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Li T, Jiang Y, Bai Y, Jiang K, Du G, Chen P, Luo C, Li L, Qiao J, Shen J. A review for the impacts of circadian disturbance on urological cancers. Sleep Biol Rhythms 2024; 22:163-180. [PMID: 38524168 PMCID: PMC10959858 DOI: 10.1007/s41105-023-00500-1] [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: 06/29/2023] [Accepted: 10/18/2023] [Indexed: 03/26/2024]
Abstract
Circadian rhythm is an internal timing system and harmonizes a variety of cellular, behavioral, and physiological processes to daily environment. Circadian disturbance caused by altered life style or disrupted sleep patterns inevitably contributes to various disorders. As the rapidly increased cancer occurrences and subsequent tremendous financial burdens, more researches focus on reducing the morbidity rather than treating it. Recently, many epidemiologic studies demonstrated that circadian disturbance was tightly related to the occurrence and development of cancers. For urinary system, numerous clinical researches observed the incidence and progress of prostate cancer were influenced by nightshift work, sleep duration, chronotypes, light exposure, and meal timing, this was also proved by many genetic and fundamental findings. Although the epidemiological studies regarding the relationship between circadian disturbance and kidney/bladder cancers were relative limited, some basic researches still claimed circadian disruption was closely correlated to these two cancers. The role of circadian chemotherapy on cancers of prostate, kidney, and bladder were also explored, however, it has not been regularly recommended considering the limited evidence and poor standard protocols. Finally, the researches for the impacts of circadian disturbance on cancers of adrenal gland, penis, testis were not found at present. In general, a better understanding the relationship between circadian disturbance and urological cancers might help to provide more scientific work schedules and rational lifestyles which finally saving health resource by reducing urological tumorigenesis, however, the underlying mechanisms are complex which need further exploration.
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Affiliation(s)
- Tao Li
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yiting Jiang
- Department of Otorhinolaryngology, The Ninth People’s Hospital of Chongqing, Chongqing, China
| | - Yunjin Bai
- Department of Urology and Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Kehua Jiang
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Guangshi Du
- Translational Medicine Research Center of Guizhou Medical University, Guiyang, China
| | - Peng Chen
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Chao Luo
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lei Li
- Gastrointestinal Surgery Center, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Qiao
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jun Shen
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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2
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Du H, Huang R, Chen DS, Zhuang T, Huang X, Zhang H, Li Z. Regulation of soldier caste differentiation by microRNAs in Formosan subterranean termite ( Coptotermes formosanus Shiraki). PeerJ 2024; 12:e16843. [PMID: 38436016 PMCID: PMC10909360 DOI: 10.7717/peerj.16843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 01/05/2024] [Indexed: 03/05/2024] Open
Abstract
The soldier caste is one of the most distinguished castes inside the termite colony. The mechanism of soldier caste differentiation has mainly been studied at the transcriptional level, but the function of microRNAs (miRNAs) in soldier caste differentiation is seldom studied. In this study, the workers of Coptotermes formosanus Shiraki were treated with methoprene, a juvenile hormone analog which can induce workers to transform into soldiers. The miRNomes of the methoprene-treated workers and the controls were sequenced. Then, the differentially expressed miRNAs (DEmiRs) were corrected with the differentially expressed genes DEGs to construct the DEmiR-DEG regulatory network. Afterwards, the DEmiR-regulated DEGs were subjected to GO enrichment and KEGG enrichment analysis. A total of 1,324 miRNAs were identified, among which 116 miRNAs were screened as DEmiRs between the methoprene-treated group and the control group. A total of 4,433 DEmiR-DEG pairs were obtained. No GO term was recognized as significant in the cellular component, molecular function, or biological process categories. The KEGG enrichment analysis of the DEmiR-regulated DEGs showed that the ribosome biogenesis in eukaryotes and circadian rhythm-fly pathways were enriched. This study demonstrates that DEmiRs and DEGs form a complex network regulating soldier caste differentiation in termites.
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Affiliation(s)
- He Du
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Runmei Huang
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Da-Song Chen
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Tianyong Zhuang
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Xueyi Huang
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Huan Zhang
- State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Zhiqiang Li
- Guangdong Key Laboratory of Integrated Pest Management in Agriculture, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
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He J, Hu J, Liu H. A three-gene random forest model for diagnosing idiopathic pulmonary fibrosis based on circadian rhythm-related genes in lung tissue. Expert Rev Respir Med 2023; 17:1307-1320. [PMID: 38285622 DOI: 10.1080/17476348.2024.2311262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/24/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND The disorder of circadian rhythm could be a key factor mediating fibrotic lung disease Therefore, our study aims to determine the diagnostic value of circadian rhythm-related genes (CRRGs) in IPF. METHODS We retrieved the data on CRRGs from previous studies and the GSE150910 dataset. The participants from the GSE150910 dataset were divided into training and internal validation sets. Next, we used several various bioinformatics methods and machine learning algorithms to screen genes. Next, we identified SEMA5A, COL7A1, and TUBB3, which were included in the random forest (RF) diagnostic model. Finally, external validation was conducted on data retrieved from the GSE184316 datasets. RESULTS The results revealed that the RF diagnostic model could diagnose patients with IPF in the internal validation set with the area under the ROC curve (AUC) value of 0.905 and in the external validation with the AUC value of 0.767. Furthermore, real-time quantitative PCR and western blotting results revealed a significant decrease in SEMA5A (p < 0.05) expression level and an increase in COL7A1 and TUBB3 expression levels in TGF-β1-treated normal human lung fibroblasts. CONCLUSION We constructed an RF diagnostic model based on SEMA5A, COL7A1, and TUBB3 expression in lung tissue for diagnosing patients with IPF.
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Affiliation(s)
- Jie He
- Clinical Medical College of Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Jun Hu
- Clinical Medical College of Chengdu Medical College, Chengdu, Sichuan, China
- Department of Otolaryngology - Head and Neck Surgery, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Hairong Liu
- Clinical Medical College of Chengdu Medical College, Chengdu, Sichuan, China
- Department of Geriatric Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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Malik MZ, Dashti M, Fatima Y, Channanath A, John SE, Singh RKB, Al-Mulla F, Thanaraj TA. Disruption in the regulation of casein kinase 2 in circadian rhythm leads to pathological states: cancer, diabetes and neurodegenerative disorders. Front Mol Neurosci 2023; 16:1217992. [PMID: 37475884 PMCID: PMC10354274 DOI: 10.3389/fnmol.2023.1217992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
Introduction Circadian rhythm maintains the sleep-wake cycle in biological systems. Various biological activities are regulated and modulated by the circadian rhythm, disruption of which can result in onset of diseases. Robust rhythms of phosphorylation profiles and abundances of PERIOD (PER) proteins are thought to be the master keys that drive circadian clock functions. The role of casein kinase 2 (CK2) in circadian rhythm via its direct interactions with the PER protein has been extensively studied; however, the exact mechanism by which it affects circadian rhythms at the molecular level is not known. Methods Here, we propose an extended circadian rhythm model in Drosophila that incorporates the crosstalk between the PER protein and CK2. We studied the regulatory role of CK2 in the dynamics of PER proteins involved in circadian rhythm using the stochastic simulation algorithm. Results We observed that variations in the concentration of CK2 in the circadian rhythm model modulates the PER protein dynamics at different cellular states, namely, active, weakly active, and rhythmic death. These oscillatory states may correspond to distinct pathological cellular states of the living system. We find molecular noise at the expression level of CK2 to switch normal circadian rhythm to any of the three above-mentioned circadian oscillatory states. Our results suggest that the concentration levels of CK2 in the system has a strong impact on its dynamics, which is reflected in the time evolution of PER protein. Discussion We believe that our findings can contribute towards understanding the molecular mechanisms of circadian dysregulation in pathways driven by the PER mutant genes and their pathological states, including cancer, obesity, diabetes, neurodegenerative disorders, and socio-psychological disease.
