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Thapa R, Marianesan AB, Rekha A, Ganesan S, Kumari M, Bhat AA, Ali H, Singh SK, Chakraborty A, MacLoughlin R, Gupta G, Dua K. Hypoxia-inducible factor and cellular senescence in pulmonary aging and disease. Biogerontology 2025; 26:64. [PMID: 40011266 PMCID: PMC11865175 DOI: 10.1007/s10522-025-10208-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 02/18/2025] [Indexed: 02/28/2025]
Abstract
Cellular senescence and hypoxia-inducible factor (HIF) signaling are crucial in pulmonary aging and age-related lung diseases such as chronic obstructive pulmonary disease idiopathic pulmonary fibrosis and lung cancer. HIF plays a pivotal role in cellular adaptation to hypoxia, regulating processes like angiogenesis, metabolism, and inflammation. Meanwhile, cellular senescence leads to irreversible cell cycle arrest, triggering the senescence-associated secretory phenotype which contributes to chronic inflammation, tissue remodeling, and fibrosis. Dysregulation of these pathways accelerates lung aging and disease progression by promoting oxidative stress, mitochondrial dysfunction, and epigenetic alterations. Recent studies indicate that HIF and senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Furthermore, emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression. Additionally, we discuss potential interventions, including senolytic therapies and HIF modulators, that could enhance lung health and longevity.
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Affiliation(s)
- Riya Thapa
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | | | - A Rekha
- Dr D Y Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India
| | - Subbulakshmi Ganesan
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Mukesh Kumari
- NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Asif Ahmad Bhat
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo, NSW, 2007, Australia
| | - Amlan Chakraborty
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
| | - Ronan MacLoughlin
- Aerogen, IDA Business Park, Dangan, Galway, H91 HE94, Ireland
- School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, D02 YN77, Ireland
- School of Pharmacy & Pharmaceutical Sciences, Trinity College, Dublin, D02 PN40, Ireland
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology, Sydney, Ultimo, NSW, 2007, Australia.
- Discipline of Pharmacy, Graduate School of Health, University of Technology, Sydney, Ultimo, NSW, 2007, Australia.
- Woolcock Institute of Medical Research, Macquarie University, Sydney, Australia.
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Han P, Zhang B, Li Y, Gao R, Li X, Ren H, Shi P, Zhao A, Xue J, Yang A, Liang Y. MiR-183-5p inhibits lung squamous cell carcinoma survival through disrupting hypoxia adaptation mediated by HIF-1α/NDUFA4L2 axis. Oncogene 2024; 43:2821-2834. [PMID: 39154121 DOI: 10.1038/s41388-024-03129-7] [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: 11/16/2023] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 08/19/2024]
Abstract
Hypoxia is a common feature of lung squamous cell carcinoma (LUSC), and hypoxia-inducible factor-1 (HIF-1) overexpression is associated with poor clinical outcome in LUSC. NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) is a recently identified target of HIF-1, but its roles in LUSC remain unclear. Herein, the expression and regulatory mechanisms of NDUFA4L2 were investigated in LUSC, and the influences on LUSC cell oxidative metabolism and survival of NDUFA4L2 were determined. The potential microRNA targeting to NDUFA4L2 was identified and its roles on LUSC cell were detected. We found that NDUFA4L2 were overexpressed in LUSC tissues, and that NDUFA4L2 expression correlated with shorter overall survival. NDUFA4L2 was regulated by HIF-1α under hypoxia, and NDUFA4L2 decreased mitochondrial reactive oxygen species (mitoROS) production through inhibiting mitochondrial complex I activity in LUSC cells. NDUFA4L2 silencing effectively suppressed LUSC cell growth and enhanced apoptosis by inducing mitoROS accumulation. Additionally, NDUFA4L2 was a target for miR-183-5p, and LUSC patients with high miR-183-5p levels had better prognoses. MiR-183-5p significantly induced mitoROS production and suppressed LUSC survival through negatively regulating NDUFA4L2 in vitro and in vivo. Our results suggested that regulation of NDUFA4L2 by HIF-1α is an important mechanism promoting LUSC progression under hypoxia. NDUFA4L2 inhibition using enforced miR-183-5p expression might be an effective strategy for LUSC treatment.
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Affiliation(s)
- Peng Han
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Boxiang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yixing Li
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Rui Gao
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinru Li
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hui Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Puyu Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Aomei Zhao
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jianjun Xue
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Aimin Yang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yiqian Liang
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Jiang W, Zhang T, Zhang H, Han T, Ji P, Ou Z. Metabolic Patterns of High-Invasive and Low-Invasive Oral Squamous Cell Carcinoma Cells Using Quantitative Metabolomics and 13C-Glucose Tracing. Biomolecules 2023; 13:1806. [PMID: 38136676 PMCID: PMC10742159 DOI: 10.3390/biom13121806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/24/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Most current metabolomics studies of oral squamous cell carcinoma (OSCC) are mainly focused on identifying potential biomarkers for early screening and diagnosis, while few studies have investigated the metabolic profiles promoting metastasis. In this study, we aimed to explore the altered metabolic pathways associated with metastasis of OSCC. Here, we identified four OSCC cell models (CAL27, HN6, HSC-3, SAS) that possess different invasive heterogeneity via the transwell invasion assay and divided them into high-invasive (HN6, SAS) and low-invasive (CAL27, HSC-3) cells. Quantitative analysis and stable isotope tracing using [U-13C6] glucose were performed to detect the altered metabolites in high-invasive OSCC cells, low-invasive OSCC cells and normal human oral keratinocytes (HOK). The metabolic changes in the high-invasive and low-invasive cells included elevated glycolysis, increased fatty acid metabolism and an impaired TCA cycle compared with HOK. Moreover, pathway analysis demonstrated significant differences in fatty acid biosynthesis; arachidonic acid (AA) metabolism; and glycine, serine and threonine metabolism between the high-invasive and low-invasive cells. Furthermore, the high-invasive cells displayed a significant increase in the percentages of 13C-glycine, 13C-palmitate, 13C-stearic acid, 13C-oleic acid, 13C-AA and estimated FADS1/2 activities compared with the low-invasive cells. Overall, this exploratory study suggested that the metabolic differences related to the metastatic phenotypes of OSCC cells were concentrated in glycine metabolism, de novo fatty acid synthesis and polyunsaturated fatty acid (PUFA) metabolism, providing a comprehensive understanding of the metabolic alterations and a basis for studying related molecular mechanisms in metastatic OSCC cells.
