER2-Positive Breast Cancer Cells. Front Pharmacol 2021; 12:651516. [PMID: 34290605 PMCID: PMC8287059 DOI: 10.3389/fphar.2021.651516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 06/23/2021] [Indexed: 11/23/2022] Open
Abstract
Lapatinib is an FDA-approved EGFR and HER2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer patients. However, its therapeutic efficacy is limited by primary or acquired resistance. In the present study, we established breast cancers cells with acquired lapatinib resistance and investigated the antitumor activity of the second-generation HSP90 inhibitor ganetespib in association with lapatinib in lapatinib-sensitive and -resistant cells. The combination treatment showed synergistic inhibition of HER and the downstream PI3K/Akt and Ras/MEK/ERK pathways, in addition to enhancing induction of early apoptotic cell death and G1 arrest in both parent and lapatinib-resistant cells in vitro. The joint administration of ganetespib and lapatinib depleted the aberrant nuclear transcription factor STAT3, a mediator of the cell cycle and apoptosis-related pathways that is probably involved in the lapatinib resistance of HER2-positive breast cancer cells. In conjunctive with the augmented inhibition of tumor growth observed in both SKBR3 and SKBR3-L xenografts compared to monotherapy, our data provide a sound preclinical basis for combination treatment with lapatinib and ganetespib for refractory HER2-positive breast cancer.
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Affiliation(s)
- Min Ye
- School of Pharmacy, Fujian Medical University, Fuzhou, China
- Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou, China
| | - Wei Huang
- School of Pharmacy, Fujian Medical University, Fuzhou, China
- College of Life Sciences, Fujian Agriculature and Forestry University, Fuzhou, China
| | - Rui Liu
- School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Yingli Kong
- School of Pharmacy, Fujian Medical University, Fuzhou, China
| | - Yang Liu
- School of Pharmacy, Fujian Medical University, Fuzhou, China
- Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou, China
| | - Xiaole Chen
- School of Pharmacy, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Drug Target Discovery and Structural and Functional Research, Fuzhou, China
| | - Jianhua Xu
- School of Pharmacy, Fujian Medical University, Fuzhou, China
- Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou, China
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Shen Shuai II Recipe Attenuates Renal Interstitial Fibrosis by Improving Hypoxia via the IL-1 β/ c-Myc Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5539584. [PMID: 34211565 PMCID: PMC8205594 DOI: 10.1155/2021/5539584] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/22/2021] [Indexed: 11/29/2022]
Abstract
Background Renal interstitial fibrosis is a pathological manifestation of progression of chronic kidney disease induced by various factors. Shen Shuai II Recipe (SSR) has been used in clinical practice for more than 20 years, and clinical studies have confirmed that SSR significantly improves the renal function of patients with chronic kidney disease. However, the specific mechanisms underlying its efficacy require further research. This study aims to explore the influencing factors of renal interstitial fibrosis in the context of hypoxia via the IL-1β/c-Myc pathway and the potential molecular mechanisms of SSR intervention in vivo and in vitro. Methods A rat model of chronic renal failure was developed by performing 5/6 (ablation/infarction, A/I) surgery on randomly selected, male Sprague Dawley rats. Thirty-six successfully modeled rats were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + SSR, and 5/6 (A/I) + losartan. Another 12 rats were used as the sham group. After 8 weeks of the corresponding intervention, renal function, liver function, and protein expression of renal-fibrosis-related factors, HIF-1α, IL-1β, and c-Myc, were detected. In vitro analysis was performed using hypoxia-induced rat renal tubular epithelial cells (NRK-52E) and IL-1β-stimulated rat renal interstitial fibroblasts (NRK-49F). IL-1β concentration in the culture medium and IL-1β protein expression in hypoxic NRK-52E treated with different concentrations of SSR were investigated. Furthermore, we also studied the changes in protein expression of c-Myc and fibrosis-related factors after c-Myc gene silencing in IL-1β-stimulated NRK-49F treated with SSR. Results Shen Shuai II Recipe significantly reduced RIF and downregulated the expression of HIF-1α, c-Myc, and IL-1β proteins in 5/6 (A/I) rats with chronic renal failure. It also inhibited IL-1β secretion from NRK-52E induced by hypoxia, which in turn inhibited fibroblast activation mediated by the IL-1β/c-Myc pathway, and finally reduced the overproduction of the extracellular matrix. Conclusion The renoprotective effects of SSR in rats with chronic renal failure may be related to its inhibition of hypoxia via the IL-1β/c-Myc pathway. Thus, SSR is a potentially effective drug for delaying the progression of renal interstitial fibrosis.