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Affiliation(s)
- Md. Zubbair Malik
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mohammed Dashti
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Yasmin Fatima
- Department of Computational Biology and Bioinformatics, Sam Higginbottom Institute of Agriculture, Technology and Sciences (Formerly Allahabad Agricultural Institute-Deemed University), Allahabad, India
| | - Arshad Channanath
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Sumi Elsa John
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - R. K. Brojen Singh
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait City, Kuwait
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Lopes-Júnior LC, Veronez LC. Circadian rhythms disruption in cancer. BIOL RHYTHM RES 2022; 53:1382-1399. [DOI: 10.1080/09291016.2021.1951470] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Luís Carlos Lopes-Júnior
- Postgraduate Program in Nutrition and Health in Sciences. Health Sciences Center at the Universidade Federal Do Espírito Santo (UFES), Vitória, ES, Brazil
| | - Luciana Chain Veronez
- BSc in Biology., Ph.D. In Immunology. Post-doctoral Fellow at the Department of Childcare and Pediatrics at the Ribeirão PretoMedical School at the University of São Paulo (USP). (FMRP-USP)., Ribeirão Preto, SP, Brazil
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Li J, Cao D, Huang Y, Chen Z, Wang R, Dong Q, Wei Q, Liu L. Sleep duration and health outcomes: an umbrella review. Sleep Breath 2022; 26:1479-1501. [PMID: 34435311 DOI: 10.1007/s11325-021-02458-1] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/18/2021] [Accepted: 07/28/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE To collect existing evidence on the relationship between sleep duration and health outcomes. METHODS A thorough search was conducted in PubMed, Web of Science, Embase, and the Cochrane Database of Systematic Reviews from inception to January, 2021. Meta-analyses of observational and interventional studies were eligible if they examined the associations between sleep duration and human health. RESULTS In total, this umbrella review identified 69 meta-analyses with 11 outcomes for cancers and 30 outcomes for non-cancer conditions. Inappropriate sleep durations may significantly elevate the risk for cardiovascular disease (CVD), cognitive decline, coronary heart disease (CHD), depression, falls, frailty, lung cancer, metabolic syndrome (MS), and stroke. Dose-response analysis revealed that a 1-h reduction per 24 hours is associated with an increased risk by 3-11% of all-cause mortality, CHD, osteoporosis, stroke, and T2DM among short sleepers. Conversely, a 1-h increment in long sleepers is associated with a 7-17% higher risk of stroke mortality, CHD, stroke, and T2DM in adults. CONCLUSION Inappropriate sleep duration is a risk factor for developing non-cancer conditions. Decreasing and increasing sleep hours towards extreme sleep durations are associated with poor health outcomes.
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Affiliation(s)
- Jin Li
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Dehong Cao
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Yin Huang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Zeyu Chen
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Ruyi Wang
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiang Dong
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Qiang Wei
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Liangren Liu
- Department of Urology/Institute of Urology, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
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Kaur P, Mohamed NE, Archer M, Figueiro MG, Kyprianou N. Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers. Front Oncol 2022; 12:759153. [PMID: 35356228 PMCID: PMC8959649 DOI: 10.3389/fonc.2022.759153] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 01/24/2022] [Indexed: 01/27/2023] Open
Abstract
The circadian system is an innate clock mechanism that governs biological processes on a near 24-hour cycle. Circadian rhythm disruption (i.e., misalignment of circadian rhythms), which results from the lack of synchrony between the master circadian clock located in the suprachiasmatic nuclei (SCN) and the environment (i.e., exposure to day light) or the master clock and the peripheral clocks, has been associated with increased risk of and unfavorable cancer outcomes. Growing evidence supports the link between circadian disruption and increased prevalence and mortality of genitourinary cancers (GU) including prostate, bladder, and renal cancer. The circadian system also plays an essential role on the timely implementation of chronopharmacological treatments, such as melatonin and chronotherapy, to reduce tumor progression, improve therapeutic response and reduce negative therapy side effects. The potential benefits of the manipulating circadian rhythms in the clinical setting of GU cancer detection and treatment remain to be exploited. In this review, we discuss the current evidence on the influence of circadian rhythms on (disease) cancer development and hope to elucidate the unmet clinical need of defining the extensive involvement of the circadian system in predicting risk for GU cancer development and alleviating the burden of implementing anti-cancer therapies.
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Affiliation(s)
- Priya Kaur
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nihal E. Mohamed
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Maddison Archer
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Mariana G. Figueiro
- Light and Health Research Center, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, United States,Tisch Cancer Institute, Mount Sinai Health, New York, NY, United States,*Correspondence: Natasha Kyprianou, ; Mariana G. Figueiro,
| | - Natasha Kyprianou
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, United States,Tisch Cancer Institute, Mount Sinai Health, New York, NY, United States,Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States,*Correspondence: Natasha Kyprianou, ; Mariana G. Figueiro,
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Malik S, Stokes Iii J, Manne U, Singh R, Mishra MK. Understanding the significance of biological clock and its impact on cancer incidence. Cancer Lett 2022; 527:80-94. [PMID: 34906624 PMCID: PMC8816870 DOI: 10.1016/j.canlet.2021.12.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/01/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022]
Abstract
The circadian clock is an essential timekeeper that controls, for humans, the daily rhythm of biochemical, physiological, and behavioral functions. Irregular performance or disruption in circadian rhythms results in various diseases, including cancer. As a factor in cancer development, perturbations in circadian rhythms can affect circadian homeostasis in energy balance, lead to alterations in the cell cycle, and cause dysregulation of chromatin remodeling. However, knowledge gaps remain in our understanding of the relationship between the circadian clock and cancer. Therefore, a mechanistic understanding by which circadian disruption enhances cancer risk is needed. This review article outlines the importance of the circadian clock in tumorigenesis and summarizes underlying mechanisms in the clock and its carcinogenic mechanisms, highlighting advances in chronotherapy for cancer treatment.
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Affiliation(s)
- Shalie Malik
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA; Department of Zoology and Dr. Giri Lal Gupta Institute of Public Health and Public Affairs, University of Lucknow, Lucknow, UP, India
| | - James Stokes Iii
- Department of Biological and Environmental Sciences, Auburn University, Montgomery, AL, USA
| | - Upender Manne
- Departments of Pathology, Surgery and Epidemiology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rajesh Singh
- Department of Microbiology, Biochemistry, and Immunology, Cancer Health Equity Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Manoj K Mishra
- Cancer Biology Research and Training, Department of Biological Sciences, Alabama State University, Montgomery, AL, USA.
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Liu W, Zhang H. Do sleep quality and psychological factors link precancerous conditions of colorectal cancer? A retrospective case-control study. Expert Rev Gastroenterol Hepatol 2022; 16:173-179. [PMID: 35043737 DOI: 10.1080/17474124.2022.2029701] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Little is known about the effect of sleep quality on the risk of precancerous conditions of colorectal cancer (PCRC). The role of psychological factors, including stress, resilience, and social support as closely related factors of sleep quality, was also discussed. RESEARCH DESIGN AND METHODS Fifty-one patients with PCRC were compared with two control groups during the previous year in a retrospective case-control analysis: 74 patients with colorectal cancer and 145 healthy controls. Participants completed questionnaires measuring sleep quality, perceived stress, resilience, and social support one year prior to disease diagnosis. Univariate and multivariate logistic regression models were used to analyze the data. RESULTS Increased risk of PCRC was associated with sleep disturbance≥2 and the negative factors of stress ≥14 compared with healthy controls. Decreased risk of PCRC was associated with resilience ≥31 and family support ≥18. In a multivariate model, sleep disturbance≥2 was significantly associated with an elevated risk of PCRC (OR = 20.15, 95% CI: 4.22 to 96.26). CONCLUSIONS Physicians should be aware of the strong association between sleep disturbance≥2 and the increased risk for PCRC and explain the need for colonoscopy in patients with sleep disturbance≥2.