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Affiliation(s)
- Wenrong Jiang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Ting Zhang
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Hua Zhang
- Ministry of Education of China International Collaborative Joint Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing 400016, China; (H.Z.); (T.H.)
- State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, Chongqing Medical University, Chongqing 400016, China
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Tingli Han
- Ministry of Education of China International Collaborative Joint Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing 400016, China; (H.Z.); (T.H.)
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Ping Ji
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Zhanpeng Ou
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, China; (W.J.); (T.Z.)
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China
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Kim S, Park S, Moon EH, Kim GJ, Choi J. Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3. Cancer Cell Int 2023; 23:79. [PMID: 37095487 PMCID: PMC10123966 DOI: 10.1186/s12935-023-02924-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/10/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a highly malignant tumor that is frequently associated with lymph node metastasis, resulting in poor prognosis and survival in patients. In the tumor microenvironment, hypoxia plays an important role in regulating cellular responses such as progressive and rapid growth and metastasis. In these processes, tumor cells autonomously undergo diverse transitions and acquire functions. However, hypoxia-induced transition of OSCC and the involvement of hypoxia in OSCC metastasis remain unclear. Therefore, in this study, we aimed to elucidate the mechanism of hypoxia-induced OSCC metastasis and particularly, its impact on tight junctions (TJs). METHODS The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was detected in tumor tissues and adjacent normal tissues from 29 patients with OSCC using reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC). The migration and invasion abilities of OSCC cell lines treated with small interfering (si)RNA targeting HIF-1α or cultured in hypoxic conditions were analyzed using Transwell assays. The effect of HIF-1α expression on in vivo tumor metastasis of OSCC cells was evaluated using lung metastasis model. RESULTS HIF-1α was overexpressed in patients with OSCC. OSCC metastasis was correlated with HIF-1α expression in OSCC tissues. Hypoxia increased the migration and invasion abilities of OSCC cell lines by regulating the expression and localization of partitioning-defective protein 3 (Par3) and TJs. Furthermore, HIF-1α silencing effectively decreased the invasion and migration abilities of OSCC cell lines and restored TJ expression and localization via Par3. The expression of HIF-1α was positively regulated the OSCC metastasis in vivo. CONCLUSIONS Hypoxia promotes OSCC metastasis by regulating the expression and localization of Par3 and TJ proteins. HIF-1α positively correlates to OSCC metastasis. Lastly, HIF-1α expression could regulate the expression of Par3 and TJs in OSCC. This finding may aid in elucidating the molecular mechanisms of OSCC metastasis and progression and developing new diagnostic and therapeutic approaches for OSCC metastasis.
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Affiliation(s)
- Shihyun Kim
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Suyeon Park
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Eun-Hye Moon
- Institute of Lee Gil Ya Cancer and Diabetes, Gachon University, Incheon, 21999, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Jongho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea.
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Nourian YH, Salimian J, Ahmadi A, Salehi Z, Karimi M, Emamvirdizadeh A, Azimzadeh Jamalkandi S, Ghanei M. cAMP-PDE signaling in COPD: Review of cellular, molecular and clinical features. Biochem Biophys Rep 2023; 34:101438. [PMID: 36865738 PMCID: PMC9971187 DOI: 10.1016/j.bbrep.2023.101438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/21/2023] [Accepted: 02/02/2023] [Indexed: 02/18/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death among non-contagious diseases in the world. PDE inhibitors are among current medicines prescribed for COPD treatment of which, PDE-4 family is the predominant PDE isoform involved in hydrolyzing cyclic adenosine monophosphate (cAMP) that regulates the inflammatory responses in neutrophils, lymphocytes, macrophages and epithelial cells The aim of this study is to investigate the cellular and molecular mechanisms of cAMP-PDE signaling, as an important pathway in the treatment management of patients with COPD. In this review, a comprehensive literature review was performed about the effect of PDEs in COPD. Generally, PDEs are overexpressed in COPD patients, resulting in cAMP inactivation and decreased cAMP hydrolysis from AMP. At normal amounts, cAMP is one of the essential agents in regulating metabolism and suppressing inflammatory responses. Low amount of cAMP lead to activation of downstream inflammatory signaling pathways. PDE4 and PDE7 mRNA transcript levels were not altered in polymorphonuclear leukocytes and CD8 lymphocytes originating from the peripheral venous blood of stable COPD subjects compared to healthy controls. Therefore, cAMP-PDE signaling pathway is one of the most important signaling pathways involved in COPD. By examining the effects of different drugs in this signaling pathway critical steps can be taken in the treatment of this disease.
