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Liu Z, Wu B, Shi X, Zhou J, Huang H, Li Z, Yang M. Immune profiling of premalignant lesions in patients with Peutz-Jeghers syndrome. United European Gastroenterol J 2025; 13:338-348. [PMID: 39174496 PMCID: PMC11999043 DOI: 10.1002/ueg2.12650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 07/12/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Peutz-Jeghers syndrome (PJS), is a rare autosomal dominant hereditary disease characterized by an elevated risk of various cancers. Serine/Threonine Kinase 11 (STK11) gene is a major tumor suppressor crucial for immune evasion with and beyond tumorigenic cells. It has garnered increasing attention in the realm of oncology treatment, particularly in the context of immunotherapy development. OBJECTIVE This study aimed to assess the suitability of polyps obtained from individuals with PJS, resulting from germline STK11 deficiency, for immunotherapy. Additionally, we seek to identify potential shared mechanisms related to immune evasion between PJS polyps and cancers. To achieve this, we examined PJS polyps alongside familial adenomatous polyposis (FAP) and sporadic polyps. METHODS Polyps were compared among themselves and with either the paracancerous tissues or colon cancers. Pathological and gene expression profiling approaches were employed to characterize infiltrating immune cells and assess the expression of immune checkpoint genes. RESULTS Our findings revealed that PJS polyps exhibited a closer resemblance to cancer tissues than other polyps in terms of their immune microenvironment. Notably, PJS polyps displayed heightened expression of the immune checkpoint gene CD80 and an accumulation of myeloid cells, particularly myeloid-derived suppressor cells (MDSCs). CONCLUSION The findings suggest an immunobiological foundation for the increased cancer susceptibility in PJS patients, paving the way for potential immune therapy applications in this population. Furthermore, utilizing PJS as a model may facilitate the exploration of immune evasion mechanisms, benefiting both PJS and cancer patients.
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Affiliation(s)
- Zhongyue Liu
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
- Department of NeurosurgeryThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Boda Wu
- Department of GastroenterologyPeking University Shenzhen HospitalShenzhenGuangdongChina
| | - Xiaoliu Shi
- Department of Medical GeneticsThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
- Department of GastroenterologyThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Junfeng Zhou
- Endoscopic Medical CenterThe Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaHunanChina
| | - Hui Huang
- Department of Medical GeneticsThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Zhihong Li
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
- Department of OrthopedicsThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Mei Yang
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
- Department of OrthopedicsThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
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2
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Chen Y, Lee K, Woo J, Kim DW, Keum C, Babbi G, Casadio R, Martelli PL, Savojardo C, Manfredi M, Shen Y, Sun Y, Katsonis P, Lichtarge O, Pejaver V, Seward DJ, Kamandula A, Bakolitsa C, Brenner SE, Radivojac P, O'Donnell-Luria A, Mooney SD, Jain S. Evaluating predictors of kinase activity of STK11 variants identified in primary human non-small cell lung cancers. Hum Genet 2025; 144:127-142. [PMID: 39934475 PMCID: PMC11976797 DOI: 10.1007/s00439-025-02726-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025]
Abstract
Critical evaluation of computational tools for predicting variant effects is important considering their increased use in disease diagnosis and driving molecular discoveries. In the sixth edition of the Critical Assessment of Genome Interpretation (CAGI) challenge, a dataset of 28 STK11 rare variants (27 missense, 1 single amino acid deletion), identified in primary non-small cell lung cancer biopsies, was experimentally assayed to characterize computational methods from four participating teams and five publicly available tools. Predictors demonstrated a high level of performance on key evaluation metrics, measuring correlation with the assay outputs and separating loss-of-function (LoF) variants from wildtype-like (WT-like) variants. The best participant model, 3Cnet, performed competitively with well-known tools. Unique to this challenge was that the functional data was generated with both biological and technical replicates, thus allowing the assessors to realistically establish maximum predictive performance based on experimental variability. Three out of the five publicly available tools and 3Cnet approached the performance of the assay replicates in separating LoF variants from WT-like variants. Surprisingly, REVEL, an often-used model, achieved a comparable correlation with the real-valued assay output as that seen for the experimental replicates. Performing variant interpretation by combining the new functional evidence with computational and population data evidence led to 16 new variants receiving a clinically actionable classification of likely pathogenic (LP) or likely benign (LB). Overall, the STK11 challenge highlights the utility of variant effect predictors in biomedical sciences and provides encouraging results for driving research in the field of computational genome interpretation.
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Affiliation(s)
- Yile Chen
- Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, 98105, USA
| | - Kyoungyeul Lee
- 3billion, 3billion Biotechnology Company, Seoul, South Korea
| | - Junwoo Woo
- 3billion, 3billion Biotechnology Company, Seoul, South Korea
| | - Dong-Wook Kim
- 3billion, 3billion Biotechnology Company, Seoul, South Korea
| | - Changwon Keum
- 3billion, 3billion Biotechnology Company, Seoul, South Korea
| | - Giulia Babbi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Rita Casadio
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Pier Luigi Martelli
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Castrense Savojardo
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Matteo Manfredi
- Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy
| | - Yang Shen
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Yuanfei Sun
- Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Panagiotis Katsonis
- Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Olivier Lichtarge
- Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Vikas Pejaver
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - David J Seward
- Department of Pathology, University of Vermont, Burlington, VT, 5445, USA
| | - Akash Kamandula
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, 02115, USA
| | | | | | - Predrag Radivojac
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, 02115, USA
| | - Anne O'Donnell-Luria
- Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA
| | - Sean D Mooney
- Center for Information Technology, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Shantanu Jain
- Khoury College of Computer Sciences, Northeastern University, Boston, MA, 02115, USA.
- The Institute for Experiential AI, Northeastern University, Boston, MA, 02115, USA.
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3
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Kang J, Gallucci S, Pan J, Oakhill JS, Sanij E. The role of STK11/LKB1 in cancer biology: implications for ovarian tumorigenesis and progression. Front Cell Dev Biol 2024; 12:1449543. [PMID: 39544365 PMCID: PMC11560430 DOI: 10.3389/fcell.2024.1449543] [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: 06/15/2024] [Accepted: 10/11/2024] [Indexed: 11/17/2024] Open
Abstract
STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer.
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Affiliation(s)
- Jian Kang
- St Vincent’s Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medicine-St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Stefano Gallucci
- St Vincent’s Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medicine-St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Junqi Pan
- St Vincent’s Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medicine-St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Jonathan S. Oakhill
- St Vincent’s Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medicine-St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
| | - Elaine Sanij
- St Vincent’s Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medicine-St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
- Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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4
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. FASEB J 2024; 38:e23885. [PMID: 39139039 PMCID: PMC11378476 DOI: 10.1096/fj.202401078r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell-selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors (TFs) important for β-cell identity, such as FOXA, MAFA or RFX6, and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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Affiliation(s)
- Nejc Haberman
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
- Division of Neuroscience, Department of Brain Sciences, Imperial College London, London, UK
| | - Rebecca Cheung
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Grazia Pizza
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
| | - Nevena Cvetesic
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Dorka Nagy
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Hannah Maude
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Lorea Blazquez
- Department of Neurosciences, Biogipuzkoa Health Research Institute, San Sebastián, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- CIBERNED, ISCIII (CIBER, Carlos III Institute, Spanish Ministry of Sciences and Innovation), Madrid, Spain
| | - Boris Lenhard
- MRC London Institute of Medical Sciences, London, UK
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK
| | - Inês Cebola
- Section of Genetics and Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
- Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Faculté de Médecine, Université de Montréal, Montréal, Quebec, Canada
- Lee Kong Chian Medical School, Nanyang Technological University, Singapore, Singapore
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, UK
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5
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Li M, Kong X, Jian X, Bo Y, Miao X, Chen H, Shang P, Zhou X, Wang L, Zhang Q, Deng Q, Xue Y, Feng F. Fatty acids metabolism in ozone-induced pulmonary inflammatory injury: Evidence, mechanism and prevention. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 933:173222. [PMID: 38750750 DOI: 10.1016/j.scitotenv.2024.173222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/10/2024] [Accepted: 05/11/2024] [Indexed: 05/20/2024]
Abstract
Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.
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Affiliation(s)
- Mengyuan Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xiangbing Kong
- College of Public Health, Qingdao University, Qingdao, Shandong Province, China
| | - Xiaotong Jian
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yacong Bo
- College of Public Health, Qingdao University, Qingdao, Shandong Province, China
| | - Xinyi Miao
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Lung Regenerative Medicine, Tianjin, China
| | - Pingping Shang
- Key Laboratory of Tobacco Chemistry, Zhengzhou Tobacco Research Institute, CNC, Zhengzhou, Henan, China
| | - Xiaolei Zhou
- Department of Pulmonary Medicine, Chest Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Ling Wang
- Faculty of Medicine, Macau University of Science and Technology, Macau
| | - Qiao Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Qihong Deng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yuan Xue
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China.
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6
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Fernández Aceñero MJ, Díaz del Arco C. Hereditary Gastrointestinal Tumor Syndromes: When Risk Comes with Your Genes. Curr Issues Mol Biol 2024; 46:6440-6471. [PMID: 39057027 PMCID: PMC11275188 DOI: 10.3390/cimb46070385] [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: 05/27/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients.