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Affiliation(s)
- Wei Liu
- Department of Gastroenterology in the First Affiliated Hospital, Zhengzhou University, Zhengzhou Henan, China
| | - Huijie Zhang
- Department of Gastroenterology in the First Affiliated Hospital, Zhengzhou University, Zhengzhou Henan, China
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Tan XG, Zhu J, Cui L. MicroRNA expression signature and target prediction in familial and sporadic primary macronodular adrenal hyperplasia (PMAH). BMC Endocr Disord 2022; 22:11. [PMID: 34986816 PMCID: PMC8729020 DOI: 10.1186/s12902-021-00910-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 12/05/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Primary macronodular adrenal hyperplasia (PMAH), previously termed ACTH-independent macronodular adrenal hyperplasia (AIMAH), is a rare cause of Cushing's syndrome usually characterized by functioning adrenal macronodules and increased cortisol production. METHODS To screen and analyse the microRNA (miRNA) profile of PMAH in order to elucidate its possible pathogenesis, a miRNA microarray was used to test tissue samples from patients with familial PMAH, patients with sporadic PMAH and normal control samples of other nontumour adrenocortical tissues and identify characteristic microRNA expression signatures. Randomly selected miRNAs were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, the key signalling pathways and miRNAs involved in PMAH pathogenesis were determined by gene ontology and pathway analysis. RESULTS Characteristic microRNA expression signatures were identified for patients with familial PMAH (16 differentially expressed microRNAs) and patients with sporadic PMAH (8 differentially expressed microRNAs). The expression of the selected miRNAs was confirmed by qRT-PCR, suggesting the high reliability of the miRNA array analysis results. Pathway analysis showed that the most enriched pathway was the renal cell carcinoma pathway. Overexpression of miR-17, miR-20a and miR-130b may inhibit glucocorticoid-induced apoptosis in PMAH pathogenesis. CONCLUSION We identified the miRNA signatures in patients with familial and sporadic PMAH. The differentially expressed miRNAs may be involved in the mechanisms of PMAH pathogenesis. Specific miRNAs, such as miR-17, miR-20a and miR-130b, may be new targets for further functional studies of PMAH.
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Affiliation(s)
- Xiao-Gang Tan
- Department of Thoracic Surgery, Xuan Wu Hospital of Capital Medical University, Beijing, 100053, China
| | - Jie Zhu
- Department of Urology Surgery, Chinese PLA General Hospital, Beijing, 100082, China
| | - Liang Cui
- Department of Urology Surgery, Civil Aviation General Hospital, Beijing, 100123, China.
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Zhang G, Liu X, Sun Z, Feng X, Wang H, Hao J, Zhang X. A2M is a potential core gene in intrahepatic cholangiocarcinoma. BMC Cancer 2022; 22:5. [PMID: 34979994 PMCID: PMC8722218 DOI: 10.1186/s12885-021-09070-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 11/29/2021] [Indexed: 12/31/2022] Open
Abstract
Background Intrahepatic cholangiocarcinoma (ICC) is a type of malignant tumor ranking the second in the incidence of primary liver cancer following hepatocellular carcinoma. Both the morbidity and mortality have been increasing in recent years. Small duct type of ICC has potential therapeutic targets. But overall, the prognosis of patients with ICC is usually very poor. Methods To search latent therapeutic targets for ICC, we programmatically selected the five most suitable microarray datasets. Then, we made an analysis of these microarray datasets (GSE26566, GSE31370, GSE32958, GSE45001 and GSE76311) collected from the Gene Expression Omnibus (GEO) database. The GEO2R tool was effective to find out differentially expressed genes (DEGs) between ICC and normal tissue. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were executed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) v 6.8. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to analyze protein–protein interaction of these DEGs and protein–protein interaction of these DEGs was modified by Cytoscape3.8.2. Survival analysis was performed using Gene Expression Profiling Interactive Analysis (GEPIA) online analysis tool. Results A total of 28 upregulated DEGs and 118 downregulated DEGs were screened out. Then twenty hub genes were selected according to the connectivity degree. The survival analysis results showed that A2M was closely related to the pathogenesis and prognosis of ICC and was a potential therapeutic target for ICC. Conclusions According to our study, low A2M expression in ICC compared to normal bile duct tissue was an adverse prognostic factor in ICC patients. The value of A2M in the treatment of ICC needs to be further studied.
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Affiliation(s)
- Guanran Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Xuyue Liu
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Zhengyang Sun
- School of Information Engineering, Zhengzhou University, Zhengzhou, 450001, Henan, China
| | - Xiaoning Feng
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Haiyan Wang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jing Hao
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology & Embryology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
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Barth E, Srivastava A, Wengerodt D, Stojiljkovic M, Axer H, Witte OW, Kretz A, Marz M. Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging. Aging (Albany NY) 2021; 13:25694-25716. [PMID: 34923482 PMCID: PMC8751596 DOI: 10.18632/aging.203788] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022]
Abstract
The circadian clock system influences the biology of life by establishing circadian rhythms in organisms, tissues, and cells, thus regulating essential biological processes based on the day/night cycle. Circadian rhythms change over a lifetime due to maturation and aging, and disturbances in the control of the circadian system are associated with several age-related pathologies. However, the impact of chronobiology and the circadian system on healthy organ and tissue aging remains largely unknown. Whether aging-related changes of the circadian system’s regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear. Based on a cross-sectional transcriptome analysis covering 329 RNA-Seq libraries, we provide indications that the circadian system is subjected to aging-related gene alterations shared between evolutionarily distinct species, such as Homo sapiens, Mus musculus, Danio rerio, and Nothobranchius furzeri. We discovered differentially expressed genes by comparing tissue-specific transcriptional profiles of mature, aged, and old-age individuals and report on six genes (per2, dec2, cirp, klf10, nfil3, and dbp) of the circadian system, which show conserved aging-related expression patterns in four organs of the species examined. Our results illustrate how the circadian system and aging might influence each other in various tissues over a long lifespan and conceptually complement previous studies tracking short-term diurnal and nocturnal gene expression oscillations.
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Affiliation(s)
- Emanuel Barth
- Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany
| | - Akash Srivastava
- Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany.,FLI Leibniz Institute for Age Research, Jena, Germany.,Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Diane Wengerodt
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Milan Stojiljkovic
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Hubertus Axer
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Otto W Witte
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Alexandra Kretz
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Manja Marz
- Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany.,FLI Leibniz Institute for Age Research, Jena, Germany.,German Center for Integrative Biodiversity Research (iDiv), Halle-Jena-Leipzig, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
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13
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Zampetidis CP, Galanos P, Angelopoulou A, Zhu Y, Polyzou A, Karamitros T, Kotsinas A, Lagopati N, Mourkioti I, Mirzazadeh R, Polyzos A, Garnerone S, Mizi A, Gusmao EG, Sofiadis K, Gál Z, Larsen DH, Pefani DE, Demaria M, Tsirigos A, Crosetto N, Maya-Mendoza A, Papaspyropoulos A, Evangelou K, Bartek J, Papantonis A, Gorgoulis VG. A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization. Mol Cell 2021; 81:4907-4923.e8. [PMID: 34793711 DOI: 10.1016/j.molcel.2021.10.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 07/14/2021] [Accepted: 10/16/2021] [Indexed: 12/12/2022]
Abstract
Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying "escape" from oncogene-induced senescence.
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Affiliation(s)
- Christos P Zampetidis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Panagiotis Galanos
- Genome Integrity Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
| | - Andriani Angelopoulou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Yajie Zhu
- Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Aikaterini Polyzou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Timokratis Karamitros
- Unit of Bioinformatics and Applied Genomics, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece
| | - Athanassios Kotsinas
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nefeli Lagopati
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioanna Mourkioti
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Reza Mirzazadeh
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden
| | - Alexandros Polyzos
- Sanford I. Weill Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Silvano Garnerone
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden
| | - Athanasia Mizi
- Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Eduardo G Gusmao
- Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Konstantinos Sofiadis
- Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Zita Gál
- Nucleolar Stress and Disease Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
| | - Dorthe H Larsen
- Nucleolar Stress and Disease Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
| | | | - Marco Demaria
- University of Groningen (RUG), European Research Institute for the Biology of Aging (ERIBA), University Medical Center Groningen (UMCG), 9713 AV Groningen, the Netherlands
| | | | - Nicola Crosetto
- Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden
| | - Apolinar Maya-Mendoza
- DNA Replication and Cancer Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
| | - Angelos Papaspyropoulos
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Evangelou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece
| | - Jiri Bartek
- Genome Integrity Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Solna, Stockholm, Sweden.
| | - Argyris Papantonis
- Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
| | - Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Faculty of Medicine, National Kapodistrian University of Athens, 11527 Athens, Greece; Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, University of Manchester, M20 4GJ Manchester, UK; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; Faculty of Health and Medical Sciences, University of Surrey, Surrey GU2 7YH, UK.