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de Carvalho PS, Leal FE, Soares MA. Clinical and Molecular Properties of Human Immunodeficiency Virus-Related Diffuse Large B-Cell Lymphoma. Front Oncol 2021; 11:675353. [PMID: 33996608 PMCID: PMC8117347 DOI: 10.3389/fonc.2021.675353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/14/2021] [Indexed: 12/15/2022] Open
Abstract
Non-Hodgkin lymphoma is the most common malignancy affecting people living with HIV (PLWH). Among its several subtypes, diffuse large B-cell lymphoma (DLBCL) is an important manifestation within the HIV-infected compartment of the population. Since HIV is able to modulate B cells and promote lymphomagenesis through direct and indirect mechanisms, HIV-related DLBCL has specific characteristics. In this review, we address the clinical and molecular properties of DLBCL disease in the context of HIV infection, as well as the mechanisms by which HIV is able to modulate B lymphocytes and induce their transformation into lymphoma.
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Affiliation(s)
- Pedro S de Carvalho
- Programa de Oncovirologia, Instituto Nacional do Câncer, Rio de Janeiro, Brazil
| | - Fabio E Leal
- Programa de Oncovirologia, Instituto Nacional do Câncer, Rio de Janeiro, Brazil
| | - Marcelo A Soares
- Programa de Oncovirologia, Instituto Nacional do Câncer, Rio de Janeiro, Brazil.,Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Cho YA, Hyeon J, Lee H, Cho J, Kim SJ, Kim WS, Ko YH. MYC single-hit large B-cell lymphoma: clinicopathologic difference from MYC-negative large B-cell lymphoma and MYC double-hit/triple-hit lymphoma. Hum Pathol 2021; 113:9-19. [PMID: 33771538 DOI: 10.1016/j.humpath.2021.03.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/02/2021] [Accepted: 03/04/2021] [Indexed: 11/30/2022]
Abstract
MYC-rearranged large B-cell lymphoma with BCL2 and/or BCL6 rearrangement, double-hit (DH) or triple-hit (TH) lymphoma, is associated with poor survival after standard treatment. To investigate the clinical impact of single-hit (SH) MYC rearrangement, we analyzed 241 cases of diffuse large B-cell lymphoma (DLBCL) for MYC, BCL2, and BCL6 rearrangement by fluorescence in situ hybridization. Fifty-five of 241 (22.8%) cases showed MYC rearrangements. Twenty-three cases were diagnosed as DLBCL; 18 as high-grade B-cell lymphoma (HGBCL)-DH; 3 as HGBCL-TH; and 11 as HGBCL, not otherwise specified. Both DH and TH lymphomas showed high-grade morphology (P = 0.002), higher stage (P = 0.022), and more frequent germinal center B-cell-like phenotype (P = 0.008). SH lymphomas displayed high-grade morphology (P = 0.002) but were not different from MYC-negative lymphomas in cell of origin, clinical stage, international prognostic index (IPI), or extranodal involvement. Patients with DH/TH lymphomas had worse overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P < 0.001), while OS and PFS of SH lymphomas were not different from those of MYC-negative lymphomas. There was no survival difference between cases of BCL2 and BCL6 rearrangements. Poorer prognostic factors included higher ECOG class, higher IPI, and DH or TH translocation for OS, and higher IPI and DH or TH translocation for PFS. Higher IPI was an independent prognostic factor for OS and PFS. In conclusion, large B-cell lymphomas with single MYC rearrangement showed high-grade morphology but were otherwise not different from MYC-negative lymphomas.