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Affiliation(s)
- Yazdan Hasani Nourian
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Jafar Salimian
- Applied Virology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Ahmadi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Zahra Salehi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Karimi
- Department of Traditional Medicine, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Emamvirdizadeh
- Department of Molecular Genetics, Faculty of Bio Sciences, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Sadegh Azimzadeh Jamalkandi
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran,Corresponding author.
| | - Mostafa Ghanei
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Deng H, Gao Y, Trappetti V, Hertig D, Karatkevich D, Losmanova T, Urzi C, Ge H, Geest GA, Bruggmann R, Djonov V, Nuoffer JM, Vermathen P, Zamboni N, Riether C, Ochsenbein A, Peng RW, Kocher GJ, Schmid RA, Dorn P, Marti TM. Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage. Cell Mol Life Sci 2022; 79:445. [PMID: 35877003 PMCID: PMC9314287 DOI: 10.1007/s00018-022-04453-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/21/2022] [Accepted: 06/27/2022] [Indexed: 02/08/2023]
Abstract
Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal's health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis.
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Affiliation(s)
- Haibin Deng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Yanyun Gao
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | | | - Damian Hertig
- Department of Neuroradiology, University of Bern, Bern, Switzerland
- Institute of Clinical Chemistry, University Hospital Bern, Bern, Switzerland
| | - Darya Karatkevich
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | | | - Christian Urzi
- Department of Neuroradiology, University of Bern, Bern, Switzerland
- Institute of Clinical Chemistry, University Hospital Bern, Bern, Switzerland
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Huixiang Ge
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Graduate School of Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Gerrit Adriaan Geest
- Interfaculty Bioinformatics Unit, Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | - Remy Bruggmann
- Interfaculty Bioinformatics Unit, Swiss Institute of Bioinformatics, University of Bern, Bern, Switzerland
| | | | - Jean-Marc Nuoffer
- Department of Neuroradiology, University of Bern, Bern, Switzerland
- Department of Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital of Bern, Bern, Switzerland
| | - Peter Vermathen
- Translational Imaging Center (TIC), Swiss Institute for Translational and Entrepreneurial Medicine, Bern, Switzerland
| | - Nicola Zamboni
- Institute for Molecular Systems Biology, ETH Zurich, Zurich, Switzerland
| | - Carsten Riether
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Adrian Ochsenbein
- Department for BioMedical Research, University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Ren-Wang Peng
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Gregor Jan Kocher
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Ralph Alexander Schmid
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Patrick Dorn
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Thomas Michael Marti
- Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
- Department for BioMedical Research, University of Bern, Bern, Switzerland.
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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8
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Fan Z, Duan J, Luo P, Shao L, Chen Q, Tan X, Zhang L, Xu X. SLC25A38 as a novel biomarker for metastasis and clinical outcome in uveal melanoma. Cell Death Dis 2022; 13:330. [PMID: 35411037 PMCID: PMC9001737 DOI: 10.1038/s41419-022-04718-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 02/18/2022] [Accepted: 03/09/2022] [Indexed: 01/03/2023]
Abstract
Risk of metastasis is increased by the presence of chromosome 3 monosomy in uveal melanoma (UM). This study aimed to identify more accurate biomarker for risk of metastasis in UM. A total of 80 patients with UM from TCGA were assigned to two groups based on the metastatic status, and bioinformatic analyses were performed to search for critical genes for risk of metastasis. SLC25A38, located on chromosome 3, was the dominant downregulated gene in metastatic UM patients. Low expression of SLC25A38 was an independent predictive and prognostic factor in UM. The predictive potential of SLC25A38 expression was superior to that of pervious reported biomarkers in both TCGA cohort and GSE22138 cohort. Subsequently, its role in promoting metastasis was explored in vitro and in vivo. Knock-out of SLC25A38 could enhance the migration ability of UM cells, and promote distant metastasis in mice models. Through the inhibition of CBP/HIF-mediated pathway followed by the suppression of pro-angiogenic factors, SLC25A38 was situated upstream of metastasis-related pathways, especially angiogenesis. Low expression of SLC25A38 promotes angiogenesis and metastasis, and identifies increased metastatic risk and worse survival in UM patients. This finding may further improve the accuracy of prognostic prediction for UM.
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Affiliation(s)
- Zhongyi Fan
- Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Shenzhen, 518112, China.,Department of Oncology, The First Medical Center, General Hospital of PLA, Beijing, 100853, China
| | - Jingjing Duan
- Department of Gastrointestinal Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Pu Luo
- Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Shenzhen, 518112, China
| | - Ling Shao
- Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Shenzhen, 518112, China
| | - Qiong Chen
- Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Shenzhen, 518112, China
| | - Xiaohua Tan
- Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Shenzhen, 518112, China.
| | - Lei Zhang
- Department of Ophthalmology, Xuanwu Hospital Attached to the Capital Medical University, Beijing, 100053, China.
| | - Xiaojie Xu
- Department of Genetic Engineering, Beijing Institute of Biotechnology, Beijing, 100850, China.
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9
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Fang P, Li XD. The assessment of glycine decarboxylase levels in p53-mutated B-cell lymphoma. Asian J Surg 2022; 45:936-938. [PMID: 35033414 DOI: 10.1016/j.asjsur.2021.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 12/10/2021] [Indexed: 11/29/2022] Open
Affiliation(s)
- Ping Fang
- Department of Blood Transfusion, The First Affiliated Hospital of Shandong First Medical University (Shandong Province Qianfoshan Hospital), Jinan, 250014, Shandong, China
| | - Xiang-Dong Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Shandong First Medical University (Shandong Province Qianfoshan Hospital), Jinan, 250014, Shandong, China.