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Sadiq Z, Varghese E, Büsselberg D. Cisplatin's dual-effect on the circadian clock triggers proliferation and apoptosis. Neurobiol Sleep Circadian Rhythms 2020; 9:100054. [PMID: 33364523 PMCID: PMC7752721 DOI: 10.1016/j.nbscr.2020.100054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 02/16/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
The circadian clock, which generates the internal daily rhythm largely mediated through release of melatonin, can be disrupted in various ways. Multiple factors result in a disruption of the circadian cycle in the clinical context, of interest are anti-cancer drugs such as cisplatin. Cisplatin modulates the circadian clock through two mechanisms: 1) the circadian clock control of DNA excision repair and 2) the effect of circadian clock disruption on apoptosis. Cisplatin can stimulate multiple classified molecules, including DNA repair factors, DNA damage recognition factors and transcription factors in drug resistance and cisplatin-induced signal transduction. These factors interact with each other and can be transformed by DNA damage. Hence, these molecular interactions are intimately involved in cell proliferation and damage-induced apoptosis. Cisplatin has a dual-effect on circadian genes: upregulation of CLOCK expression causes an increase in proliferation but upregulation of BMAL1 expression causes an increase in apoptosis. Therefore, the interference of circadian genes by cisplatin can have multiple, opposing effects on apoptosis and cell proliferation, which may have unintended pro-cancer effects. Melatonin and intracellular Ca2+ also have a dual-effect on cell proliferation and apoptosis and can disrupt circadian rhythms.
Cisplatin has a dual-effect on components of the circadian clock, increasing or decreasing cell proliferation and apoptosis. DNA excision repair and apoptosis are controlled by circadian rhythms. When cisplatin is combined with other agents, the effects are enhanced. These findings provide clinicians with the prospect to create effective chrono-cisplatin regimens for patients.
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Affiliation(s)
- Zuhair Sadiq
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box, 24144, Qatar
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box, 24144, Qatar
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, P.O. Box, 24144, Qatar
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15
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Dagmura H, Yiğit S, Nursal AF, Duman E, Gumusay O. Possible Association of PER2/PER3 Variable Number Tandem Repeat Polymorphism Variants with Susceptibility and Clinical Characteristics in Pancreatic Cancer. Genet Test Mol Biomarkers 2020; 25:124-130. [PMID: 33393850 DOI: 10.1089/gtmb.2020.0179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective: Pancreatic cancer (PC) is a serious disease with poor outcomes, and its prevalence has been increasing steadily. The circadian rhythm (CR) is involved in multiple physiological events and maintains homeostasis. Alterations in the CR elevate the risk of developing cancer. The present case-control research was carried out to estimate the possible association between PERIOD2/PERIOD3 (PER2/PER3) gene variable number tandem repeat polymorphism (VNTR) variants and PC in the Turkish population. Materials and Methods: A total of 198 subjects (78 patients with PC and 120 healthy controls) were enrolled in this work. Genomic DNA was collected from peripheral blood mononuclear cells, and genotypic analyses was performed using a polymerase chain reaction (PCR) method. Odds ratio (OR) with a 95% confidence interval (95% CI) was calculated using the χ2 test. Results: The frequency of the 4R (4 repeats)/3R (3 repeats), 3R/3R genotypes, and 3R allele of PER2 VNTR in patients with PC was significantly higher than in the control group (p = 0003, p = 0.00004, respectively). PER2 VNTR 4/5 genotype was related to perineural invasion (p = 0.040). The genotype and allele distribution of PER3 VNTR variant did not show any statistical difference between the two groups (p > 0.05). The PER2/PER3 VNTR 4/5-4R/3R combined genotype was increased in the patient group (p = 0.013), while 4/5-4R/4R combined genotype was increased in the control group (p = 0.0001). Conclusions: Our work has indicated that PER2 VNTR 3R allele may play a crucial role in the pathogenesis of PC in Turkish patients, which may become a useful marker for predicting the development of PC. Furthermore, the PER2 VNTR genotype seems to be related to perineural invasion in PC.
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Affiliation(s)
- Hasan Dagmura
- Department of Surgical Oncology, Kütahya Health Sciences University, Evliya Çelebi Training and Research Hospital, Kütahya, Turkey
| | - Serbulent Yiğit
- Department of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey
| | | | - Esra Duman
- Department of Veterinary Medicine, Experimental Medicine Center, Gaziosmanpasa University, Kaleardi Mah., Tokat, Turkey
| | - Ozge Gumusay
- Department of Medical Oncology, Gaziosmanpasa University, Kaleardi Mah., Tokat, Turkey
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16
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Walker WH, Bumgarner JR, Walton JC, Liu JA, Meléndez-Fernández OH, Nelson RJ, DeVries AC. Light Pollution and Cancer. Int J Mol Sci 2020; 21:E9360. [PMID: 33302582 PMCID: PMC7764771 DOI: 10.3390/ijms21249360] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/04/2020] [Accepted: 12/06/2020] [Indexed: 01/03/2023] Open
Abstract
For many individuals in industrialized nations, the widespread adoption of electric lighting has dramatically affected the circadian organization of physiology and behavior. Although initially assumed to be innocuous, exposure to artificial light at night (ALAN) is associated with several disorders, including increased incidence of cancer, metabolic disorders, and mood disorders. Within this review, we present a brief overview of the molecular circadian clock system and the importance of maintaining fidelity to bright days and dark nights. We describe the interrelation between core clock genes and the cell cycle, as well as the contribution of clock genes to oncogenesis. Next, we review the clinical implications of disrupted circadian rhythms on cancer, followed by a section on the foundational science literature on the effects of light at night and cancer. Finally, we provide some strategies for mitigation of disrupted circadian rhythms to improve health.
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Affiliation(s)
- William H. Walker
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - Jacob R. Bumgarner
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - James C. Walton
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - Jennifer A. Liu
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - O. Hecmarie Meléndez-Fernández
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - Randy J. Nelson
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
| | - A. Courtney DeVries
- Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, USA; (J.R.B.); (J.C.W.); (J.A.L.); (O.H.M.-F.); (R.J.N.); (A.C.D.)
- Department of Medicine, Division of Oncology/Hematology, West Virginia University, Morgantown, WV 26506, USA
- West Virginia University Cancer Institute, West Virginia University, Morgantown, WV 26506, USA
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Risk factors including night shift work of colorectal polyp. Ann Occup Environ Med 2020; 32:e26. [PMID: 32802342 PMCID: PMC7406667 DOI: 10.35371/aoem.2020.32.e26] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 06/26/2020] [Indexed: 12/15/2022] Open
Abstract
Background The destruction of circadian rhythms by night shift work affects major circadian genes, which are known to play a role in advancing or killing the cell cycle through tumor suppressor genes. To find out whether night shift work affects the incidence of colorectal cancer, which was found to be associated with long-term night shift work in previous studies, we surveyed effect of night shift work on colorectal polyps that have a higher incidence than colorectal cancer and can progress to colorectal cancer. Methods To examine the correlation between rotating night shifts and colorectal polyps, a survey was conducted with 299 men aged 40–60 years from two university hospitals. We examined lifestyle, work history, work patterns, and colonoscopy results. The differences in prevalence among the groups was compared, and prevalence ratio (PR) was calculated via generalized linear modeling. Results The prevalence of colorectal polyps in night shift and non-shift workers were 53.0% and 33.5%, respectively. After adjusting for age, smoking status, dietary habits, family history of colorectal cancer, obesity, job type, night shift work (PR: 1.13, 95% CI: 1.02–1.25) was a risk factor of colorectal polyps. Conclusions The risk of colorectal polyps was greater in night shift workers than non-shift workers. Also risk of colorectal polyp was higher in older group. Our study investigated colorectal polyp instead of colorectal cancer and lacks information about types and gene mutations of colorectal polyps. Further study is needed to clarify effect of night shift work on development of colorectal cancer.