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Affiliation(s)
- Yoon Ah Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea; Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Republic of Korea
| | - Jiyeon Hyeon
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Hyunwoo Lee
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Junhun Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Seok-Jin Kim
- Division of Hematology-oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Won Seog Kim
- Division of Hematology-oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Young-Hyeh Ko
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
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Ross J, Miron CE, Plescia J, Laplante P, McBride K, Moitessier N, Möröy T. Targeting MYC: From understanding its biology to drug discovery. Eur J Med Chem 2020; 213:113137. [PMID: 33460833 DOI: 10.1016/j.ejmech.2020.113137] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/22/2020] [Accepted: 12/23/2020] [Indexed: 01/06/2023]
Abstract
The MYC oncogene is considered to be a high priority target for clinical intervention in cancer patients due to its aberrant activation in more than 50% of human cancers. Direct small molecule inhibition of MYC has traditionally been hampered by its intrinsically disordered nature and lack of both binding site and enzymatic activity. In recent years, however, a number of strategies for indirectly targeting MYC have emerged, guided by the advent of protein structural information and the growing set of computational tools that can be used to accelerate the hit to lead process in medicinal chemistry. In this review, we provide an overview of small molecules developed for clinical applications of these strategies, which include stabilization of the MYC guanine quadruplex, inhibition of BET factor BRD4, and disruption of the MYC:MAX heterodimer. The recent identification of novel targets for indirect MYC inhibition at the protein level is also discussed.
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Affiliation(s)
- Julie Ross
- Institut de recherches cliniques de Montréal (IRCM), 110 Pine Ave W., Montréal, Québec, H2W 1R7, Canada
| | - Caitlin E Miron
- Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada
| | - Jessica Plescia
- Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada
| | - Patricia Laplante
- AmorChem II Ventures Inc., 4 Westmount Sq. Bureau 160, Westmount, Québec, H3Z 2S6, Canada
| | - Kevin McBride
- AmorChem II Ventures Inc., 4 Westmount Sq. Bureau 160, Westmount, Québec, H3Z 2S6, Canada
| | - Nicolas Moitessier
- Department of Chemistry, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada.
| | - Tarik Möröy
- Institut de recherches cliniques de Montréal (IRCM), 110 Pine Ave W., Montréal, Québec, H2W 1R7, Canada; Département de microbiologie, infectiologie et immunologie, Université de Montréal, 2900, boul. Édouard-Montpetit, Montréal, Québec, H3T 1J4, Canada; Division of Experimental Medicine, McGill University, 801 Sherbrooke St. W., Montréal, Québec, H3A 0B8, Canada.
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The Molecular 'Myc-anisms' Behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics. Int J Mol Sci 2020; 21:ijms21249486. [PMID: 33322239 PMCID: PMC7764474 DOI: 10.3390/ijms21249486] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 02/07/2023] Open
Abstract
MYC, a well-studied proto-oncogene that is overexpressed in >20% of tumors across all cancers, is classically known as “undruggable” due to its crucial roles in cell processes and its lack of a drug binding pocket. Four decades of research and creativity led to the discovery of a myriad of indirect (and now some direct!) therapeutic strategies targeting Myc. This review explores the various mechanisms in which Myc promotes cancer and highlights five key therapeutic approaches to disrupt Myc, including transcription, Myc-Max dimerization, protein stability, cell cycle regulation, and metabolism, in order to develop more specific Myc-directed therapies.
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Wang Y, Li J, Li J, Li P, Wang L, Di L. An Enhancer-Based Analysis Revealed a New Function of Androgen Receptor in Tumor Cell Immune Evasion. Front Genet 2020; 11:595550. [PMID: 33343635 PMCID: PMC7738566 DOI: 10.3389/fgene.2020.595550] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Cancer is characterized by dysregulation at multiple levels, such as gene transcription. Enhancers are well-studied transcription regulators that can enhance target transcripts through DNA loop formation mediated by chromosome folding. The gain or loss of the interaction between an enhancer and its target gene has a critical effect on gene expression. In this study, we analyzed GRO-seq data to identify active enhancers from seven common cancer cell lines and studied the function of these enhancers across multiple cancer types. By constructing an "enhancer effect score" (EES), we found a significant correlation between EES and tumor-infiltrating lymphocytes (TILs) in prostate cancer. Further analysis revealed that androgen receptor (AR) plays an important role in regulating the immune checkpoint gene PVR via its enhancer. These results suggest that AR contributes to prostate cancer aggressiveness by promoting cancer cell immune evasion.