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Affiliation(s)
- María Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Cristina Díaz del Arco
- Department of Legal Medicine, Psychiatry and Pathology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Pathology, Hospital Clínico San Carlos, Health Research Institute of the Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Haberman N, Cheung R, Pizza G, Cvetesic N, Nagy D, Maude H, Blazquez L, Lenhard B, Cebola I, Rutter GA, Martinez-Sanchez A. Liver kinase B1 (LKB1) regulates the epigenetic landscape of mouse pancreatic beta cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593867. [PMID: 38798508 PMCID: PMC11118353 DOI: 10.1101/2024.05.13.593867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Liver kinase B1 (LKB1/STK11) is an important regulator of pancreatic β-cell identity and function. Elimination of Lkb1 from the β-cell results in improved glucose-stimulated insulin secretion and is accompanied by profound changes in gene expression, including the upregulation of several neuronal genes. The mechanisms through which LKB1 controls gene expression are, at present, poorly understood. Here, we explore the impact of β cell- selective deletion of Lkb1 on chromatin accessibility in mouse pancreatic islets. To characterize the role of LKB1 in the regulation of gene expression at the transcriptional level, we combine these data with a map of islet active transcription start sites and histone marks. We demonstrate that LKB1 elimination from β-cells results in widespread changes in chromatin accessibility, correlating with changes in transcript levels. Changes occurred in hundreds of promoter and enhancer regions, many of which were close to neuronal genes. We reveal that dysregulated enhancers are enriched in binding motifs for transcription factors important for β-cell identity, such as FOXA, MAFA or RFX6 and we identify microRNAs (miRNAs) that are regulated by LKB1 at the transcriptional level. Overall, our study provides important new insights into the epigenetic mechanisms by which LKB1 regulates β-cell identity and function.
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8
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Yuan T, Zeng C, Liu J, Zhao C, Ge F, Li Y, Qian M, Du J, Wang W, Li Y, Liu Y, Dai X, Zhou J, Chen X, Ma S, Zhu H, He Q, Yang B. Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity. Signal Transduct Target Ther 2024; 9:11. [PMID: 38177135 PMCID: PMC10766984 DOI: 10.1038/s41392-023-01706-y] [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: 01/05/2023] [Revised: 10/17/2023] [Accepted: 11/15/2023] [Indexed: 01/06/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs' contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment.
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Affiliation(s)
- Tao Yuan
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Chenming Zeng
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, 311199, China
| | - Jiawei Liu
- Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan, Research Center of Medicinal Plants Resource Science and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chenxi Zhao
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Fujing Ge
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yuekang Li
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Meijia Qian
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jiamin Du
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Weihua Wang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yonghao Li
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yue Liu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xiaoyang Dai
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, 310058, China
| | - Jianya Zhou
- Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310006, China
| | - Xueqin Chen
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China
| | - Shenglin Ma
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Cancer Center of Zhejiang University, Hangzhou, China.
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, Hangzhou, China.
| | - Bo Yang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Lenahan SM, Sarausky HM, Deming P, Seward DJ. STK11 loss leads to YAP1-mediated transcriptional activation in human KRAS-driven lung adenocarcinoma cell lines. Cancer Gene Ther 2024; 31:1-8. [PMID: 37968341 PMCID: PMC10794139 DOI: 10.1038/s41417-023-00687-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 10/16/2023] [Accepted: 10/31/2023] [Indexed: 11/17/2023]
Abstract
Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD-1 therapy resistance in patients with KRAS-driven lung adenocarcinoma (LUAD). The molecular mechanisms governing this observation remain unclear and represent a critical outstanding question in the field of lung oncology. As an initial approach to understand this phenomenon, we knocked-out (KO) STK11 in multiple KRAS-driven, STK11-competent human LUAD cell lines and performed whole transcriptome analyses to identify STK11-loss-dependent differential gene expression. Subsequent pathway enrichment studies highlighted activation of the HIPPO/YAP1 signaling axis, along with the induction of numerous tumor-intrinsic cytokines. To validate that YAP1-mediated transcriptional activation occurs in response to STK11 loss, we pursued YAP1 perturbation as a strategy to restore an STK11-competent gene expression profile in STK11-KO LUAD cell lines. Together, our data link STK11 loss with YAP1-mediated transcriptional activation, including the upregulation of immune-evasion promoting cytokines IL-6, CXCL8 and CXCL2. Further, our results raise the intriguing possibility that YAP1 antagonism may represent a therapeutic approach to counter anti-PD-1 therapy resistance in STK11-null, KRAS-driven LUADs by modulating tumor-intrinsic gene expression to promote a "hot" tumor immune microenvironment.
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Affiliation(s)
- Sean M Lenahan
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Hailey M Sarausky
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Paula Deming
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA
- University of Vermont Cancer Center, Burlington, VT, USA
| | - David J Seward
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
- University of Vermont Cancer Center, Burlington, VT, USA.
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10
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Tan I, Xu S, Huo J, Huang Y, Lim HH, Lam KP. Identification of a novel mitochondria-localized LKB1 variant required for the regulation of the oxidative stress response. J Biol Chem 2023; 299:104906. [PMID: 37302555 PMCID: PMC10404683 DOI: 10.1016/j.jbc.2023.104906] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/13/2023] Open
Abstract
The tumor suppressor Liver Kinase B1 (LKB1) is a multifunctional serine/threonine protein kinase that regulates cell metabolism, polarity, and growth and is associated with Peutz-Jeghers Syndrome and cancer predisposition. The LKB1 gene comprises 10 exons and 9 introns. Three spliced LKB1 variants have been documented, and they reside mainly in the cytoplasm, although two possess a nuclear-localization sequence (NLS) and are able to shuttle into the nucleus. Here, we report the identification of a fourth and novel LKB1 isoform that is, interestingly, targeted to the mitochondria. We show that this mitochondria-localized LKB1 (mLKB1) is generated from alternative splicing in the 5' region of the transcript and translated from an alternative initiation codon encoded by a previously unknown exon 1b (131 bp) hidden within the long intron 1 of LKB1 gene. We found by replacing the N-terminal NLS of the canonical LKB1 isoform, the N-terminus of the alternatively spliced mLKB1 variant encodes a mitochondrial transit peptide that allows it to localize to the mitochondria. We further demonstrate that mLKB1 colocalizes histologically with mitochondria-resident ATP Synthase and NAD-dependent deacetylase sirtuin-3, mitochondrial (SIRT3) and that its expression is rapidly and transiently upregulated by oxidative stress. We conclude that this novel LKB1 isoform, mLKB1, plays a critical role in regulating mitochondrial metabolic activity and oxidative stress response.
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Affiliation(s)
- Ivan Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Shengli Xu
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jianxin Huo
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Yuhan Huang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore
| | - Hong-Hwa Lim
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
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11
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Ke P, Zhu Q, Xu T, Yang X, Wang Y, Qiu H, Wu D, Bao X, Chen S. Identification and validation of a 7-genes prognostic signature for adult acute myeloid leukemia based on aging-related genes. Aging (Albany NY) 2023; 15:5826-5853. [PMID: 37367950 PMCID: PMC10333094 DOI: 10.18632/aging.204843] [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: 03/31/2023] [Accepted: 06/10/2023] [Indexed: 06/28/2023]
Abstract
To explore effects of aging-related genes (ARGs) on the prognosis of Acute Myeloid Leukemia (AML), a seven-ARGs signature was developed and validated in AML patients. The numbers of seven-ARG sequences were selected to construct the survival prognostic signature in TCGA-LAML cohort, and two GEO datasets were used independently to verify the prognostic values of signature. According to seven-ARGs signature, patients were categorized into two subgroups. Patients with high-risk prognostic score were defined as HRPS-group/high-risk group, while others were set as LRPS-group/low-risk group. HRPS-group presented adverse overall survival (OS) than LRPS-group in TCGA-AML cohort (HR=3.39, P<0.001). In validation, the results emphasized a satisfactory discrimination in different time points, and confirmed the poor OS of HRPS-group both in GSE37642 (HR=1.96, P=0.001) and GSE106291 (HR=1.88, P<0.001). Many signal pathways, including immune- and tumor-related processes, especially NF-κB signaling, were highly enriched in HRPS-group. Coupled with high immune-inflamed infiltration, the HRPS-group was highly associated with the driver gene and oncogenic signaling pathway of TP53. Prediction of blockade therapy targeting immune checkpoint indicated varied benefits base on the different ARGs signature score, and the results of predicted drug response suggested that Pevonedistat, an inhibitor of NEDD8-activating enzyme, targeting NF-κB signaling, may have potential therapeutic value for HRPS-group. Compared with clinical factors alone, the signature had an independent value and more predictive power of AML prognosis. The 7-ARGs signature may help to guide clinical-decision making to predict drug response, and survival in AML patients.
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Affiliation(s)
- Peng Ke
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Qian Zhu
- Soochow Hopes Hematonosis Hospital, Suzhou, China
| | - Ting Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiaofei Yang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ying Wang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Huiying Qiu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiebing Bao
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Suning Chen
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
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12
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Baba SK, Baba SK, Mir R, Elfaki I, Algehainy N, Ullah MF, Barnawi J, Altemani FH, Alanazi M, Mustafa SK, Masoodi T, Akil ASA, Bhat AA, Macha MA. Long non-coding RNAs modulate tumor microenvironment to promote metastasis: novel avenue for therapeutic intervention. Front Cell Dev Biol 2023; 11:1164301. [PMID: 37384249 PMCID: PMC10299194 DOI: 10.3389/fcell.2023.1164301] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
Cancer is a devastating disease and the primary cause of morbidity and mortality worldwide, with cancer metastasis responsible for 90% of cancer-related deaths. Cancer metastasis is a multistep process characterized by spreading of cancer cells from the primary tumor and acquiring molecular and phenotypic changes that enable them to expand and colonize in distant organs. Despite recent advancements, the underlying molecular mechanism(s) of cancer metastasis is limited and requires further exploration. In addition to genetic alterations, epigenetic changes have been demonstrated to play an important role in the development of cancer metastasis. Long non-coding RNAs (lncRNAs) are considered one of the most critical epigenetic regulators. By regulating signaling pathways and acting as decoys, guides, and scaffolds, they modulate key molecules in every step of cancer metastasis such as dissemination of carcinoma cells, intravascular transit, and metastatic colonization. Gaining a good knowledge of the detailed molecular basis underlying lncRNAs regulating cancer metastasis may provide previously unknown therapeutic and diagnostic lncRNAs for patients with metastatic disease. In this review, we concentrate on the molecular mechanisms underlying lncRNAs in the regulation of cancer metastasis, the cross-talk with metabolic reprogramming, modulating cancer cell anoikis resistance, influencing metastatic microenvironment, and the interaction with pre-metastatic niche formation. In addition, we also discuss the clinical utility and therapeutic potential of lncRNAs for cancer treatment. Finally, we also represent areas for future research in this rapidly developing field.