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Emeklİ R, İsmaİloğullari S, Bayram A, Akalin H, Tuncel G, Dündar M. Comparing expression levels of PERIOD genes PER1, PER2 and PER3 in chronic insomnia patients and medical staff working in the night shift. Sleep Med 2020; 73:101-105. [PMID: 32805476 DOI: 10.1016/j.sleep.2020.04.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/22/2020] [Accepted: 04/28/2020] [Indexed: 10/24/2022]
Abstract
AIM This study was done to determine the changes in expression levels of PERIOD family genes in chronic insomnia patients and night shift healthcare staff with irregular sleep hours. METHOD A total of 24 chronic insomnia patients aged between 25 and 55 that were admitted to Erciyes University Medical Faculty Neurology Polyclinic, 32 medical staff aged between 23 and 42 that work in night shifts with no neurological diagnosis were included as volunteers in the experiment. Additionally, a control group consisting of 29 healthy individuals between 21 and 50 years of age who do not work in shifts was volunteered in the study. Since PERIOD family gene expressions are affected by time of day and season changes, blood samples were taken from the groups within the same week and at the same time periods. RNA isolation followed by cDNA synthesis from leukocytes was performed from blood samples that were kept in 10 cc EDTA tubes. Expression levels of the genes were then determined by quantitative PCR method and analysed. RESULTS There was a significant decrease in the expression levels of PER1 and PER2 genes in chronic insomnia and night shift healthcare professional groups compared to the control group (p = 0.0001 for PER1; p = 0.0023 for PER2), but no significant change was observed in PER3 gene (p = 0.619). DISCUSSION The decrease in PER1 and PER2 gene expressions in chronic insomnia and shift working healthcare personnel seems to be more of a result for short sleep periods than a cause.
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Affiliation(s)
- Rabia Emeklİ
- Department of Medical Genetics, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Sevda İsmaİloğullari
- Department of Neurology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Arslan Bayram
- Department of Medical Genetics, Etlik Zübeyde Hanım Women's Diseases Education and Research Hospital, Ankara, Turkey
| | - Hilal Akalin
- Department of Medical Genetics, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Gülten Tuncel
- Institute of Experimental Health Sciences (DESAM), Near East University, Nicosia, Turkish Republic of Northern Cyprus, Cyprus
| | - Munis Dündar
- Department of Medical Genetics, Erciyes University Faculty of Medicine, Kayseri, Turkey.
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Effect of naive and cancer-educated fibroblasts on colon cancer cell circadian growth rhythm. Cell Death Dis 2020; 11:289. [PMID: 32341349 PMCID: PMC7184765 DOI: 10.1038/s41419-020-2468-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 02/18/2020] [Accepted: 02/18/2020] [Indexed: 01/28/2023]
Abstract
Opportunistic modification of the tumour microenvironment by cancer cells enhances tumour expansion and consequently eliminates tumour suppressor components. We studied the effect of fibroblasts on the circadian rhythm of growth and protein expression in colon cancer HCT116 cells and found diminished oscillation in the proliferation of HCT116 cells co-cultured with naive fibroblasts, compared with those co-cultured with tumour-associated fibroblasts (TAFs) or those cultured alone, suggesting that TAFs may have lost or gained factors that regulate circadian phenotypes. Based on the fibroblast paracrine factor analysis, we tested IL6, which diminished HCT116 cell growth oscillation, inhibited early phase cell proliferation, increased early phase expression of the differentiation markers CEA and CDX2, and decreased early phase ERK5 phosphorylation. In conclusion, our data demonstrate how the cancer education of naive fibroblasts influences the circadian parameters of neighbouring cancer cells and highlights a putative role for IL6 as a novel candidate for preoperative treatments.
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20
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Role of Non-Coding RNAs in Lung Circadian Clock Related Diseases. Int J Mol Sci 2020; 21:ijms21083013. [PMID: 32344623 PMCID: PMC7215637 DOI: 10.3390/ijms21083013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent in other organs. Circadian dysregulation has been attributed to dysregulation of peripheral clock and also associated with several diseases. Components of the molecular clock are disrupted in lung diseases like chronic obstructive pulmonary disease (COPD), asthma and IPF. Airway epithelial cells play an important role in temporally organizing magnitude of immune response, DNA damage response and acute airway inflammation. Non-coding RNAs play an important role in regulation of molecular clock and in turn are also regulated by clock components. Dysregulation of these non-coding RNAs have been shown to impact the expression of core clock genes as well as clock output genes in many organs. However, no studies have currently looked at the potential impact of these non-coding RNAs on lung molecular clock. This review focuses on the ways how these non-coding RNAs regulate and in turn are regulated by the lung molecular clock and its potential impact on lung diseases.
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Keshvari M, Nejadtaghi M, Hosseini-Beheshti F, Rastqar A, Patel N. Exploring the role of circadian clock gene and association with cancer pathophysiology. Chronobiol Int 2019; 37:151-175. [PMID: 31791146 DOI: 10.1080/07420528.2019.1681440] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues.The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock.Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body's internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients.In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns.
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Affiliation(s)
- Mahtab Keshvari
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada
| | - Mahdieh Nejadtaghi
- Department of Medical Genetics, faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Ali Rastqar
- Department of Psychiatry and Neuroscience, Université Laval, Quebec, Canada
| | - Niraj Patel
- Centre de Recherche CERVO, Université Laval, Québec, Canada
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Hurley S, Goldberg D, Von Behren J, DeHart JC, Wang S, Reynolds P. Chronotype and postmenopausal breast cancer risk among women in the California Teachers Study. Chronobiol Int 2019; 36:1504-1514. [PMID: 31452403 PMCID: PMC6818501 DOI: 10.1080/07420528.2019.1658113] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/26/2019] [Accepted: 08/17/2019] [Indexed: 01/07/2023]
Abstract
Chronotype is the behavioral manifestation of an individual's underlying circadian rhythm, generally characterized by one's propensity to sleep at a particular time during the 24 hour cycle. Evening chronotypes ("night owls") generally suffer from worse physical and mental health compared to morning chronotypes ("morning larks") - for reasons that have yet to be explained. One hypothesis is that evening chronotypes may be more susceptible to circadian disruption, a condition where the coordinated timing of biologic processes breaks down. The role of chronotype as an independent or modifying risk factor for cancer has not been widely explored. The objective of the current study was to evaluate the risk of breast cancer associated with chronotype in a case-control study nested within the California Teachers Study (CTS) cohort. The study population consisted of 39686 post-menopausal CTS participants who provided information on chronotype by completing a questionnaire in 2012-2013. 2719 cases of primary invasive breast cancer diagnosed from 1995/1996 through completion of the chronotype questionnaire were identified by linkage of the CTS to the California Cancer Registry. 36967 CTS participants who had remained cancer-free during this same time period served as controls. Chronotype was ascertained by responses to an abbreviated version of the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) and was characterized into five categories: definite morning, more morning than evening, neither morning or evening, more evening than morning, definite evening. Multivariable unconditional logistic regression analyses were performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for each of the chronotypes, adjusted for established breast cancer risk factors. Compared to definite morning types, definite evening types had an increased risk of breast cancer with elevated ORs that were statistically significant in both the crude (OR = 1.24, 95% CI: 1.10-1.40) and fully-adjusted models (OR = 1.20, 95% CI: 1.06-1.35). The risk estimates in the fully-adjusted model for all other chronotypes did not significantly differ from one. These results suggest that evening chronotype may be an independent risk factor for breast cancer among a population of women who are not known to have engaged in any substantial night shift work. Further research in other populations of non-shift workers is warranted.