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10
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Chen Y, Lee K, Liang Y, Qin S, Zhu Y, Liu J, Yao S. A Cholesterol Homeostasis-Related Gene Signature Predicts Prognosis of Endometrial Cancer and Correlates With Immune Infiltration. Front Genet 2021; 12:763537. [PMID: 34790227 PMCID: PMC8591263 DOI: 10.3389/fgene.2021.763537] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/13/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Endometrial cancer (EC) is one of the most common gynecological malignancies in women. Cholesterol metabolism has been confirmed to be closely related to tumor proliferation, invasion and metastasis. However, the correlation between cholesterol homeostasis-related genes and prognosis of EC remains unclear. Methods: EC patients from the Cancer Genome Atlas (TCGA) database were randomly divided into training cohort and test cohort. Transcriptome analysis, univariate survival analysis and LASSO Cox regression analysis were adopted to construct a cholesterol homeostasis-related gene signature from the training cohort. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) were utilized to verify the predictive performance of the gene signature in two cohorts. Additionally, enrichment analysis and immune infiltration analysis were performed on differentially expressed genes (DEGs) between two risk groups. Results: Seven cholesterol homeostasis-related genes were selected to establish a gene signature. KM plot, ROC curve and PCA in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally had lower immune infiltrating cells and immune function. Conclusion: We constructed and validated a cholesterol homeostasis-related gene signature to predict the prognosis of EC, which correlated to immune infiltration and expected to help the diagnosis and precision treatment of EC.
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Affiliation(s)
- Yili Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kaping Lee
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yanchun Liang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuhang Qin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Zhu
- Department of Obstetrics and Gynecology, Nanjing Maternity and Child Health Care Hospital, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Junxiu Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuzhong Yao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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11
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Yu L, Li J, Peng B, Cai P, Zhao B, Chen Y, Zhu H. CircASXL1 Knockdown Restrains Hypoxia-Induced DDP Resistance and NSCLC Progression by Sponging miR-206. Cancer Manag Res 2021; 13:5077-5089. [PMID: 34234552 PMCID: PMC8253994 DOI: 10.2147/cmar.s276964] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 10/17/2020] [Indexed: 12/25/2022] Open
Abstract
Background Non-small cell lung carcinoma (NSCLC) is a primary prevalent type of cancer in people worldwide. Cisplatin (DDP) has been widely used to treat NSCLC; however, its curative effect was restrained under hypoxia. In this study, the effects of hypoxia treatment on DDP resistance and NSCLC progression and underneath mechanism were revealed. Methods The expression of circular RNA ASXL1 (circASXL1) and microRNA-206 (miR-206) in NSCLC tissues, cells and hypoxia-mediated NSCLC cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of proliferation, metastasis and apoptosis-related proteins, drug resistance-related protein and hypoxia-inducible factor-1alpha (HIF-1α) protein was detected by Western blot. The effects of circASXL1 knockdown on hypoxia-induced DDP resistance and NSCLC progression were revealed by cell counting kit-8 proliferation (CCK-8), cell colony formation, transwell and flow apoptosis assays. RNA immunoprecipitation (RIP) assay was performed to determine whether circASXL1 could form silence-inducing complexes with miRNA. The associated relationship between circASXL1 and miR-206 was predicted by circBank online database, and identified by RNA pull-down and dual-luciferase reporter assays. The effects between circASXL1 knockdown and miR-206 downregulation on tumor growth in vivo were investigated by in vivo tumor formation assay. Results CircASXL1 expression was dramatically upregulated, whereas miR-206 was significantly down-regulated in NSCLC tissues, cells and hypoxia-mediated NSCLC cells as compared to control groups. CircASXL1 knockdown reversed hypoxia-mediated promotion effects on DDP resistance, cell proliferation, migration, and invasion, and inhibition impact on cell apoptosis, whereas these effects were restored by miR-206 inhibitor. Additionally, circASXL1 was found to form silence-inducing complexes with miRNA and act as a sponge of miR-206. CircASXL1 silencing downregulated HIF-1α expression by controlling miR-206 expression. Furthermore, circASXL1 silencing repressed tumor growth in vivo by sponging miR-206. Conclusion CircASXL1 knockdown inhibited DDP resistance, cell proliferation, migration and invasion, whereas induced cell apoptosis under hypoxia by associating with miR-206 in NSCLC. This study provides a new sight in treating NSCLC with DDP under hypoxia.
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Affiliation(s)
- Liuyang Yu
- Department of Oncology, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Jing Li
- Department of Imaging, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Bing Peng
- Department of Oncology, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Peng Cai
- Department of Oncology, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Bailin Zhao
- Department of Oncology, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Ying Chen
- Department of Radiotherapy, Jing Men No. 2 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
| | - Hailing Zhu
- Department of Emergency, Jing Men No. 1 People's Hospital, Jingmen, Hubei, 448000, People's Republic of China
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12
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Vallespi MG, Mestre B, Marrero MA, Uranga R, Rey D, Lugiollo M, Betancourt M, Silva K, Corrales D, Lamadrid Y, Rodriguez Y, Maceo A, Chaviano PP, Lemos G, Cabrales A, Freyre FM, Santana H, Garay HE, Oliva B, Fernandez JR. A first-in-class, first-in-human, phase I trial of CIGB-552, a synthetic peptide targeting COMMD1 to inhibit the oncogenic activity of NF-κB in patients with advanced solid tumors. Int J Cancer 2021; 149:1313-1321. [PMID: 34019700 DOI: 10.1002/ijc.33695] [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: 02/09/2021] [Revised: 04/05/2021] [Accepted: 04/29/2021] [Indexed: 11/06/2022]
Abstract
CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.