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Affiliation(s)
- Sana Khurshid Baba
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, India
| | - Sadaf Khursheed Baba
- Department of Microbiology, Sher-I-Kashmir Institute of Medical Science (SKIMS), Soura, Kashmir, India
| | - Rashid Mir
- Department of Medical Lab Technology, Prince Fahd Bin Sultan Research Chair Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Naseh Algehainy
- Department of Medical Lab Technology, Prince Fahd Bin Sultan Research Chair Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Fahad Ullah
- Department of Medical Lab Technology, Prince Fahd Bin Sultan Research Chair Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Jameel Barnawi
- Department of Medical Lab Technology, Prince Fahd Bin Sultan Research Chair Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Faisal H. Altemani
- Department of Medical Lab Technology, Prince Fahd Bin Sultan Research Chair Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Alanazi
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Syed Khalid Mustafa
- Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia
| | - Tariq Masoodi
- Human Immunology Department, Research Branch, Sidra Medicine, Doha, Qatar
| | - Ammira S. Alshabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity, and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Ajaz A. Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity, and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Muzafar A. Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, India
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13
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Ishitsuka K, Yoshizawa Y, Nishikii H, Kusakabe M, Ito Y, Inadome Y, Sakamoto T, Kato T, Kurita N, Yokoyama Y, Obara N, Hasegawa Y, Nannya Y, Ogawa S, Sakata-Yanagimoto M, Chiba S. Novel translocation of POGZ/ STK11 in de novo mast cell leukemia with KIT D816H mutation. Leuk Lymphoma 2022; 63:3475-3479. [PMID: 36126964 DOI: 10.1080/10428194.2022.2123235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Kantaro Ishitsuka
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan
| | - Yuki Yoshizawa
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan
| | - Hidekazu Nishikii
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Manabu Kusakabe
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yufu Ito
- Department of Hematology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan
| | - Yukinori Inadome
- Department of Pathology, National Hospital Organization Mito Medical Center, Ibaraki, Japan
| | - Tatsuhiro Sakamoto
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Takayasu Kato
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Naoki Kurita
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yasuhisa Yokoyama
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Naoshi Obara
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yuichi Hasegawa
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yasuhito Nannya
- Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.,Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan
| | - Mamiko Sakata-Yanagimoto
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Shigeru Chiba
- Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan.,Department of Hematology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
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14
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González-Moles MÁ, Keim-del Pino C, Ramos-García P. Hallmarks of Cancer Expression in Oral Lichen Planus: A Scoping Review of Systematic Reviews and Meta-Analyses. Int J Mol Sci 2022; 23:13099. [PMID: 36361889 PMCID: PMC9658487 DOI: 10.3390/ijms232113099] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 09/05/2023] Open
Abstract
Oral lichen planus (OLP) is a common chronic inflammatory disease of unknown etiology and likely autoimmune nature that is currently considered an oral potentially malignant disorder, implying that patients suffering from this process are at risk of developing oral cancer in their lifetime. The molecular alterations that develop in OLP and that make the affected oral epithelium predisposed to malignancy are unknown, although, as in other autoimmune diseases (ulcerative colitis, primary biliary cirrhosis, etc.), they may be linked to oncogenesis-promoting effects mediated by the inflammatory infiltrate. So far there is no in-depth knowledge on how these hallmarks of cancer are established in the cells of the oral epithelium affected by OLP. In this scoping review of systematic reviews and meta-analyses the state of evidence based knowledge in this field is presented, to point out gaps of evidence and to indicate future lines of research. MEDLINE, Embase, Cochrane Library and Dare were searched for secondary-level studies published before October 2022. The results identified 20 systematic reviews and meta-analyses critically appraising the hallmarks tumor-promoting inflammation (n = 17, 85%), sustaining proliferative signaling (n = 2, 10%), and evading growth suppressors (n = 1, 5%). No evidence was found for the other hallmarks of cancer in OLP. In conclusion, OLP malignization hypothetically derives from the aggressions of the inflammatory infiltrate and a particular type of epithelial response based on increased epithelial proliferation, evasion of growth-suppressive signals and lack of apoptosis. Future evidence-based research is required to support this hypothesis.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Carmen Keim-del Pino
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18071 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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15
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lncRNAs: Key Regulators of Signaling Pathways in Tumor Glycolysis. DISEASE MARKERS 2022; 2022:2267963. [PMID: 36124026 PMCID: PMC9482549 DOI: 10.1155/2022/2267963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 12/01/2022]
Abstract
In response to overstimulation of growth factor signaling, tumor cells can reprogram their metabolism to preferentially utilize and metabolize glucose to lactate even in the presence of abundant oxygen, which is termed the “Warburg effect” or aerobic glycolysis. Long noncoding RNAs (lncRNAs) are a group of transcripts longer than 200 nucleotides and do not encode proteins. Accumulating evidence suggests that lncRNAs can affect aerobic glycolysis through multiple mechanisms, including the regulation of glycolytic transporters and key rate-limiting enzymes. In addition, maladjusted signaling pathways are critical for glycolysis. Therefore, this article mainly reviews the lncRNAs involved in the regulation of tumor glycolysis key signal pathways in recent years and provides an in-depth understanding of the role of differentially expressed lncRNAs in the key signal pathways of glucose metabolism, which may help to provide new therapeutic targets and new diagnostic and prognostic markers for human cancer.
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16
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Mohindroo C, De Jesus-Acosta A, Yurgelun MB, Maitra A, Mork M, McAllister F. The Evolving Paradigm of Germline Testing in Pancreatic Ductal Adenocarcinoma and Implications for Clinical Practice. Surg Pathol Clin 2022; 15:491-502. [PMID: 36049831 DOI: 10.1016/j.path.2022.05.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Identification of deleterious germline mutations in pancreatic ductal adenocarcinoma (PDAC) patients can have therapeutic implications for the patients and result in cascade testing and prevention in their relatives. Universal testing for germline mutations is now considered standard of care in patients with PDAC, regardless of family history, personal history, or age. Here, we highlight the commonly identified germline mutations in PDAC patients as well as the impact of multigene panel testing. We further discuss therapeutic implications of germline testing on the index cases, and the impact of cascade testing on cancer early detection and prevention in relatives.
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Affiliation(s)
- Chirayu Mohindroo
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Department of Internal Medicine, Sinai Hospital of Baltimore, 2435 W. Belvedere Ave, Ste 56, Baltimore, MD 21215, USA
| | - Ana De Jesus-Acosta
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 401 North Broadway, Baltimore, MD 21231, USA
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - Anirban Maitra
- Department of Translational Molecular Pathology, Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Boulevard, Houston, TX 77030, USA
| | - Maureen Mork
- Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA
| | - Florencia McAllister
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Unit 1360, Houston, TX 77030, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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17
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Prakasam G, Iqbal MA, Srivastava A, Bamezai RNK, Singh RK. HPV18 oncoproteins driven expression of PKM2 reprograms HeLa cell metabolism to maintain aerobic glycolysis and viability. Virusdisease 2022; 33:223-235. [PMID: 36277414 PMCID: PMC9481809 DOI: 10.1007/s13337-022-00776-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/21/2022] [Indexed: 11/30/2022] Open
Abstract
The molecular basis of human papillomavirus (HPV)-mediated cellular immortalization and malignant transformation has illustrated an indispensable role of viral E6/E7-oncoproteins. However, the impact of viral-oncoproteins on the metabolic phenotype of cancer cells remains ambiguous. We showed silencing of HPV18-encoded E6/E7-oncoprotein significantly reduced glucose consumption, lactate production, ATP level and viability. Silencing of HPV18-encoded E6/E7 in HeLa cells significantly down-regulated expression and activity of HK1, HK2, LDHA, and LDHB. Interestingly, there was an increased pyruvate kinase activity due to switch in expression from PKM2 isoform to PKM1. The switch in favor of alternatively spliced isoform PKM1, was regulated by viral-E6/E7-oncoprotein by inhibiting the c-Myc/hnRNP-axis. Further, the near absence of the PKM1 protein despite an adequate amount of PKM1 mRNA in HeLa cells was due to its proteasomal degradation. Our results suggests HPV18-encoded E6/E7 driven preferential expression of PKM2 is essential to support aerobic glycolysis and cell proliferation. Supplementary Information The online version contains supplementary material available at 10.1007/s13337-022-00776-w.
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Affiliation(s)
- Gopinath Prakasam
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India
| | - Mohammad Askandar Iqbal
- Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, 110025 India
| | - Anusha Srivastava
- Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005 India
| | - Rameshwar N. K. Bamezai
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India
- Delhi School of Public Health, University of Delhi, New Delhi, 110007 India
| | - Rajnish Kumar Singh
- Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005 India
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18
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González-Moles MÁ, Warnakulasuriya S, López-Ansio M, Ramos-García P. Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews. Cancers (Basel) 2022; 14:3834. [PMID: 35954497 PMCID: PMC9367256 DOI: 10.3390/cancers14153834] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 02/07/2023] Open
Abstract
In 2000 and 2011, Hanahan and Weinberg published two papers in which they defined the characteristics that cells must fulfil in order to be considered neoplastic cells in all types of tumours that affect humans, which the authors called "hallmarks of cancer". These papers have represented a milestone in our understanding of the biology of many types of cancers and have made it possible to reach high levels of scientific evidence in relation to the prognostic impact that these hallmarks have on different tumour types. However, to date, there is no study that globally analyses evidence-based knowledge on the importance of these hallmarks in oral and oropharyngeal squamous cell carcinomas. For this reason, we set out to conduct this scoping review of systematic reviews with the aim of detecting evidence gaps in relation to the relevance of the cancer hallmarks proposed by Hanahan and Weinberg in oral and oropharyngeal cancer, and oral potentially malignant disorders, and to point out future lines of research in this field.