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Affiliation(s)
- S Hurley
- Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA
| | - D Goldberg
- Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA
| | - J Von Behren
- Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA
| | - J Clague DeHart
- School of Community and Global Health, Claremont Graduate University, Claremont, CA, USA
| | - S Wang
- Division of Health Analytics, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - P Reynolds
- Department of Epidemiology and Biostatistics, University of California San Francisco, CA, USA
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23
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Lin CL, Liu TC, Wang YN, Chung CH, Chien WC. The Association Between Sleep Disorders and the Risk of Colorectal Cancer in Patients: A Population-based Nested Case-Control Study. In Vivo 2019; 33:573-579. [PMID: 30804144 DOI: 10.21873/invivo.11513] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 12/08/2018] [Accepted: 12/11/2018] [Indexed: 12/20/2022]
Abstract
AIM To investigate the risk of colorectal cancer in patients with sleep disorders. MATERIALS AND METHODS We identified 7,355 participants with colorectal cancer between January 1, 2000, and December 31, 2013, from the Longitudinal Health Insurance Database 2005 of the Taiwan National Health Insurance Research Database; 29,420 controls were also identified from the same database based on frequency matching on age, sex, and index date of the cases. Diagnoses of sleep disorders by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) in the cases and controls prior to the index date were assessed. The risk of colorectal cancer in patients with sleep disorders was estimated with multivariate logistic regression analyses. RESULTS The mean age of the 36,775 patients was 63.05 years, and 56% of them were males. The risk of colorectal cancer was higher in patients with sleep disorders compared to those without [adjusted odds ratio (OR)=1.29, 95% confidence interval (CI)=1.13-1.47]. The risk of colorectal cancer was higher in patients having sleep disorders with depression compared to those without the condition (adjusted OR=5.69, 95% CI=4.01-6.98). CONCLUSION The risk of colorectal cancer in patients with sleep disorders was found to be significantly higher by case-control study and particularly pronounced among those with sleep disorders with depression, exhibiting a joint effect on colorectal cancer risk.
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Affiliation(s)
- Chia-Ling Lin
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan, R.O.C
| | - Ta-Chun Liu
- Department of Molecular Oncology, Medical Science Division, University of Oxford, Oxford, U.K
| | - Ya-Ni Wang
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan, R.O.C
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C.,Taiwanese Injury Prevention and Safety Promotion Association (TIPSPA), Taipei, Taiwan, R.O.C
| | - Wu-Chien Chien
- Department of Medical Research, Tri-Service General Hospital and National, Defense Medical Center, Taipei, Taiwan, R.O.C. .,School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C
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24
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Chok KC, Ng CH, Koh RY, Ng KY, Chye SM. The potential therapeutic actions of melatonin in colorectal cancer. Horm Mol Biol Clin Investig 2019; 39:hmbci-2019-0001. [DOI: 10.1515/hmbci-2019-0001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 04/01/2019] [Indexed: 12/24/2022]
Abstract
Abstract
Colorectal cancer (CRC) is the third most common cancer and lethal disease worldwide. Melatonin, an indoleamine produced in pineal gland, shows anticancer effects on a variety of cancers, especially CRC. After clarifying the pathophysiology of CRC, the association of circadian rhythm with CRC, and the relationship between shift work and the incidence of CRC is reviewed. Next, we review the role of melatonin receptors in CRC and the relationship between inflammation and CRC. Also included is a discussion of the mechanism of gene regulation, control of cell proliferation, apoptosis, autophagy, antiangiogenesis and immunomodulation in CRC by melatonin. A review of the drug synergy of melatonin with other anticancer drugs suggests its usefulness in combination therapy. In summary, the information compiled may serve as comprehensive reference for the various mechanisms of action of melatonin against CRC, and as a guide for the design of future experimental research and for advancing melatonin as a therapeutic agent for CRC.
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Affiliation(s)
- Kian Chung Chok
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia
| | - Chew Hee Ng
- School of Pharmacy, International Medical University , Kuala Lumpur , Malaysia
| | - Rhun Yian Koh
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia
| | - Khuen Yen Ng
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia , Selangor , Malaysia
| | - Soi Moi Chye
- School of Health Sciences, International Medical University , Kuala Lumpur , Malaysia , Phone: +6032731 7220; Fax: +60386567229
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25
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Voigt RM, Forsyth CB, Keshavarzian A. Circadian rhythms: a regulator of gastrointestinal health and dysfunction. Expert Rev Gastroenterol Hepatol 2019; 13:411-424. [PMID: 30874451 PMCID: PMC6533073 DOI: 10.1080/17474124.2019.1595588] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Circadian rhythms regulate much of gastrointestinal physiology including cell proliferation, motility, digestion, absorption, and electrolyte balance. Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases. Areas covered: In this review, we evaluate some of the many gastrointestinal functions that are regulated by circadian rhythms and how dysregulation of these functions may contribute to disease. This review also discusses some common gastrointestinal disorders that are known to be influenced by circadian rhythms as well as speculation about the mechanisms by which circadian rhythm disruption promotes dysfunction and disease pathogenesis. We discuss how knowledge of circadian rhythms and the advent of chrono-nutrition, chrono-pharmacology, and chrono-therapeutics might influence clinical practice. Expert opinion: As our knowledge of circadian biology increases, it may be possible to incorporate strategies that take advantage of circadian rhythms and chronotherapy to prevent and/or treat disease.
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Affiliation(s)
- Robin M Voigt
- Rush Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - Christopher B Forsyth
- Rush Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - Ali Keshavarzian
- Rush Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
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26
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Sánchez DI, González-Fernández B, Crespo I, San-Miguel B, Álvarez M, González-Gallego J, Tuñón MJ. Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine-induced hepatocellular carcinoma. J Pineal Res 2018; 65:e12506. [PMID: 29770483 DOI: 10.1111/jpi.12506] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 04/17/2018] [Indexed: 01/07/2023]
Abstract
Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg-1 d-1 ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.
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Affiliation(s)
- Diana I Sánchez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
| | | | - Irene Crespo
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | | | | | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - María Jesús Tuñón
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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27
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Sloin HE, Ruggiero G, Rubinstein A, Smadja Storz S, Foulkes NS, Gothilf Y. Interactions between the circadian clock and TGF-β signaling pathway in zebrafish. PLoS One 2018; 13:e0199777. [PMID: 29940038 PMCID: PMC6016920 DOI: 10.1371/journal.pone.0199777] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 06/13/2018] [Indexed: 12/22/2022] Open
Abstract
Background TGF-β signaling is a cellular pathway that functions in most cells and has been shown to play a role in multiple processes, such as the immune response, cell differentiation and proliferation. Recent evidence suggests a possible interaction between TGF-β signaling and the molecular circadian oscillator. The current study aims to characterize this interaction in the zebrafish at the molecular and behavioral levels, taking advantage of the early development of a functional circadian clock and the availability of light-entrainable clock-containing cell lines. Results Smad3a, a TGF-β signaling-related gene, exhibited a circadian expression pattern throughout the brain of zebrafish larvae. Both pharmacological inhibition and indirect activation of TGF-β signaling in zebrafish Pac-2 cells caused a concentration dependent disruption of rhythmic promoter activity of the core clock gene Per1b. Inhibition of TGF-β signaling in intact zebrafish larvae caused a phase delay in the rhythmic expression of Per1b mRNA. TGF-β inhibition also reversibly disrupted, phase delayed and increased the period of circadian rhythms of locomotor activity in zebrafish larvae. Conclusions The current research provides evidence for an interaction between the TGF-β signaling pathway and the circadian clock system at the molecular and behavioral levels, and points to the importance of TGF-β signaling for normal circadian clock function. Future examination of this interaction should contribute to a better understanding of its underlying mechanisms and its influence on a variety of cellular processes including the cell cycle, with possible implications for cancer development and progression.
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Affiliation(s)
- Hadas E. Sloin
- School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Gennaro Ruggiero
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein, Germany
| | - Amir Rubinstein
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel
| | - Sima Smadja Storz
- School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Nicholas S. Foulkes
- Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein, Germany
| | - Yoav Gothilf
- School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
- Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- * E-mail:
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28
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McKenna H, van der Horst GTJ, Reiss I, Martin D. Clinical chronobiology: a timely consideration in critical care medicine. Crit Care 2018; 22:124. [PMID: 29747699 PMCID: PMC5946479 DOI: 10.1186/s13054-018-2041-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 04/13/2018] [Indexed: 12/29/2022] Open
Abstract
A fundamental aspect of human physiology is its cyclical nature over a 24-h period, a feature conserved across most life on Earth. Organisms compartmentalise processes with respect to time in order to promote survival, in a manner that mirrors the rotation of the planet and accompanying diurnal cycles of light and darkness. The influence of circadian rhythms can no longer be overlooked in clinical settings; this review provides intensivists with an up-to-date understanding of the burgeoning field of chronobiology, and suggests ways to incorporate these concepts into daily practice to improve patient outcomes. We outline the function of molecular clocks in remote tissues, which adjust cellular and global physiological function according to the time of day, and the potential clinical advantages to keeping in time with them. We highlight the consequences of "chronopathology", when this harmony is lost, and the risk factors for this condition in critically ill patients. We introduce the concept of "chronofitness" as a new target in the treatment of critical illness: preserving the internal synchronisation of clocks in different tissues, as well as external synchronisation with the environment. We describe methods for monitoring circadian rhythms in a clinical setting, and how this technology may be used for identifying optimal time windows for interventions, or to alert the physician to a critical deterioration of circadian rhythmicity. We suggest a chronobiological approach to critical illness, involving multicomponent strategies to promote chronofitness (chronobundles), and further investment in the development of personalised, time-based treatment for critically ill patients.