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Affiliation(s)
| | - Braulio Mestre
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Maria A Marrero
- National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Rolando Uranga
- National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Diana Rey
- National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Martha Lugiollo
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Mircea Betancourt
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Kirenia Silva
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Danay Corrales
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Yanet Lamadrid
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Yamilka Rodriguez
- National Institute of Oncology and Radiobiology (INOR), Havana, Cuba
| | - Anaelys Maceo
- National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Pedro P Chaviano
- National Coordinating Center for Clinical Trials (CENCEC), Havana, Cuba
| | - Gilda Lemos
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Ania Cabrales
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Freya M Freyre
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Hector Santana
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Hilda E Garay
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Brizaida Oliva
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Julio R Fernandez
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
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13
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Li R, Wang L, Wang X, Geng RX, Li N, Liu XH. Identification of hub genes associated with outcome of clear cell renal cell carcinoma. Oncol Lett 2020; 19:2846-2860. [PMID: 32218839 PMCID: PMC7068649 DOI: 10.3892/ol.2020.11389] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 12/05/2019] [Indexed: 12/17/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is one of the most common tumor types of the urinary system. Bioinformatics tools have been used to identify new biomarkers of ccRCC and to explore the mechanisms underlying development and progression of ccRCC. The present study analyzed the differentially expressed genes (DEGs) associated with RCC using data obtained from Gene Expression Omnibus datasets and GEO2R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of these DEGs was performed and analyzed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes to identify the hub genes, defined as the genes with the highest degree of interrelation. Subsequently, differential expression and survival analyses of hub genes was performed using The Cancer Genome Atlas database and Gene Expression Profiling Interactive Analysis (GEPIA) online tool. Using GEO2R, 1,650 DEGs were identified, including 743 upregulated and 907 downregulated genes. GO and KEGG pathway analyses indicated that the upregulated DEGs were primarily involved in blood vessel and vasculature development, whereas downregulated DEGs were primarily involved in organic acid metabolic processes and carboxylic acid metabolic processes. Subsequently, important modules were identified in the PPI network using Cytoscape's Molecular Complex Detection. The 15 most connected hub genes were identified among DEGs, including glycine decarboxylase (GLDC), enolase 2 (ENO2) and topoisomerase II alpha. GEPIA revealed the association between expression levels of hub genes and survival. Specifically, GLDC and ENO2 were associated with the prognosis of patients with RCC and thus, the effects of GLDC and ENO2 involvement in renal cancer were investigated in vitro. GLDC and ENO2 affected the proliferation and apoptosis of renal cancer cells. These hub genes may reveal a new mechanism underlying development or progression of RCC and identify new markers for its diagnosis and prognosis.
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Affiliation(s)
- Rengui Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lei Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiao Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Rong-Xin Geng
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiu-Heng Liu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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14
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Hu X, Lin J, Jiang M, He X, Wang K, Wang W, Hu C, Shen Z, He Z, Lin H, Wu D, Wang M. HIF-1α Promotes the Metastasis of Esophageal Squamous Cell Carcinoma by Targeting SP1. J Cancer 2020; 11:229-240. [PMID: 31892989 PMCID: PMC6930417 DOI: 10.7150/jca.35537] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 09/08/2019] [Indexed: 02/07/2023] Open
Abstract
Background: In microenvironment of malignant tumors, Hypoxia-Inducible Factors (HIF), most importantly HIF-1α, play an important role in regulation of adaptive biological response to hypoxia, promoting angiogenesis and metastasis. However, the underlying mechanism that HIF-1α regulates metastasis needs to be further clarified. Methods: The expressions of HIF-1α and SP1 were detected in 182 samples of esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues by immunohistochemistry (IHC), and the correlation between the expression levels of HIF-1α and SP1 was analyzed. The expression of HIF-1α in ESCC cell lines TE1 and KYSE30 was then detected using qRT-PCR and western blot. The potential binding sites of HIF-1α on the SP1 promoter were analyzed using UCSC and JASPAR databases, verified by chromosomal immunoprecipitation (ChIP) assay and qRT-PCR. The effects of HIF-1α and SP1 on ESCC cell migration and invasion were then tested with Transwell and Matrigel experiments. Results: The expression of HIF-1α in cancer tissues is higher than adjacent normal tissues, and is correlated with metastasis, recurrence and poor prognosis. Upon silencing HIF-1α by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1. Hypoxic conditions significantly increased the expression of HIF-1α and SP1 at both protein and mRNA levels in ESCC cells. HIF-1α enhanced SP1 transcription through binding to the promoter region. The expression of protein and mRNA levels of SP1 was decreased by silencing HIF-1α in cells. In contrast, overexpression of HIF-1α significantly increased the mRNA and protein levels of SP1. The expression of SP1 in ESCC was positively correlated with the protein expression of HIF-1α and poor prognosis. Conclusion: The results of our study indicate that HIF-1α promotes metastasis of ESCC by targeting SP1 in a hypoxic microenvironment. Further study on this mechanism may elucidate the possibility of HIF-1α and SP1 as new targets for the treatment of ESCC.
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Affiliation(s)
- Xueting Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Jiatong Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Ming Jiang
- Department of Thoracic Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China 510120
| | - Xiaotian He
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Kefeng Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Wenjian Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Chuwen Hu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Zhiwen Shen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Zhanghai He
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Huayue Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Duoguang Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
| | - Minghui Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120.,Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 510120
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15
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Chen W, Zhang W, Wu R, Cai Y, Xue X, Cheng J. Identification of biomarkers associated with histological grade and prognosis of gastric cancer by co-expression network analysis. Oncol Lett 2019; 18:5499-5507. [PMID: 31612058 PMCID: PMC6781762 DOI: 10.3892/ol.2019.10869] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 08/23/2019] [Indexed: 12/11/2022] Open
Abstract
The biological characteristics and clinical outcomes of gastric cancer (GC) are largely dependent on the histopathological type and degree of differentiation. The identification of the molecular mechanisms underlying the histological grade of GC may provide information about tumorigenesis and tumor progression, and may subsequently be used to develop novel therapeutic agents. The present study obtained the RNA sequencing data and clinical characteristics of patients with GC from The Cancer Genome Atlas. A total of 1,400 differentially expressed genes (DEGs) were screened between two histological grades. Weighted gene co-expression network analysis (WGCNA) was subsequently used to identify nine co-expressed gene modules, and the black module was found to be the most significant for prognosis prediction of tumor. Additionally, the black module was associated with overall survival time, death event, N stage and tumor-node-metastasis (TNM) stage. Functional enrichment analysis revealed that the biological processes of the genes in the black module included ‘Wnt signaling pathway’ and ‘structural molecule activity’. Additionally, 10 network hub genes that were significantly associated with the progression of GC were identified from the black module, and the significance of each hub gene was determined across different TNM stages. Kaplan-Meier survival curves revealed that keratin 40 and glycine decarboxylase were significantly associated with patient prognosis (P<0.05), suggesting that these genes may serve as potential progression and prognosis biomarkers in GC. The present study identified molecular markers that correlated with histological grade in GC. Therefore, the results obtained in the present study may have important clinical implications on treatment selection, risk stratification and prognosis prediction in patients with GC.