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Affiliation(s)
- Miguel Ángel González-Moles
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Saman Warnakulasuriya
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
- WHO Collaborating for Oral Cancer, King’s College London, London SE1 9RT, UK
| | - María López-Ansio
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
| | - Pablo Ramos-García
- School of Dentistry, University of Granada, 18011 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain
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19
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Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis. Cancers (Basel) 2022; 14:cancers14030628. [PMID: 35158896 PMCID: PMC8833640 DOI: 10.3390/cancers14030628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/22/2022] [Accepted: 01/23/2022] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Familiarity with nonmalignant features and comorbidities of cancer predisposition syndromes may raise awareness and assist clinicians in the diagnosis and interpretation of molecular test results. Genetic predisposition to colorectal cancer (CRC) should be suspected mainly in young patients, in patients with significant family histories, multiple polyps, mismatch repair-deficient tumors, and in association with malignant or nonmalignant comorbidities. The aim of this review is to describe the main nonmalignant comorbidities associated with selected CRC predisposition syndromes that may serve as valuable diagnostic clues for clinicians and genetic professionals. Abstract Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-β, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation.
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20
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Pascale RM, Simile MM, Calvisi DF, Feo CF, Feo F. S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent. Cells 2022; 11:409. [PMID: 35159219 PMCID: PMC8834208 DOI: 10.3390/cells11030409] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/10/2022] [Accepted: 01/14/2022] [Indexed: 02/07/2023] Open
Abstract
Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcinoma and MCF-7 breast cancer cells. SAM plus Decitabine arrest cancer growth and potentiate doxorubicin effects on breast, head, and neck cancers. Furthermore, SAM enhances the antitumor effect of gemcitabine against pancreatic cancer cells, inhibits growth of human prostate cancer PC-3, colorectal cancer, and osteosarcoma LM-7 and MG-63 cell lines; increases genomic stability of SW480 cells. SAM reduces colorectal cancer progression and inhibits the proliferation of preneoplastic rat liver cells in vivo. The discrepancy between positive results of SAM treatment of experimental tumors and modest effects against human disease may depend on more advanced human disease stage at moment of diagnosis.
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Affiliation(s)
- Rosa M. Pascale
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Maria M. Simile
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Diego F. Calvisi
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
| | - Claudio F. Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Surgery, University of Sassari, 07100 Sassari, Italy;
| | - Francesco Feo
- Department of Medical, Surgical and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy; (M.M.S.); (D.F.C.); (F.F.)
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21
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Sumbly V, Landry I. Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer. Cureus 2022; 14:e21078. [PMID: 35165542 PMCID: PMC8826623 DOI: 10.7759/cureus.21078] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2022] [Indexed: 12/25/2022] Open
Abstract
There are two major groups of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLCs can be further separated into three different categories: lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Pulmonary adenocarcinomas represent nearly half of all lung cancer cases and are known to be caused by smoking, certain occupational exposures, and specific genetic mutations. Scientists have noticed that most NSCLCs are driven by defects in the following genes: EGFR, BRAF, ALK, MET, and HER. Abnormalities in the STK11/LKB1 gene have also been shown to induce lung adenocarcinoma. LKB1-deficient cancer cells contain an overactive AMPK “energy sensor,” which inhibits cellular death and promotes glucose, lipid, and protein synthesis via the mTOR protein complex. Studies have also discovered that the loss of STK11/LKB1 favors oncogenesis by creating an immunosuppressive environment for tumors to grow and accelerate events such as angiogenesis, epithelial-mesenchymal transition (EMT), and cell polarity destabilization. STK11/LKB1-mutant lung cancers are currently treated with radiotherapy with or without chemotherapy. Recent clinical trials studying the effects of glutaminase inhibitors, mTOR inhibitors, and anti-PD-L1 therapy in lung cancer patients have yielded promising results. This narrative review provides an overview of the STK11/LKB1 gene and its role in cancer development. Additionally, a summary of the LKB1/APMK/mTOR is provided.
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Affiliation(s)
- Vikram Sumbly
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals/Queens, Jamaica, USA
| | - Ian Landry
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York City Health and Hospitals/Queens, Jamaica, USA
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22
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Donnelly LL, Hogan TC, Lenahan SM, Nandagopal G, Eaton JG, Lebeau MA, McCann CL, Sarausky HM, Hampel KJ, Armstrong JD, Cameron MP, Sidiropoulos N, Deming P, Seward DJ. Functional assessment of somatic STK11 variants identified in primary human non-small cell lung cancers. Carcinogenesis 2021; 42:1428-1438. [PMID: 34849607 PMCID: PMC8727739 DOI: 10.1093/carcin/bgab104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/13/2021] [Accepted: 10/26/2021] [Indexed: 12/31/2022] Open
Abstract
Serine/Threonine Kinase 11 (STK11) encodes an important tumor suppressor that is frequently mutated in lung adenocarcinoma. Clinical studies have shown that mutations in STK11 resulting in loss of function correlate with resistance to anti-PD-1 monoclonal antibody therapy in KRAS-driven non-small cell lung cancer (NSCLC), but the molecular mechanisms responsible remain unclear. Despite this uncertainty, STK11 functional status is emerging as a reliable biomarker for predicting non-response to anti-PD-1 therapy in NSCLC patients. The clinical utility of this biomarker ultimately depends upon accurate classification of STK11 variants. For nonsense variants occurring early in the STK11 coding region, this assessment is straightforward. However, rigorously demonstrating the functional impact of missense variants remains an unmet challenge. Here we present data characterizing four STK11 splice-site variants by analyzing tumor mRNA, and 28 STK11 missense variants using an in vitro kinase assay combined with a cell-based p53-dependent luciferase reporter assay. The variants we report were identified in primary human NSCLC biopsies in collaboration with the University of Vermont Genomic Medicine group. Additionally, we compare our experimental results with data from 22 in silico predictive algorithms. Our work highlights the power, utility and necessity of functional variant assessment and will aid STK11 variant curation, provide a platform to assess novel STK11 variants and help guide anti-PD-1 therapy utilization in KRAS-driven NSCLCs.
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Affiliation(s)
- Liam L Donnelly
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Tyler C Hogan
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA
| | - Sean M Lenahan
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Gopika Nandagopal
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA
| | - Jenna G Eaton
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA
| | - Meagan A Lebeau
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA
| | | | - Hailey M Sarausky
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Kenneth J Hampel
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Jordan D Armstrong
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Margaret P Cameron
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA
| | - Nikoletta Sidiropoulos
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.,University of Vermont Cancer Center, Burlington, VT, USA
| | - Paula Deming
- Department of Biomedical and Health Sciences, University of Vermont College of Nursing and Health Sciences, Burlington, VT, USA.,University of Vermont Cancer Center, Burlington, VT, USA
| | - David J Seward
- Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.,University of Vermont Cancer Center, Burlington, VT, USA
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23
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Abstract
STK11 encodes for the protein liver kinase B1, a serine/threonine kinase which is involved in a number of physiological processes including regulation of cellular metabolism, cell polarity and the DNA damage response. It acts as a tumour suppressor via multiple mechanisms, most classically through AMP-activated protein kinase-mediated inhibition of the mammalian target of rapamycin signalling pathway. Germline loss-of-function mutations in STK11 give rise to Peutz-Jeghers syndrome, which is associated with hamartomatous polyps of the gastrointestinal tract, mucocutaneous pigmentation and a substantially increased lifetime risk of many cancers. In the sporadic setting, STK11 mutations are commonly seen in a subset of adenocarcinomas of the lung in addition to a number of other tumours occurring at various sites. Mutations in STK11 have been associated with worse prognoses across a range of malignancies and may be a predictor of poor response to immunotherapy in a subset of lung cancers, though further studies are needed before the presence of STK11 mutations can be implemented as a routine clinical biomarker.
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Affiliation(s)
- Roman E Zyla
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Elan Hahn
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Anatomic Pathology, University Health Network, Toronto, Ontario, Canada
| | - Anjelica Hodgson
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Anatomic Pathology, University Health Network, Toronto, Ontario, Canada
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24
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Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19. Int J Mol Sci 2021; 22:ijms22158180. [PMID: 34360945 PMCID: PMC8347486 DOI: 10.3390/ijms22158180] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 07/24/2021] [Accepted: 07/24/2021] [Indexed: 01/05/2023] Open
Abstract
Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.
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25
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Huang P, Zhu S, Liang X, Zhang Q, Luo X, Liu C, Song L. Regulatory Mechanisms of LncRNAs in Cancer Glycolysis: Facts and Perspectives. Cancer Manag Res 2021; 13:5317-5336. [PMID: 34262341 PMCID: PMC8275123 DOI: 10.2147/cmar.s314502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/19/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer cells exhibit distinct metabolic characteristics that employ glycolysis to provide energy and intermediary metabolites. This aberrant metabolic phenotype favors cancer progression. LncRNAs are transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs contribute to cancer progression and therapeutic resistance and affect aerobic glycolysis via multiple mechanisms, including modulating glycolytic transporters and enzymes. Further, dysregulated signaling pathways are vital for glycolysis. In this review, we highlight regulatory mechanisms for lncRNAs in aerobic glycolysis that provide novel insights into cancer development. Moreover, a comprehensive understanding of the regulatory mechanisms of lncRNAs in aerobic glycolysis can provide new strategies for clinical cancer management.