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Affiliation(s)
- Helen McKenna
- University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, First Floor, 170 Tottenham Court Road, London, W1T 7HA UK
| | | | - Irwin Reiss
- Division of Neonatology, Department of Paediatrics, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Daniel Martin
- University College London Centre for Altitude Space and Extreme Environment Medicine, University College London Hospitals NIHR Biomedical Research Centre, Institute of Sport and Exercise Health, First Floor, 170 Tottenham Court Road, London, W1T 7HA UK
- Division of Neonatology, Department of Paediatrics, Erasmus Medical Center, Rotterdam, the Netherlands
- Critical Care Unit, Royal Free Hospital, Pond Street, London, NW3 2QG UK
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29
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Kurz S, Thieme R, Amberg R, Groth M, Jahnke HG, Pieroh P, Horn LC, Kolb M, Huse K, Platzer M, Volke D, Dehghani F, Buzdin A, Engel K, Robitzki A, Hoffmann R, Gockel I, Birkenmeier G. The anti-tumorigenic activity of A2M-A lesson from the naked mole-rat. PLoS One 2017; 12:e0189514. [PMID: 29281661 PMCID: PMC5744951 DOI: 10.1371/journal.pone.0189514] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 11/28/2017] [Indexed: 12/30/2022] Open
Abstract
Cancer resistance is a major cause for longevity of the naked mole-rat. Recent liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M) and cell adhesion molecules, which contribute to the naked mole-rat’s cancer resistance. Notably, A2M is known to dramatically decrease with age in humans. We hypothesize that this might facilitate tumour development. Here we found that A2M modulates tumour cell adhesion, migration and growth by inhibition of tumour promoting signalling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21, in vitro and in tumour xenografts. A2M increases the expression of CD29 and CD44 but did not evoke EMT. Transcriptome analysis of A2M-treated tumour cells, xenografts and mouse liver demonstrated a multifaceted regulation of tumour promoting signalling pathways indicating a less tumorigenic environment mediated by A2M. By virtue of these multiple actions the naturally occurring A2M has strong potential as a novel therapeutic agent.
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Affiliation(s)
- Susanne Kurz
- Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - Ronny Amberg
- Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - Marco Groth
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, Germany
| | - Heinz-Georg Jahnke
- Centre for Biotechnology and Biomedicine, Molecular Biological-Biochemical Processing Technology, University of Leipzig, Germany
| | - Philipp Pieroh
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, Halle (Saale), Germany
| | - Lars-Christian Horn
- Institute of Pathology, Division of Breast, Gynaecological and Perinatal Pathology, University of Leipzig, Leipzig, Germany
| | - Marlen Kolb
- Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - Klaus Huse
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, Germany
| | - Matthias Platzer
- Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, Germany
| | - Daniela Volke
- Center for Biotechnology and Biomedicine, University of Leipzig, Leipzig, Germany
| | - Faramarz Dehghani
- Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, Halle (Saale), Germany
| | - Anton Buzdin
- Pharmaceutical Artificial Intelligence Department, Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, Baltimore, Maryland, United States of America
- Department of Pathway Engineering for Cancer Research, OmicsWay Corp., Walnut, CA, United States of America
- National Research Centre “Kurchatov Institute”, Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, 1, Akademika Kurchatova sq., Moscow, Russia
| | - Kathrin Engel
- Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - Andrea Robitzki
- Centre for Biotechnology and Biomedicine, Molecular Biological-Biochemical Processing Technology, University of Leipzig, Germany
| | - Ralf Hoffmann
- Center for Biotechnology and Biomedicine, University of Leipzig, Leipzig, Germany
| | - Ines Gockel
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University of Leipzig, Medical Faculty, Leipzig, Germany
| | - Gerd Birkenmeier
- Institute of Biochemistry, University of Leipzig, Medical Faculty, Leipzig, Germany
- * E-mail:
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30
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Xiong H, Yang Y, Yang K, Zhao D, Tang H, Ran X. Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. Int J Oncol 2017; 52:279-287. [PMID: 29115399 DOI: 10.3892/ijo.2017.4180] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Accepted: 10/24/2017] [Indexed: 11/05/2022] Open
Abstract
Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase‑8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was significantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2‑negative expression had a significantly shorter survival time than those with PER2‑positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase‑8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase‑8 pathways.
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Affiliation(s)
- Honggang Xiong
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yixin Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Kai Yang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Dan Zhao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hong Tang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiongwen Ran
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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31
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miR-181d and c-myc-mediated inhibition of CRY2 and FBXL3 reprograms metabolism in colorectal cancer. Cell Death Dis 2017; 8:e2958. [PMID: 28749470 PMCID: PMC5550850 DOI: 10.1038/cddis.2017.300] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 04/23/2017] [Accepted: 05/18/2017] [Indexed: 01/23/2023]
Abstract
Colorectal cancer (CRC) is the second major cause of tumor-related deaths. MicroRNAs (miRNAs) have pivotal roles in CRC progression. Here, we describe the effect of miR-181d on CRC cell metabolism and underlying molecular mechanism. Our data firmly demonstrated that knockdown of miR-181d suppressed CRC cell proliferation, migration, and invasion by impairing glycolysis. Mechanistically, miR-181d stabilized c-myc through directly targeting the 3'-UTRs of CRY2 and FBXL3, which subsequently increased the glucose consumption and the lactate production. Inhibition of c-myc via siRNA or small molecular inhibitor abolished the oncogenic effects of miR-181d on the growth and metastasis of CRC cells. Furthermore, c-myc/HDAC3 transcriptional suppressor complex was found to co-localize on the CRY2 and FBXL3 promoters, epigenetically inhibit their transcription, and finally induce their downregulation in CRC cells. In addition, miR-181d expression could be directly induced by an activation of c-myc signaling. Together, our data indicate an oncogenic role of miR-181d in CRC by promoting glycolysis, and miR-181d/CRY2/FBXL3/c-myc feedback loop might be a therapeutic target for patients with CRC.
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32
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Schroll MM, LaBonia GJ, Ludwig KR, Hummon AB. Glucose Restriction Combined with Autophagy Inhibition and Chemotherapy in HCT 116 Spheroids Decreases Cell Clonogenicity and Viability Regulated by Tumor Suppressor Genes. J Proteome Res 2017. [PMID: 28650662 DOI: 10.1021/acs.jproteome.7b00293] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Drug resistance is a prevalent phenomenon that decreases the efficacy of cancer treatments and contributes to cancer progression and metastasis. Weakening drug-resistant cancer cells prior to chemotherapy is a potential strategy to combat chemoresistance. One approach to damage resistant cancer cells is modulation of nutritional intake. The combination of nutrient restriction with targeted compound treatment results in pronounced molecular changes. This study provides valuable information about augmenting existing chemotherapeutic regimes with simultaneous glucose restriction and autophagy inhibition in colorectal cancer cells. In this study, we explore the chemical pathways that drive the cellular response to nutrient restriction, autophagy inhibition, and the chemotherapy irinotecan using global quantitative proteomics and imaging mass spectrometry. We determined that significant pathways were altered including autophagy and metabolism via glycolysis, gluconeogenesis, and sucrose degradation. We also found that period circadian clock 2 (PER2), a tumor suppressor protein, was significantly up-regulated only when glucose was restricted with autophagy inhibition and chemotherapy. The upstream regulators of these differentially regulated pathways were determined to have implications in cancer, showing an increase in tumor suppressor proteins and a decrease in nuclear protein 1 (NUPR1) an important protein in chemoresistance. We also evaluated the phenotypic response of these cells and discovered autophagy inhibition and chemotherapy treatment increased apoptosis and decreased cell clonogenicity and viability. When glucose restriction was combined with autophagy inhibition and chemotherapy, all of the phenotypic results were intensified. In sum, our results indicate that glucose metabolism is of great importance in the ability of cancer cells to survive chemotherapy. By weakening cancer cells with glucose restriction and autophagy inhibition prior to chemotherapy, cancer cells become more sensitive to therapy.