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Affiliation(s)
- Wenjing Chen
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Weiteng Zhang
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Ruisen Wu
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yiqi Cai
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Xiangyang Xue
- Department of Microbiology and Immunology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Jun Cheng
- Department of General Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
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16
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Mini E, Lapucci A, Perrone G, D'Aurizio R, Napoli C, Brugia M, Landini I, Tassi R, Picariello L, Simi L, Mancini I, Messerini L, Magi A, Pinzani P, Mazzei T, Tonelli F, Nobili S. RNA sequencing reveals PNN and KCNQ1OT1 as predictive biomarkers of clinical outcome in stage III colorectal cancer patients treated with adjuvant chemotherapy. Int J Cancer 2019; 145:2580-2593. [PMID: 30973654 DOI: 10.1002/ijc.32326] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/13/2019] [Accepted: 04/01/2019] [Indexed: 12/16/2022]
Abstract
Five-year overall survival of stage III colorectal cancer (CRC) patients treated with standard adjuvant chemotherapy (ACHT) is highly variable. Genomic biomarkers and/or transcriptomic profiles identified lack of adequate validation. Aim of our study was to identify and validate molecular biomarkers predictive of ACHT response in stage III CRC patients by a transcriptomic approach. From a series of CRC patients who received ACHT, two stage III extreme cohorts (unfavorable vs. favorable prognosis) were selected. RNA-sequencing was performed from fresh frozen explants. Tumors were characterized for somatic mutations. Validation was performed in stage III CRC patients extracted from two GEO datasets. According to disease-free survival (DFS), 108 differentially expressed genes (104/4 up/downregulated in the unfavorable prognosis group) were identified. Among 104 upregulated genes, 42 belonged to olfactory signaling pathways, 62 were classified as pseudogenes (n = 17), uncharacterized noncoding RNA (n = 10), immune response genes (n = 4), microRNA (n = 1), cancer-related genes (n = 14) and cancer-unrelated genes (n = 16). Three out of four down-regulated genes were cancer-related. Mutational status (i.e., RAS, BRAF, PIK3CA) did not differ among the cohorts. In the validation cohort, multivariate analysis showed high PNN and KCNQ1OT1 expression predictive of shorter DFS in ACHT treated patients (p = 0.018 and p = 0.014, respectively); no difference was observed in untreated patients. This is the first study that identifies by a transcriptomic approach and validates PNN and KCNQ1OT1 as molecular biomarkers predictive of chemotherapy response in stage III CRC patients. After a further validation in an independent cohort, PNN and KCNQ1OT1 evaluation could be proposed to prospectively identify stage III CRC patients benefiting from ACHT.
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Affiliation(s)
- Enrico Mini
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
| | - Andrea Lapucci
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
| | - Gabriele Perrone
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
| | - Romina D'Aurizio
- Institute of Informatics and Telematics (IIT), National Research Council (CNR), Pisa, Italy
| | - Cristina Napoli
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
| | - Marco Brugia
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Ida Landini
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
| | - Renato Tassi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Lucia Picariello
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Lisa Simi
- Molecular and Clinical Biochemistry Laboratory, Careggi University Hospital, Florence, Italy
| | - Irene Mancini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alberto Magi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Pamela Pinzani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.,Molecular and Clinical Biochemistry Laboratory, Careggi University Hospital, Florence, Italy
| | - Teresita Mazzei
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Francesco Tonelli
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Stefania Nobili
- Department of Health Sciences, University of Florence, Florence, Italy.,DENOTHE Excellence Center, University of Florence, Florence, Italy
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17
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Zhang Y, Li Y, Zhang R, Zhang Y, Ma H. RNSCLC-PRSP software to predict the prognostic risk and survival in patients with resected T 1-3N 0-2 M 0 non-small cell lung cancer. BioData Min 2019; 12:17. [PMID: 31462928 PMCID: PMC6708148 DOI: 10.1186/s13040-019-0205-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 08/14/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The clinical outcomes of patients with resected T1-3N0-2M0 non-small cell lung cancer (NSCLC) with the same tumor-node-metastasis (TNM) stage are diverse. Although other prognostic factors and prognostic prediction tools have been reported in many published studies, a convenient, accurate and specific prognostic prediction software for clinicians has not been developed. The purpose of our research was to develop this type of software that can analyze subdivided T and N staging and additional factors to predict prognostic risk and the corresponding mean and median survival time and 1-5-year survival rates of patients with resected T1-3N0-2M0 NSCLC. RESULTS Using a Cox proportional hazard regression model, we determined the independent prognostic factors and obtained a prognostic index (PI) eq. PI = ∑βixi.=0.379X1-0.403X2-0.267X51-0.167X61-0.298X62 + 0.460X71 + 0.617X72-0.344X81-0.105X91-0.243X92 + 0.305X101 + 0.508X102 + 0.754X103 + 0.143X111 + 0.170X112 + 0.434X113-0.327X122-0.247X123 + 0.517X133 + 0.340X134 + 0.457X143 + 0.419X144 + 0.407X145. Using the PI equation, we determined the PI value of every patient. According to the quantile of the PI value, patients were divided into three risk groups: low-, intermediate-, and high-risk groups with significantly different survival rates. Meanwhile, we obtained the mean and median survival times and 1-5-year survival rates of the three groups. We developed the RNSCLC-PRSP software which is freely available on the web at http://www.rnsclcpps.com with all major browsers supported to determine the prognostic risk and associated survival of patients with resected T1-3N0-2 M0 non-small cell lung cancer. CONCLUSIONS After prognostic factor analysis, prognostic risk grouping and corresponding survival assessment, we developed a novel software program. It is practical and convenient for clinicians to evaluate the prognostic risk and corresponding survival of patients with resected T1-3N0-2M0 NSCLC. Additionally, it has guiding significance for clinicians to make decisions about complementary treatment for patients.