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Affiliation(s)
- Peng Huang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Shaomi Zhu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Xin Liang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Qinxiu Zhang
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Xiaohong Luo
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Chi Liu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
| | - Linjiang Song
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, People's Republic of China
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26
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Eibl G, Rozengurt E. Metformin: review of epidemiology and mechanisms of action in pancreatic cancer. Cancer Metastasis Rev 2021; 40:865-878. [PMID: 34142285 DOI: 10.1007/s10555-021-09977-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 05/27/2021] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma continues to be a lethal disease, for which efficient treatment options are very limited. Increasing efforts have been taken to understand how to prevent or intercept this disease at an early stage. There is convincing evidence from epidemiologic and preclinical studies that the antidiabetic drug metformin possesses beneficial effects in pancreatic cancer, including reducing the risk of developing the disease and improving survival in patients with early-stage disease. This review will summarize the current literature about the epidemiological data on metformin and pancreatic cancer as well as describe the preclinical evidence illustrating the anticancer effects of metformin in pancreatic cancer. Underlying mechanisms and targets of metformin will also be discussed. These include direct effects on transformed pancreatic epithelial cells and indirect, systemic effects on extra-pancreatic tissues.
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Affiliation(s)
- Guido Eibl
- Department of Surgery, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA.
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine At UCLA, Los Angeles, CA, USA
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27
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Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles. Cells 2021; 10:cells10061491. [PMID: 34199299 PMCID: PMC8231864 DOI: 10.3390/cells10061491] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/14/2022] Open
Abstract
The mammalian ovary has two main functions-producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation.
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28
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Koenig MJ, Agana BA, Kaufman JM, Sharpnack MF, Wang WZ, Weigel C, Navarro FCP, Amann JM, Cacciato N, Arasada RR, Gerstein MB, Wysocki VH, Oakes C, Carbone DP. STK11/LKB1 Loss of Function Is Associated with Global DNA Hypomethylation and S-Adenosyl-Methionine Depletion in Human Lung Adenocarcinoma. Cancer Res 2021; 81:4194-4204. [PMID: 34045189 DOI: 10.1158/0008-5472.can-20-3199] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/14/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022]
Abstract
STK11 (liver kinase B1, LKB1) is the fourth most frequently mutated gene in lung adenocarcinoma, with loss of function observed in up to 30% of all cases. Our previous work identified a 16-gene signature for LKB1 loss of function through mutational and nonmutational mechanisms. In this study, we applied this genetic signature to The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples and discovered a novel association between LKB1 loss and widespread DNA demethylation. LKB1-deficient tumors showed depletion of S-adenosyl-methionine (SAM-e), which is the primary substrate for DNMT1 activity. Lower methylation following LKB1 loss involved repetitive elements (RE) and altered RE transcription, as well as decreased sensitivity to azacytidine. Demethylated CpGs were enriched for FOXA family consensus binding sites, and nuclear expression, localization, and turnover of FOXA was dependent upon LKB1. Overall, these findings demonstrate that a large number of lung adenocarcinomas exhibit global hypomethylation driven by LKB1 loss, which has implications for both epigenetic therapy and immunotherapy in these cancers. SIGNIFICANCE: Lung adenocarcinomas with LKB1 loss demonstrate global genomic hypomethylation associated with depletion of SAM-e, reduced expression of DNMT1, and increased transcription of repetitive elements.
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Affiliation(s)
- Michael J Koenig
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
| | - Bernice A Agana
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio
| | - Jacob M Kaufman
- Department of Medicine, Duke University, Durham, North Carolina
| | | | - Walter Z Wang
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Christoph Weigel
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Fabio C P Navarro
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.,Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut
| | - Joseph M Amann
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Nicole Cacciato
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | | | - Mark B Gerstein
- Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut.,Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut.,Department of Computer Science, Yale University, New Haven, Connecticut
| | - Vicki H Wysocki
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio
| | - Christopher Oakes
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - David P Carbone
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
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29
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Yamamoto M, Iwamoto K, Suzuki R, Mukai Y, Takeoka T, Asukai K, Shinno N, Hara H, Kanemura T, Nakai N, Hasegawa S, Sugimura K, Haraguchi N, Nishimura J, Wada H, Takahashi H, Matsuda C, Yasui M, Omori T, Miyata H, Ohue M, Murata M. Laparoscopic-assisted disinvagination and polypectomy for multiple intussusceptions induced by small intestinal polyps in patients with Peutz-Jeghers syndrome: a case report. World J Surg Oncol 2021; 19:22. [PMID: 33478478 PMCID: PMC7819471 DOI: 10.1186/s12957-021-02133-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 01/13/2021] [Indexed: 11/17/2022] Open
Abstract
Background Peutz–Jeghers syndrome (PJS) is a very rare autosomal dominant genetic disorder characterized by hamartomatous polyps in the gastrointestinal tract and hyperpigmentation of the lips, hands, and feet. The hamartomatous polyps in the small intestine often cause intussusception and bleeding. Case presentation A 62-year-old male was hospitalized for treatment of deep vein thrombosis and pulmonary embolism. In the small intestine, computed tomography showed three small polyps with intussusceptions. Since the patient had gastrointestinal polyposis and pigmentation of his lips, fingers, and toes, he was diagnosed with PJS. After an inferior vena cava filter was placed, he underwent laparoscopic-assisted surgery. The polyps causing intussusception were resected as far as possible without intestinal resection, since they had caused progressive anemia and might cause intestinal obstruction in the future. The patient was discharged from the hospital on postoperative day 9 without complications. Conclusions Laparoscopic-assisted disinvagination and polypectomy is a useful, minimally invasive treatment for multiple intussusceptions caused by small intestinal polyps in patients with PJS. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02133-5.
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Affiliation(s)
- Masaaki Yamamoto
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan. .,Department of Surgery, JCHO Hoshigaoka Medical Center, 4-8-1, Hoshigaoka, Hirakata, Osaka, 573-8511, Japan.
| | - Kazuya Iwamoto
- Department of Surgery, JCHO Hoshigaoka Medical Center, 4-8-1, Hoshigaoka, Hirakata, Osaka, 573-8511, Japan.,Department of Surgery, Osaka Police Hospital, Kitayama-cho 10-31, Tennozi-ku, Osaka, 543-0035, Japan
| | - Rei Suzuki
- Department of Surgery, JCHO Hoshigaoka Medical Center, 4-8-1, Hoshigaoka, Hirakata, Osaka, 573-8511, Japan
| | - Yosuke Mukai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Tomohira Takeoka
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Kei Asukai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Naoki Shinno
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hisashi Hara
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Takashi Kanemura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Nozomu Nakai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Shinichiro Hasegawa
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Keijiro Sugimura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masayoshi Yasui
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Takeshi Omori
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masayuki Ohue
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masaru Murata
- Department of Surgery, JCHO Hoshigaoka Medical Center, 4-8-1, Hoshigaoka, Hirakata, Osaka, 573-8511, Japan
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30
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Pavan A, Bragadin AB, Calvetti L, Ferro A, Zulato E, Attili I, Nardo G, Dal Maso A, Frega S, Menin AG, Fassan M, Calabrese F, Pasello G, Guarneri V, Aprile G, Conte P, Rosell R, Indraccolo S, Bonanno L. Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome. Transl Lung Cancer Res 2021; 10:202-220. [PMID: 33569305 PMCID: PMC7867770 DOI: 10.21037/tlcr-20-674] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 11/12/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs). METHODS Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360® test, and MAGIC (Monitoring Advanced NSCLC through plasma Genotyping during Immunotherapy: Clinical feasibility and application), using Myriapod NGS-IL 56G Assay. A control group of patients not receiving ICIs was analyzed. RESULTS A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role. CONCLUSIONS Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.
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Affiliation(s)
- Alberto Pavan
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Andrea Boscolo Bragadin
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Lorenzo Calvetti
- Department of Oncology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy
| | - Alessandra Ferro
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Elisabetta Zulato
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Ilaria Attili
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Giorgia Nardo
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Alessandro Dal Maso
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Stefano Frega
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Andrea Giovanni Menin
- Department of Pathology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy
| | - Matteo Fassan
- Department of Medicine, Surgical Pathology and Cytopathology Unit, Università degli Studi di Padova, Padova, Italy
| | - Fiorella Calabrese
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Università degli Studi di Padova, Padova, Italy
| | - Giulia Pasello
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Valentina Guarneri
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, ULSS8 Berica - East District, Vicenza, Italy
| | - PierFranco Conte
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, Padova, Italy
| | - Rafael Rosell
- Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Germans Trias I Pujol Health Sciences Institute and Hospital Badalona, Barcelona, Spain
| | - Stefano Indraccolo
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Laura Bonanno
- Medical Oncology 2, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
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Jin LY, Zhao K, Xu LJ, Zhao RX, Werle KD, Wang Y, Liu XL, Chen Q, Wu ZJ, Zhang K, Zhao Y, Jiang GQ, Cui FM, Xu ZX. LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin. Aging (Albany NY) 2020; 12:14341-14354. [PMID: 32668413 PMCID: PMC7425461 DOI: 10.18632/aging.103473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/17/2020] [Indexed: 01/25/2023]
Abstract
Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.