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Affiliation(s)
| | | | | | | | | | - Lijun Di
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, China
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Long noncoding RNA: a dazzling dancer in tumor immune microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:231. [PMID: 33148302 PMCID: PMC7641842 DOI: 10.1186/s13046-020-01727-3] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
Long noncoding RNAs (lncRNAs) are a class of endogenous, non-protein coding RNAs that are highly linked to various cellular functions and pathological process. Emerging evidence indicates that lncRNAs participate in crosstalk between tumor and stroma, and reprogramming of tumor immune microenvironment (TIME). TIME possesses distinct populations of myeloid cells and lymphocytes to influence the immune escape of cancer, the response to immunotherapy, and the survival of patients. However, hitherto, a comprehensive review aiming at relationship between lncRNAs and TIME is missing. In this review, we focus on the functional roles and molecular mechanisms of lncRNAs within the TIME. Furthermore, we discussed the potential immunotherapeutic strategies based on lncRNAs and their limitations.
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Fan Y, Jia X, Xie T, Zhu L, He F. Radiosensitizing effects of c‑myc gene knockdown‑induced G2/M phase arrest by intrinsic stimuli via the mitochondrial signaling pathway. Oncol Rep 2020; 44:2669-2677. [PMID: 33125136 PMCID: PMC7640369 DOI: 10.3892/or.2020.7806] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/18/2020] [Indexed: 11/06/2022] Open
Abstract
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and its long‑term survival rate has stagnated in the past decades. Previous studies have shown that tumors in the G2/M phase are more sensitive to radiotherapy. The proto‑oncogene c‑myc is a transformed member of the myc family and c‑myc‑interacting zinc finger protein‑1 (Miz‑1) is a poly‑Cys2His2 zinc finger (ZF) activator of cell cycle regulator genes, such as the cyclin‑dependent kinase inhibitor p21. C‑myc can repress the expression of p21 by binding to Miz‑1 and abolishing the interaction between Miz‑1 and its co‑activators, which induces G2/M phase arrest. Therefore, the present study investigated the radiosensitizing effects of the c‑myc gene and the sensitizing apoptosis pathway, aiming to identify a more effective combination radiotherapy treatment for osteosarcoma. The present study demonstrated that the c‑myc gene was overexpressed in osteosarcoma cells compared to osteoblasts. Following inhibition of c‑myc gene expression in osteosarcoma cells, tumor proliferation was significantly hindered after inducing G2/M phase arrest via regulating G2/M phase‑associated proteins. Additionally, it was revealed that inhibiting c‑myc gene expression combined with radiotherapy could significantly increase the apoptosis rate of osteosarcoma cells via the mitochondrial signaling pathway. In summary, the present study verified the radiosensitizing effects of c‑myc gene knockdown‑induced G2/M phase arrest, which was achieved by intrinsic stimuli through the mitochondrial signaling pathway.
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Affiliation(s)
- Yunpeng Fan
- The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiaofeng Jia
- College of Life Science, China Jiliang University, Hangzhou, Zhejiang 310018, P.R. China
| | - Tao Xie
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Liulong Zhu
- The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Fan He
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
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Yang L. A Practical Guide for Structural Variation Detection in the Human Genome. CURRENT PROTOCOLS IN HUMAN GENETICS 2020; 107:e103. [PMID: 32813322 PMCID: PMC7738216 DOI: 10.1002/cphg.103] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Profiling genetic variants-including single nucleotide variants, small insertions and deletions, copy number variations, and structural variations (SVs)-from both healthy individuals and individuals with disease is a key component of genetic and biomedical research. SVs are large-scale changes in the genome and involve breakage and rejoining of DNA fragments. They may affect thousands to millions of nucleotides and can lead to loss, gain, and reshuffling of genes and regulatory elements. SVs are known to impact gene expression and potentially result in altered phenotypes and diseases. Therefore, identifying SVs from the human genomes is particularly important. In this review, I describe advantages and disadvantages of the available high-throughput assays for the discovery of SVs, which are the most challenging genetic alterations to detect. A practical guide is offered to suggest the most suitable strategies for discovering different types of SVs including common germline, rare, somatic, and complex variants. I also discuss factors to be considered, such as cost and performance, for different strategies when designing experiments. Last, I present several approaches to identify potential SV artifacts caused by samples, experimental procedures, and computational analysis. © 2020 Wiley Periodicals LLC.
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Affiliation(s)
- Lixing Yang
- Ben May Department for Cancer Research, Department of Human Genetics, University of Chicago, Chicago, Illinois
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