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Affiliation(s)
- Yunkui Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215006 China
- Department of Thoracic Surgery, Shanxi Tumor Hospital, No. 3 Zhigongxin Street, Taiyuan, 030013 China
| | - YaoChen Li
- The Central Laboratory of Cancer Hospital of Shantou University Medical College, Guangdong Provincial Key Laboratory on Breast Cancer Diagnosis and Treatment Research, No. 7 Raoping Road, Shantou, 515031 China
| | - Rongsheng Zhang
- Department of Thoracic Surgery, Shanxi Tumor Hospital, No. 3 Zhigongxin Street, Taiyuan, 030013 China
| | - Yujie Zhang
- Department of Thoracic Surgery, Shanxi Tumor Hospital, No. 3 Zhigongxin Street, Taiyuan, 030013 China
| | - Haitao Ma
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215006 China
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18
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Zhao C, Lou Y, Wang Y, Wang D, Tang L, Gao X, Zhang K, Xu W, Liu T, Xiao J. A gene expression signature-based nomogram model in prediction of breast cancer bone metastases. Cancer Med 2018; 8:200-208. [PMID: 30575323 PMCID: PMC6346244 DOI: 10.1002/cam4.1932] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 11/24/2018] [Accepted: 11/27/2018] [Indexed: 12/14/2022] Open
Abstract
Breast cancer is prone to form bone metastases and subsequent skeletal‐related events (SREs) dramatically decrease patients’ quality of life and survival. Prediction and early management of bone lesions are valuable; however, proper prognostic models are inadequate. In the current study, we reviewed a total of 572 breast cancer patients in three microarray data sets including 191 bone metastases and 381 metastases‐free. Gene set enrichment analysis (GSEA) indicated less aggressive and low‐grade features of patients with bone metastases compared with metastases‐free ones, while luminal subtypes are more prone to form bone metastases. Five bone metastases‐related genes (KRT23, REEP1, SPIB, ALDH3B2, and GLDC) were identified and subjected to construct a gene expression signature‐based nomogram (GESBN) model. The model performed well in both training and testing sets for evaluation of breast cancer bone metastases (BCBM). Clinically, the model may help in prediction of early bone metastases, prevention and management of SREs, and even help to prolong survivals for patients with BCBM. The five‐gene GESBN model showed some implications as molecular diagnostic markers and therapeutic targets. Furthermore, our study also provided a way for analysis of tumor organ‐specific metastases. To the best of our knowledge, this is the first published model focused on tumor organ‐specific metastases.
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Affiliation(s)
- Chenglong Zhao
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yan Lou
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yao Wang
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dongsheng Wang
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Liang Tang
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xin Gao
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Kun Zhang
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Xu
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tielong Liu
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jianru Xiao
- Spine Tumor Center, Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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19
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GCSH antisense regulation determines breast cancer cells' viability. Sci Rep 2018; 8:15399. [PMID: 30337557 PMCID: PMC6193953 DOI: 10.1038/s41598-018-33677-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 09/27/2018] [Indexed: 11/12/2022] Open
Abstract
Since it is known that cancer cells exhibit a preference for increased glycine consumption, the respective glycine metabolizing enzymes are in focus of many research projects. However, no cancer associated studies are available for the Glycine Cleavage System Protein H (GCSH) to date. Our initial analysis revealed a GCSH-overexpression of the protein-coding transcript variant 1 (Tv1) in breast cancer cells and tissue. Furthermore, a shorter (391 bp) transcript variant (Tv*) was amplified with an increased expression in healthy breast cells and a decreased expression in breast cancer samples. The Tv1/Tv* transcript ratio is 1.0 in healthy cells on average, and between 5–10 in breast cancer cells. Thus, a GCSH-equilibrium at the transcript level is likely conceivable for optimal glycine degradation. A possible regulative role of Tv* was proven by Tv1-Tv*-RNA-binding and overexpression studies which consequently led to serious physiological alterations: decreased metabolic activity, release of the lactate dehydrogenase, increased extracellular acidification, and finally necrosis as a result of impaired plasma membranes. In contrast, Tv1-overexpression led to an additional increase in cellular vitality of the tumor cells, primarily due to the acceleration of the mitochondrial glycine decarboxylation activity. Ultimately, we provide the first evidence of a sensitive GCSH-antisense regulation which determines cancerous cell viability.