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Affiliation(s)
- Li-Yan Jin
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.,Department of General Surgery, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Kui Zhao
- Department of General Surgery, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Long-Jiang Xu
- Department of Pathology, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Rui-Xun Zhao
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kaitlin D Werle
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yong Wang
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Xiao-Long Liu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.,Department of Urology, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Qiu Chen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Zhuo-Jun Wu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Ke Zhang
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Ying Zhao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
| | - Guo-Qin Jiang
- Department of General Surgery, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
| | - Feng-Mei Cui
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.,Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province 475004, China.,Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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32
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Li Z, Sun X. Non-Coding RNAs Operate in the Crosstalk Between Cancer Metabolic Reprogramming and Metastasis. Front Oncol 2020; 10:810. [PMID: 32547948 PMCID: PMC7273922 DOI: 10.3389/fonc.2020.00810] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/24/2020] [Indexed: 01/10/2023] Open
Abstract
Metastasis, the spread of cancer cells from a primary tumor to a secondary site, represents one of the hallmarks of malignancies and the leading cause of cancer-related death. The process of metastasis is a result of the interaction of genetic heterogeneity, abnormal metabolism, and tumor microenvironments. On the other hand, metabolic reprogramming, another malignancy hallmark, refers to the ability of cancer cells to alter metabolic and nutrient acquisition modes in order to support the energy demands for accomplishing the rapid growth, dissemination, and colonization. Cancer cells remodel metabolic patterns to supplement nutrients for their metastasis and also undergo metabolic adjustments at different stages of metastasis. Genes and signaling pathways involved in tumor metabolic reprogramming crosstalk with those participating in metastasis. Non-coding RNAs are a group of RNA molecules that do not code proteins but have pivotal biological functions. Some of microRNAs and lncRNAs, which are the two most extensively studied non-coding RNAs, have been identified to participate in regulating metabolic remodeling of glucose, lipid, glutamine, oxidative phosphorylation, and mitochondrial respiration, as well as the process of metastasis involving cell motility, transit in the circulation and growth at a new site. This article reviews recent progress on non-coding RNAs operating in the crosstalk between tumor metabolic reprogramming and metastasis, particularly those influencing metastasis through regulating metabolism, and the underlying mechanisms of how they exert their regulatory functions.
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Affiliation(s)
- Ziyi Li
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xueying Sun
- The Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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Fatehi Hassanabad A. Current perspectives on statins as potential anti-cancer therapeutics: clinical outcomes and underlying molecular mechanisms. Transl Lung Cancer Res 2019; 8:692-699. [PMID: 31737505 DOI: 10.21037/tlcr.2019.09.08] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins have been shown to inhibit cell proliferation in vitro and tumor growth in animal models. Various studies have also shown a decreased cancer-specific mortality rate in patients who were prescribed these medications. Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway. Statins induce tumour-specific apoptosis through mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate (GGPP) biosynthesis. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Several studies have been conducted to further assess the association between statin use and mortality in different types of cancer. In this review, current perspectives on clinical significance of statins in prevention and treatment of various types of cancers and proposed mechanisms are discussed.
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Radu AG, Torch S, Fauvelle F, Pernet-Gallay K, Lucas A, Blervaque R, Delmas V, Schlattner U, Lafanechère L, Hainaut P, Tricaud N, Pingault V, Bondurand N, Bardeesy N, Larue L, Thibert C, Billaud M. LKB1 specifies neural crest cell fates through pyruvate-alanine cycling. SCIENCE ADVANCES 2019; 5:eaau5106. [PMID: 31328154 PMCID: PMC6636984 DOI: 10.1126/sciadv.aau5106] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 06/10/2019] [Indexed: 05/08/2023]
Abstract
Metabolic processes underlying the development of the neural crest, an embryonic population of multipotent migratory cells, are poorly understood. Here, we report that conditional ablation of the Lkb1 tumor suppressor kinase in mouse neural crest stem cells led to intestinal pseudo-obstruction and hind limb paralysis. This phenotype originated from a postnatal degeneration of the enteric nervous ganglia and from a defective differentiation of Schwann cells. Metabolomic profiling revealed that pyruvate-alanine conversion is enhanced in the absence of Lkb1. Mechanistically, inhibition of alanine transaminases restored glial differentiation in an mTOR-dependent manner, while increased alanine level directly inhibited the glial commitment of neural crest cells. Treatment with the metabolic modulator AICAR suppressed mTOR signaling and prevented Schwann cell and enteric defects of Lkb1 mutant mice. These data uncover a link between pyruvate-alanine cycling and the specification of glial cell fate with potential implications in the understanding of the molecular pathogenesis of neural crest diseases.
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Affiliation(s)
- Anca G. Radu
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Sakina Torch
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Florence Fauvelle
- Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France
- Univ. Grenoble Alpes, INSERM, US17, MRI facility IRMaGe, 38000 Grenoble, France
| | - Karin Pernet-Gallay
- Univ. Grenoble Alpes, INSERM, U1216, Grenoble Institute of Neurosciences GIN, 38000 Grenoble, France
| | - Anthony Lucas
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Renaud Blervaque
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Véronique Delmas
- Institut Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347; INSERM U1021; Equipe Labellisée–Ligue Nationale Contre le Cancer, Orsay, France
| | - Uwe Schlattner
- Laboratory of Fundamental and Applied Bioenergetics, Univ Grenoble Alpes, 38185 Grenoble, France
- INSERM U1055, 38041 Grenoble France
| | - Laurence Lafanechère
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Pierre Hainaut
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
| | - Nicolas Tricaud
- INSERM U1051, Institut des Neurosciences de Montpellier (INM), Université de Montpellier, Montpellier, France
| | | | | | - Nabeel Bardeesy
- Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Lionel Larue
- Institut Curie, Normal and Pathological Development of Melanocytes, CNRS UMR3347; INSERM U1021; Equipe Labellisée–Ligue Nationale Contre le Cancer, Orsay, France
| | - Chantal Thibert
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
- Corresponding author. (M.B.); (C.T.)
| | - Marc Billaud
- Institute for Advanced Biosciences, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, 38000 Grenoble, France
- “Clinical and experimental model of lymphomagenesis” Univ Lyon, Université Claude Bernard Lyon1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon France
- Corresponding author. (M.B.); (C.T.)
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Koutsioumpa M, Hatziapostolou M, Polytarchou C, Tolosa EJ, Almada LL, Mahurkar-Joshi S, Williams J, Tirado-Rodriguez B, Huerta-Yepez S, Karavias D, Kourea H, Poultsides GA, Struhl K, Dawson DW, Donahue TR, Fernandez-Zapico ME, lliopoulos D. Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming. Gut 2019; 68:1271-1286. [PMID: 30337373 PMCID: PMC6697184 DOI: 10.1136/gutjnl-2017-315690] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 09/06/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis. DESIGN DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo. RESULTS We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. KMT2D is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates. CONCLUSION Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.
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Affiliation(s)
- Marina Koutsioumpa
- Center for Systems Biomedicine, Vatche and Tamar Manoukian
Division of Digestive Diseases, David Geffen School of Medicine, University of
California at Los Angeles, Los Angeles, CA
| | - Maria Hatziapostolou
- Biological Sciences, University of Southampton,
Southampton, United Kingdom;,Biosciences, School of Science and Technology, Nottingham
Trent University, Nottingham, United Kingdom
| | - Christos Polytarchou
- Interdisciplinary Biomedical Research Centre, School of
Science and Technology, Nottingham Trent University, Nottingham, United
Kingdom
| | - Ezequiel J. Tolosa
- Schulze Center for Novel Therapeutics, Division of Oncology
Research, Mayo Clinic, Rochester, MN
| | - Luciana L. Almada
- Schulze Center for Novel Therapeutics, Division of Oncology
Research, Mayo Clinic, Rochester, MN
| | - Swapna Mahurkar-Joshi
- Center for Systems Biomedicine, Vatche and Tamar Manoukian
Division of Digestive Diseases, David Geffen School of Medicine, University of
California at Los Angeles, Los Angeles, CA
| | - Jennifer Williams
- Department of Surgery, Division of General Surgery, David
Geffen School of Medicine at University of California Los Angeles, Los Angeles,
CA
| | - Belen Tirado-Rodriguez
- Unidad de Investigacion en Enfermedades Oncologicas,
Hospital Infantil de Mexico, Mexico City, Mexico
| | - Sara Huerta-Yepez
- Unidad de Investigacion en Enfermedades Oncologicas,
Hospital Infantil de Mexico, Mexico City, Mexico
| | - Dimitrios Karavias
- Department of Pathology, School of Medicine, University of
Patras, Patras, Greece
| | - Helen Kourea
- Department of Pathology, School of Medicine, University of
Patras, Patras, Greece
| | | | - Kevin Struhl
- Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, MA
| | - David W. Dawson
- Department of Pathology and Laboratory Medicine, David
Geffen School of Medicine at University of California Los Angeles, Los Angeles,
CA
| | - Timothy R. Donahue
- Department of Surgery, Division of General Surgery, David
Geffen School of Medicine at University of California Los Angeles, Los Angeles,
CA
| | | | - Dimitrios lliopoulos
- Center for Systems Biomedicine, Vatche and Tamar Manoukian
Division of Digestive Diseases, David Geffen School of Medicine, University of
California at Los Angeles, Los Angeles, CA
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Pascale RM, Peitta G, Simile MM, Feo F. Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E296. [PMID: 31234428 PMCID: PMC6631235 DOI: 10.3390/medicina55060296] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/28/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022]
Abstract
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC.
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Affiliation(s)
- Rosa M Pascale
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Graziella Peitta
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Maria M Simile
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
| | - Francesco Feo
- Department of Clinical, Surgery and Experimental Sciences, Division of Experimental Pathology and Oncology, University of Sassari, 07100 Sassari, Italy.