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20
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Moreno P, Jiménez-Jiménez C, Garrido-Rodríguez M, Calderón-Santiago M, Molina S, Lara-Chica M, Priego-Capote F, Salvatierra Á, Muñoz E, Calzado MA. Metabolomic profiling of human lung tumor tissues - nucleotide metabolism as a candidate for therapeutic interventions and biomarkers. Mol Oncol 2018; 12:1778-1796. [PMID: 30099851 PMCID: PMC6165994 DOI: 10.1002/1878-0261.12369] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 07/24/2018] [Accepted: 08/03/2018] [Indexed: 12/14/2022] Open
Abstract
Although metabolomics has attracted considerable attention in the field of lung cancer (LC) detection and management, only a very limited number of works have applied it to tissues. As such, the aim of this study was the thorough analysis of metabolic profiles of relevant LC tissues, including the most important histological subtypes (adenocarcinoma and squamous cell lung carcinoma). Mass spectrometry‐based metabolomics, along with genetic expression and histological analyses, were performed as part of this study, the widest to date, to identify metabolic alterations in tumors of the most relevant histological subtypes in lung. A total of 136 lung tissue samples were analyzed and 851 metabolites were identified through metabolomic analysis. Our data show the existence of a clear metabolic alteration not only between tumor vs. nonmalignant tissue in each patient, but also inherently intrinsic changes in both AC and SCC. Significant changes were observed in the most relevant biochemical pathways, and nucleotide metabolism showed an important number of metabolites with high predictive capability values. The present study provides a detailed analysis of the metabolomic changes taking place in relevant biochemical pathways of the most important histological subtypes of LC, which can be used as biomarkers and also to identify novel targets.
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Affiliation(s)
- Paula Moreno
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Unidad de Cirugía Torácica y Trasplante Pulmonar, Hospital Universitario Reina Sofía, Cordoba, Spain
| | - Carla Jiménez-Jiménez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Cordoba, Spain
| | | | - Mónica Calderón-Santiago
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Química Analítica, Universidad de Córdoba, Cordoba, Spain
| | - Susana Molina
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Cordoba, Spain
| | - Maribel Lara-Chica
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Cordoba, Spain
| | - Feliciano Priego-Capote
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Química Analítica, Universidad de Córdoba, Cordoba, Spain
| | - Ángel Salvatierra
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Unidad de Cirugía Torácica y Trasplante Pulmonar, Hospital Universitario Reina Sofía, Cordoba, Spain
| | - Eduardo Muñoz
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Cordoba, Spain
| | - Marco A Calzado
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.,Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Cordoba, Spain
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21
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Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel) 2018; 10:E248. [PMID: 30060526 PMCID: PMC6116004 DOI: 10.3390/cancers10080248] [Citation(s) in RCA: 243] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/19/2018] [Accepted: 07/20/2018] [Indexed: 12/21/2022] Open
Abstract
Lung cancer causes the largest number of cancer-related deaths in the world. Most (85%) of lung cancers are classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). The two predominant NSCLC histological phenotypes are adenocarcinoma (ADC) and squamous cell carcinoma (LSQCC). ADCs display several recurrent genetic alterations, including: KRAS, BRAF and EGFR mutations; recurrent mutations and amplifications of several oncogenes, including ERBB2, MET, FGFR1 and FGFR2; fusion oncogenes involving ALK, ROS1, Neuregulin1 (NRG1) and RET. In LSQCC recurrent mutations of TP53, FGFR1, FGFR2, FGFR3, DDR2 and genes of the PI3K pathway have been detected, quantitative gene abnormalities of PTEN and CDKN2A. Developments in the characterization of lung cancer molecular abnormalities provided a strong rationale for new therapeutic options and for understanding the mechanisms of drug resistance. However, the complexity of lung cancer genomes is particularly high, as shown by deep-sequencing studies supporting the heterogeneity of lung tumors at cellular level, with sub-clones exhibiting different combinations of mutations. Molecular studies performed on lung tumors during treatment have shown the phenomenon of clonal evolution, thus supporting the occurrence of a temporal tumor heterogeneity.
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Affiliation(s)
- Ugo Testa
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Germana Castelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Elvira Pelosi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
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Identification of a MET-eIF4G1 translational regulation axis that controls HIF-1α levels under hypoxia. Oncogene 2018; 37:4181-4196. [DOI: 10.1038/s41388-018-0256-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 02/13/2018] [Accepted: 03/14/2018] [Indexed: 02/02/2023]
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23
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Ghanem S, El Bitar S, Hossri S, Weerasinghe C, Atallah JP. What we know about surgical therapy in early-stage non-small-cell lung cancer: a guide for the medical oncologist. Cancer Manag Res 2017; 9:267-278. [PMID: 28740431 PMCID: PMC5505543 DOI: 10.2147/cmar.s139253] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Lung cancer remains the leading cause of death in cancer patients. The gold standard for the treatment of early-stage non-small-cell lung cancer is lobectomy with mediastinal lymph-node dissection or systematic lymph-node sampling. The evidence behind this recommendation is based on the sole randomized controlled trial conducted to date, done by the Lung Cancer Study Group and published in 1995, which found a superiority for lobectomy over sublobar resection with regard to local recurrence rate and improved survival. The population studied at that time were medically fit patients at low risk for surgery with a stage IA non-small-cell lung carcinoma, ie, a solitary tumor less than 3 cm in size. In practice, however, thoracic surgeons have continued to push the limit of a more conservative surgical resection in this patient population. Since then, several retrospective studies have attempted to identify the ideal population to benefit from sublobar resection without it affecting survival or local recurrence. Several variables have been studied, including tumor size, patient age, surgical approach, histological and radiological properties, and optimal surgical resection margin, as well as promising prognostic biomarkers. In this review, we summarize the data available in the literature regarding the surgical approach to patients with stage IA non-small-cell lung cancer studying all the aforementioned variables.
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Affiliation(s)
| | | | | | - Chanudi Weerasinghe
- Department of Hematology and Oncology, Staten Island University Hospital - Northwell Health, New York, NY, USA
| | - Jean Paul Atallah
- Department of Hematology and Oncology, Staten Island University Hospital - Northwell Health, New York, NY, USA
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