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Gyurján I, Rosskopf S, Coronell JAL, Muhr D, Singer C, Weinhäusel A. IgG based immunome analyses of breast cancer patients reveal underlying signaling pathways. Oncotarget 2019; 10:3491-3505. [PMID: 31191821 PMCID: PMC6544406 DOI: 10.18632/oncotarget.26834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 03/23/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Breast cancer is the most frequent and one of the most fatal malignancies among women. Within the concept of personalized medicine, molecular characterization of tumors is usually performed by analyzing somatic mutations, RNA gene expression signatures or the proteome by mass-spectrometry. Alternatively, the immunological fingerprint of the patients can be analyzed by protein microarrays, which is able to provide another layer of molecular pathological information without invasive intervention. Results: We have investigated the immune signature of breast cancer patients and compared them with healthy controls, using protein microarray-based IgG profiling. The identified differentially reactive antigens (n=517) were further evaluated by means of various pathway analysis tools. Our results indicate that the immune signature of breast cancer patients shows a clear distinction from healthy individuals characterized by differentially reactive antigens involved in known disease relevant signaling pathways, such as VEGF, AKT/PI3K/mTOR or c-KIT, which is in close agreement with the findings from RNA-based expression profiles. Conclusion: Differential antigenic properties between breast cancer patients and healthy individual classes can be defined by serum-IgG profiling on protein microarrays. These immunome profiles provide an additional layer of molecular pathological information, which has the potential to refine and complete the systems biological map of neoplastic disease.
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Affiliation(s)
- István Gyurján
- Austrian Institute of Technology AIT, Center for Health & Environment, Molecular Diagnostics Unit, Vienna, Austria
| | - Sandra Rosskopf
- Austrian Institute of Technology AIT, Center for Health & Environment, Molecular Diagnostics Unit, Vienna, Austria
| | - Johana A Luna Coronell
- Austrian Institute of Technology AIT, Center for Health & Environment, Molecular Diagnostics Unit, Vienna, Austria
| | - Daniela Muhr
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Christian Singer
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Andreas Weinhäusel
- Austrian Institute of Technology AIT, Center for Health & Environment, Molecular Diagnostics Unit, Vienna, Austria
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Zhou S, Li Y, Qiao L, Ge Y, Huang X, Gao X, Ju H, Wang W, Zhang J, Yan J, Teng H, Jiang Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation. FASEB J 2019; 33:9476-9488. [PMID: 31091421 DOI: 10.1096/fj.201900294rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Liver serine-threonine kinase B1 (LKB1) is a tumor suppressor that has been linked to many types of tumors. However, the role of LKB1 in cartilaginous tumorigenesis is still poorly understood. In this study, we find that cartilage-specific, tamoxifen-inducible Lkb1 knockout results in multiple enchondroma-like lesions adjacent to the disorganized growth plates. We showed that chondrocytes retain an immature status caused by loss of Lkb1, which may lead to the dramatic expansion of growth-plate cartilage and the formation of enchondroma-like lesions. Additionally, increased mammalian target of rapamycin complex 1 (mTORC1) activity is observed in the Lkb1 conditional knockout (cKO) chondrocytes, and rapamycin (mTORC1 inhibitor) treatment significantly alleviates the expansion of growth-plate cartilage and eliminates the enchondroma-like lesions in Lkb1 cKO mice. Thus, our findings indicate that loss of Lkb1 leads to the expansion of chondrocytes and the formation of enchondroma-like lesions during postnatal cartilage development, and that the up-regulated mTORC1-signaling pathway is implicated in this process. Our findings suggest that modulation of LKB1 and related signaling is a potential therapy in cartilaginous tumorigenesis.-Zhou, S., Li, Y., Qiao, L., Ge, Y., Huang, X., Gao, X., Ju, H., Wang, W., Zhang, J., Yan, J., Teng, H., Jiang, Q. Inactivation of Lkb1 in postnatal chondrocytes leads to epiphyseal growth-plate abnormalities and promotes enchondroma-like formation.
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Affiliation(s)
- Sheng Zhou
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yixuan Li
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Qiao
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuxiang Ge
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | | | - Xiang Gao
- Model Animal Research Center (MARC), Nanjing, China
| | | | - Wei Wang
- Nanjing University, Nanjing, China
| | | | - Jun Yan
- Model Animal Research Center (MARC), Nanjing, China
| | - Huajian Teng
- Model Animal Research Center (MARC), Nanjing, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Model Animal Research Center (MARC), Nanjing, China
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Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World J Gastroenterol 2019; 25:1797-1816. [PMID: 31057295 PMCID: PMC6478619 DOI: 10.3748/wjg.v25.i15.1797] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/20/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
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Bonanno L, Zulato E, Pavan A, Attili I, Pasello G, Conte P, Indraccolo S. LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer. Int J Mol Sci 2019; 20:ijms20081874. [PMID: 30995715 PMCID: PMC6514929 DOI: 10.3390/ijms20081874] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/10/2019] [Accepted: 04/11/2019] [Indexed: 12/19/2022] Open
Abstract
Liver kinase B1 (LKB1) is a tumor suppressor gene whose inactivation is frequent in different tumor types, especially in lung adenocarcinoma (about 30% of cases). LKB1 has an essential role in the control of cellular redox homeostasis by regulating ROS production and detoxification. Loss of LKB1 makes the tumor cell more sensitive to oxidative stress and consequently to stress-inducing treatments, such as chemotherapy and radiotherapy. LKB1 loss triggers complex changes in tumor microenvironment, supporting a role in the regulation of angiogenesis and suggesting a potential role in the response to anti-angiogenic treatment. On the other hand, LKB1 deficiency can promote an immunosuppressive microenvironment and may be involved in primary resistance to anti-PD-1/anti-PD-L1, as it has been reported in lung cancer. The aim of this review is to discuss interactions of LKB1 with the tumor microenvironment and the potential applications of this knowledge in predicting response to treatment in lung cancer.
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Affiliation(s)
- Laura Bonanno
- Medical Oncology 2, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
| | - Elisabetta Zulato
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
| | - Alberto Pavan
- Medical Oncology 2, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, 35128 Padova, Italy.
| | - Ilaria Attili
- Medical Oncology 2, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, 35128 Padova, Italy.
| | - Giulia Pasello
- Medical Oncology 2, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
| | - PierFranco Conte
- Medical Oncology 2, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
- Department of Surgery, Oncology and Gastroenterology, Università degli Studi di Padova, 35128 Padova, Italy.
| | - Stefano Indraccolo
- Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV- IRCCS, 35128 Padova, Italy.
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Li W, Luo S, Ma G, Wang L. Impact of liver kinase B1 on p53 and survivin and its correlation with prognosis in gastric cancer. Onco Targets Ther 2019; 12:1439-1445. [PMID: 30863111 PMCID: PMC6390856 DOI: 10.2147/ott.s199138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Liver kinase B1 (LKB1) is a newly discovered tumor suppressor gene that plays a role in apoptosis induction. However, the precise impact of LKB1 expression on gastric cancer (GC) progression and its correlation with survivin and p53 in GC have not yet been elucidated. Purpose The aim of this study was to explore the significance of LKB1 expression and its correlation with p53 and survivin in GC. Patients and methods In this study, LKB1 expression was detected in GC and adjacent paracancerous tissues from 150 patients through immunohistochemical (IHC) staining. The relationship between LKB1 expression and clinical pathological factors in GC was analyzed, alongside its correlation with p53 and survivin expression. Results LKB1 expression was reduced in GC tissues compared with adjacent paracancerous tissues (P=0.001). In patients with GC, lower LKB1 expression was associated with greater invasion depth (P=0.013), higher pTNM stage (P=0.009), and lymph node metastasis (P=0.029). Furthermore, LKB1 expression in GC was inversely associated with p53 (r=-0.181, P=0.027) and survivin expression (r=-0.198, P=0.015). Kaplan-Meier analysis indicated that the expression of LKB1, p53 and survivin, as well as tumor differentiation, invasion, and pTNM and lymph node metastasis were all associated with overall survival (OS) (all P<0.05). Finally, multivariate analysis showed that LKB1 expression [hazard ratio (HR): 0.605 (0.414-0.882), P=0.009], p53 expression [hazard ratio (HR): 1.840 (1.232-2.750), P=0.003], and survivin expression [hazard ratio (HR): 1.561 (1.039-2.345), P=0.032] were all independent prognostic factors for patients with GC. Conclusion Our study suggests that LKB1 expression is reduced in GC, negatively correlated with p53 and survivin expression, and plays an important role in predicting invasion and metastasis of GC.
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Affiliation(s)
- Weiwei Li
- Department of Oncology, The First People's Hospital of Tianmen City, Hubei, China
| | - Shunxiang Luo
- Department of Oncology, The First People's Hospital of Tianmen City, Hubei, China
| | - Guowei Ma
- Department of Gastrointestinal Surgery, The First People's Hospital of Tianmen City, Hubei, China
| | - Lin Wang
- Department of Pathology, The First People's Hospital of Tianmen City, Hubei, China,
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Decreased expression of LKB1 is associated with epithelial-mesenchymal transition and led to an unfavorable prognosis in gastric cancer. Hum Pathol 2019; 83:133-139. [DOI: 10.1016/j.humpath.2018.08.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/14/2018] [Accepted: 08/16/2018] [Indexed: 12/16/2022]
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Zhang M, Li H, Zhang Y, Li H. Oncogenic miR-744 promotes prostate cancer growth through direct targeting of LKB1. Oncol Lett 2018; 17:2257-2265. [PMID: 30675291 PMCID: PMC6341651 DOI: 10.3892/ol.2018.9822] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 10/25/2018] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common malignancies worldwide, and with a limited number of treatments for this type of cancer, its incidence is rapidly increasing. Patients presenting with PCa are likely to experience disease recurrence, which represents a considerable clinical challenge. MicroRNAs (miRNAs) have been widely characterized as a critical regulator in a number of types of cancer, including PCa. miRNA-744 (miR-744) has been reported to be involved in cancer regulation; however, its role in PCa remained poorly understood. In a recent study, it was demonstrated that miR-744 was overexpressed in prostate tissue from PCa patients when compared with the surrounding tissues, and knockdown of miR-744 resulted in reduced cell growth. In addition, an increased population of apoptotic cells was detected upon miR-744 knockdown, together with a decrease in cell proliferation. Cell cycle analysis demonstrated a higher number of cells in the G1 phase and lower numbers in the S phase following miR-744 silencing. The levels of key proteins involved in cell cycle progression (cyclin D1, cyclin-dependent kinase 4, and proliferating cell nuclear antigen) were increased, whereas those proteins responsible for cell cycle inhibition (cyclin-dependent kinase inhibitor p21) were decreased. The tumor suppressor liver kinase B1 (LKB1) was revealed to be a potential target of miR-744, suggesting its potential mechanism of action. LKB1 levels were negatively correlated with miR-744, and LKB1 was indicated to be a direct target of miR-744. Furthermore, it was revealed that by targeting LKB1, miR-744 may regulate adenosine monophosphate-activated protein kinase (AMPK); the AMPK signaling pathway was activated by miR-744 knockdown, with subsequent inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. Taken together, these results demonstrated that miR-744 promoted cell growth through the AMPK signaling pathway, by targeting LKB1. The present study revealed a novel insight into the biological function of miR-744 in PCa, and that miR-744 may be a potential therapeutic target.
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Affiliation(s)
- Minglei Zhang
- Department of Orthopedics, China and Japan Union Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Hai Li
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Yun Zhang
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
| | - Hongyan Li
- Department of Urology, China and Japan Union Hospital of Jilin University, Changchun, Jilin 130000, P.R. China
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Beirowski B. The LKB1-AMPK and mTORC1 Metabolic Signaling Networks in Schwann Cells Control Axon Integrity and Myelination: Assembling and upholding nerves by metabolic signaling in Schwann cells. Bioessays 2018; 41:e1800075. [PMID: 30537168 DOI: 10.1002/bies.201800075] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 11/03/2018] [Indexed: 01/10/2023]
Abstract
The Liver kinase B1 with its downstream target AMP activated protein kinase (LKB1-AMPK), and the key nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) form two signaling systems that coordinate metabolic and cellular activity with changes in the environment in order to preserve homeostasis. For example, nutritional fluctuations rapidly feed back on these signaling systems and thereby affect cell-specific functions. Recent studies have started to reveal important roles of these strategic metabolic regulators in Schwann cells for the trophic support and myelination of axons. Because aberrant intermediate metabolism along with mitochondrial dysfunction in Schwann cells is mechanistically linked to nerve abnormalities found in acquired and inherited peripheral neuropathies, manipulation of the LKB1-AMPK, and mTORC1 signaling hubs may be a worthwhile therapeutic target to mitigate nerve damage in disease. Here, recent advances in our understanding of LKB1-AMPK and mTORC1 functions in Schwann cells are covered, and future research areas for this key metabolic signaling network are proposed.
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Affiliation(s)
- Bogdan Beirowski
- Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14203, USA.,Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, 14214, USA
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Russu MC, Nastasia Ş, Degeratu D, Stănculescu RV. Breast and Cervix Uteri: Rare Locations for Mycobacterium Tuberculosis Infections and Complications-Cases Report and Literature Review. Tuberculosis (Edinb) 2018. [DOI: 10.5772/intechopen.75044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Sun H, Huang Z, Sheng W, Xu MD. Emerging roles of long non-coding RNAs in tumor metabolism. J Hematol Oncol 2018; 11:106. [PMID: 30134946 PMCID: PMC6104013 DOI: 10.1186/s13045-018-0648-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/08/2018] [Indexed: 01/17/2023] Open
Abstract
Compared with normal cells, tumor cells display distinct metabolic characteristics. Long non-coding RNAs (lncRNAs), a large class of regulatory RNA molecules with limited or no protein-coding capacity, play key roles in tumorigenesis and progression. Recent advances have revealed that lncRNAs play a vital role in cell metabolism by regulating the reprogramming of the metabolic pathways in cancer cells. LncRNAs could regulate various metabolic enzymes that integrate cell malignant transformation and metabolic reprogramming. In addition to the known functions of lncRNAs in regulating glycolysis and glucose homeostasis, recent studies also implicate lncRNAs in amino acid and lipid metabolism. These observations reveal the high complexity of the malignant metabolism. Elucidating the metabolic-related functions of lncRNAs will provide a better understanding of the regulatory mechanisms of metabolism and thus may provide insights for the clinical development of cancer diagnostics, prognostics and therapeutics.
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Affiliation(s)
- Hui Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
| | - Zhaohui Huang
- Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu China
| | - Weiqi Sheng
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
| | - Mi-die Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Pathology, Tissue bank, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
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Canadas A, Santos M, Nogueira A, Assis J, Gomes M, Lemos C, Medeiros R, Dias-Pereira P. Canine mammary tumor risk is associated with polymorphisms in RAD51 and STK11 genes. J Vet Diagn Invest 2018; 30:733-738. [PMID: 30027822 DOI: 10.1177/1040638718789231] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Cancer is a complex disease involving genetic and phenotypic changes. Several single nucleotide polymorphisms (SNPs) have been associated with the risk of breast cancer development in women; however, little is known regarding their influence on canine mammary tumor risk. We assessed the influence of SNPs in genes related to human breast cancer susceptibility, with respect to the risk of development of mammary tumors in dogs. Sixty-seven canine SNPs in proto-oncogenes, tumor suppressor genes, genes involved in DNA repair, and in hormonal metabolism were evaluated in 212 bitches with mammary tumors and in 161 bitches free of mammary neoplasia. A significant association with mammary neoplasia risk was identified for 2 SNPs in RAD51 ( rs23623251 and rs23642734) and one SNP in the STK11 gene ( rs22928814). None of the other SNPs were related to the risk of mammary tumor development. The identification of genetic profiles associated with risk of mammary neoplasia is of great importance, supporting the implementation of specific clinical management strategies in high-risk animals.
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Affiliation(s)
- Ana Canadas
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Marta Santos
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Augusto Nogueira
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Joana Assis
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Mónica Gomes
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Carolina Lemos
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Rui Medeiros
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
| | - Patrícia Dias-Pereira
- Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto (ICBAS-UP), Porto, Portugal (Canadas, Santos, Lemos, Dias-Pereira).,Molecular Oncology and Viral Pathology Group, Portuguese Institute of Oncology of Porto (IPO Porto) Research Center (CI-IPOP), Porto, Portugal (Nogueira, Assis, Gomes, Medeiros).,i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal (Lemos).,UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Porto, Portugal (Lemos).,CEBIMED, Faculty of Health Sciences of Fernando Pessoa University, Porto, Portugal (Medeiros).,FMUP, Faculty of Medicine of Porto, University of Porto, Porto, Portugal (Medeiros).,Research Department, Portuguese League Against Cancer (LPCC-NRNorte), Porto, Portugal (Medeiros)
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Pascale RM, Feo CF, Calvisi DF, Feo F. Deregulation of methionine metabolism as determinant of progression and prognosis of hepatocellular carcinoma. Transl Gastroenterol Hepatol 2018; 3:36. [PMID: 30050996 PMCID: PMC6044036 DOI: 10.21037/tgh.2018.06.04] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/15/2018] [Indexed: 12/11/2022] Open
Abstract
The under-regulation of liver-specific MAT1A gene codifying for S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and the up-regulation of widely expressed MAT2A, MATII isozyme occurs in hepatocellular carcinoma (HCC). MATα1:MATα2 switch strongly contributes to the fall in SAM liver content both in rodent and human liver carcinogenesis. SAM administration to carcinogen-treated animals inhibits hepatocarcinogenesis. The opposite occurs in Mat1a-KO mice, in which chronic SAM deficiency is followed by HCC development. This review focuses upon the changes, induced by the MATα1:MATα2 switch, involved in HCC development. In association with MATα1:MATα2 switch there occurs, in HCC, global DNA hypomethylation, decline of DNA repair, genomic instability, and deregulation of different signaling pathways such as overexpression of c-MYC (avian myelocytomatosis viral oncogene homolog), increase of polyamine (PA) synthesis and RAS/ERK (Harvey murine sarcoma virus oncogene homolog/extracellular signal-regulated kinase), IKK/NF-kB (I-k kinase beta/nuclear factor kB), PI3K/AKT, and LKB1/AMPK axes. Furthermore, a decrease in MATα1 expression and SAM level induces HCC cell proliferation and survival. SAM treatment in vivo and enforced MATα1 overexpression or MATα2 inhibition, in cultured HCC cells, prevent these changes. A negative correlation of MATα1:MATα2 and MATI/III:MATII ratios with cell proliferation and genomic instability and a positive correlation with apoptosis and global DNA methylation are present in human HCC. Altogether, these data suggest that the decrease of SAM level and the deregulation of MATs are potential therapeutic targets for HCC.
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Affiliation(s)
- Rosa M. Pascale
- Department of Medical, Surgery, and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | - Claudio F. Feo
- Department of Medical, Surgery, and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy
| | - Diego F. Calvisi
- Department of Medical, Surgery, and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | - Francesco Feo
- Department of Medical, Surgery, and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
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Lee JH, Baek SY, Jang EJ, Ku SK, Kim KM, Ki SH, Kim CE, Park KI, Kim SC, Kim YW. Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase. Chem Biol Interact 2018; 289:68-74. [PMID: 29702089 DOI: 10.1016/j.cbi.2018.04.023] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 04/03/2018] [Accepted: 04/23/2018] [Indexed: 12/19/2022]
Abstract
Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver.
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Affiliation(s)
- Ju-Hee Lee
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea; College of Korean Medicine, Dongguk University, Gyeongju, 38066, South Korea
| | - Su Youn Baek
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea
| | - Eun Jeong Jang
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea
| | - Sae Kwang Ku
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, South Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, South Korea
| | - Chang-Eop Kim
- College of Oriental Medicine, Gachon University, Seongnam, Gyeonggido, 13120, South Korea
| | - Kwang Il Park
- Korea Institute of Oriental Medicine, Daegeon, 34054, South Korea
| | - Sang Chan Kim
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea
| | - Young Woo Kim
- College of Oriental Medicine, Daegu Haany University, Gyeongsan, 38610, South Korea.
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