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Affiliation(s)
- Monica M Schroll
- Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, University of Notre Dame , Notre Dame, Indiana 46556, United States
| | - Gabriel J LaBonia
- Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, University of Notre Dame , Notre Dame, Indiana 46556, United States
| | - Katelyn R Ludwig
- Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, University of Notre Dame , Notre Dame, Indiana 46556, United States
| | - Amanda B Hummon
- Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.,Harper Cancer Research Institute, University of Notre Dame , Notre Dame, Indiana 46556, United States
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Yaacoby-Bianu K, Hakim F. Sleep Disturbance and Cancer—Animal Models. CURRENT SLEEP MEDICINE REPORTS 2017. [DOI: 10.1007/s40675-017-0073-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Vallée A, Lecarpentier Y, Guillevin R, Vallée JN. Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma. Front Physiol 2017; 8:352. [PMID: 28620312 PMCID: PMC5451860 DOI: 10.3389/fphys.2017.00352] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 05/15/2017] [Indexed: 12/19/2022] Open
Abstract
Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1) and monocarboxylate lactate transporter 1 (MCT-1). Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid) cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.
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Affiliation(s)
- Alexandre Vallée
- Experimental and Clinical Neurosciences Laboratory, Institut National de la Santé et de la Recherche Médicale U1084, University of PoitiersPoitiers, France
- Laboratoire de Mathématiques et Applications, UMR Centre National de la Recherche Scientifique 7348, Université de PoitiersPoitiers, France
| | | | - Rémy Guillevin
- DACTIM, Laboratoire de Mathématiques et Applications, Université de Poitiers et CHU de Poitiers, UMR Centre National de la Recherche Scientifique 7348, SP2MIFuturoscope, France
| | - Jean-Noël Vallée
- Laboratoire de Mathématiques et Applications, UMR Centre National de la Recherche Scientifique 7348, Université de PoitiersPoitiers, France
- CHU Amiens Picardie, Université Picardie Jules VerneAmiens, France
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Thermodynamics in cancers: opposing interactions between PPAR gamma and the canonical WNT/beta-catenin pathway. Clin Transl Med 2017; 6:14. [PMID: 28405929 PMCID: PMC5389954 DOI: 10.1186/s40169-017-0144-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Accepted: 03/20/2017] [Indexed: 01/03/2023] Open
Abstract
Cancer cells are the site of numerous metabolic and thermodynamic abnormalities. We focus this review on the interactions between the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR gamma) in cancers and their implications from an energetic and metabolic point of view. In numerous tissues, PPAR gamma activation induces inhibition of beta-catenin pathway, while the activation of the canonical WNT/beta-catenin pathway inactivates PPAR gamma. In most cancers but not all, PPAR gamma is downregulated while the WNT/beta-catenin pathway is upregulated. In cancer cells, upregulation of the WNT/beta-catenin signaling induces dramatic changes in key metabolic enzymes that modify their thermodynamic behavior. This leads to activation of pyruvate dehydrogenase kinase1 (PDK-1) and monocarboxylate lactate transporter. Consequently, phosphorylation of PDK-1 inhibits the pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-coenzyme A (acetyl-CoA) in mitochondria and only a part of acetyl-CoA can enter the tricarboxylic acid cycle. This leads to aerobic glycolysis in spite of the availability of oxygen. This phenomenon is referred to as the Warburg effect. Cytoplasmic pyruvate is converted into lactate. The WNT/beta-catenin pathway induces the transcription of genes involved in cell proliferation, i.e., MYC and CYCLIN D1. This ultimately promotes the nucleotide, protein and lipid synthesis necessary for cell growth and multiplication. In cancer, activation of the PI3K-AKT pathway induces an increase of the aerobic glycolysis. Moreover, prostaglandin E2 by activating the canonical WNT pathway plays also a role in cancer. In addition in many cancer cells, PPAR gamma is downregulated. Moreover, PPAR gamma contributes to regulate some key circadian genes. In cancers, abnormalities in the regulation of circadian rhythms (CRs) are observed. CRs are dissipative structures which play a key-role in far-from-equilibrium thermodynamics. In cancers, metabolism, thermodynamics and CRs are intimately interrelated.
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De Ita-Pérez DL, Díaz-Muñoz M. Synchronization by Daytime Restricted Food Access Modulates the Presence and Subcellular Distribution of β-Catenin and Its Phosphorylated Forms in the Rat Liver. Front Endocrinol (Lausanne) 2017; 8:14. [PMID: 28220106 PMCID: PMC5292920 DOI: 10.3389/fendo.2017.00014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 01/16/2017] [Indexed: 12/31/2022] Open
Abstract
β-catenin, the principal effector of the Wnt pathway, is also one of the cadherin cell adhesion molecules; therefore, it fulfills signaling and structural roles in most of the tissues and organs. It has been reported that β-catenin in the liver regulates metabolic responses such as gluconeogenesis and histological changes in response to obesity-promoting diets. The function and cellular location of β-catenin is finely modulated by coordinated sequences of phosphorylation-dephosphorylation events. In this article, we evaluated the levels and cellular localization of liver β-catenin variants, more specifically β-catenin phosphorylated in serine 33 (this phosphorylation provides recognizing sites for β-TrCP, which results in ubiquitination and posterior proteasomal degradation of β-catenin) and β-catenin phosphorylated in serine 675 (phosphorylation that enhances signaling and transcriptional activity of β-catenin through recruitment of different transcriptional coactivators). β-catenin phosphorylated in serine 33 in the nucleus shows day-night fluctuations in their expression level in the Ad Libitum group. In addition, we used a daytime restricted feeding (DRF) protocol to show that the above effects are sensitive to food access-dependent circadian synchronization. We found through western blot and immunohistochemical analyses that DRF protocol promoted (1) higher total β-catenins levels mainly associated with the plasma membrane, (2) reduced the presence of cytoplasmic β-catenin phosphorylated in serine 33, (3) an increase in nuclear β-catenin phosphorylated in serine 675, (4) differential co-localization of total β-catenins/β-catenin phosphorylated in serine 33 and total β-catenins/β-catenin phosphorylated in serine 675 at different temporal points along day and in fasting and refeeding conditions, and (5) differential liver zonation of β-catenin variants studied along hepatic acinus. In conclusion, the present data comprehensively characterize the effect food synchronization has on the presence, subcellular distribution, and liver zonation of β-catenin variants. These results are relevant to understand the set of metabolic and structural liver adaptations that are associated with the expression of the food entrained oscillator (FEO).
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Affiliation(s)
- Dalia Luz De Ita-Pérez
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Querétaro, México
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Querétaro, México
- *Correspondence: Mauricio Díaz-Muñoz,
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Song SG, Yu HY, Ma YW, Zhang F, Xu XY. Inhibition on Numb/Notch signal pathway enhances radiosensitivity of lung cancer cell line H358. Tumour Biol 2016; 37:13705-13719. [PMID: 27476167 DOI: 10.1007/s13277-016-5134-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 07/06/2016] [Indexed: 12/11/2022] Open
Abstract
The objective of the study is to investigate the effects of the Numb/Notch signal pathway on the radiosensitivity of lung cancer cell line H358. MTT assay and colony forming assay were used to detect the effects of different doses of X-rays and MW167 on the in vitro proliferation of the lung cancer cell line H358. Flow cytometry was applied to evaluate the effects of X rays on the apoptosis of H358. Scratch assay and Transwell invasion assay were used to examine the effects of X-rays on the migration and invasion abilities of H358. The mRNA and protein expressions in the signal pathway were detected by real-time PCR and western blot. Assays in vitro confirmed the effects of the Numb/Notch pathway inhibitor on the radiosensitivity to lung cancer. MW167 enhanced the inhibiting effects of X-ray on the proliferation of H358 cell line. After the addition of MW167, the apoptosis rates significantly increased, but the invasion and migration abilities decreased significantly. Meanwhile, MW167 could dose-dependently promote the increase of expression of Numb, which is the upstream gene of the Numb/Notch signaling pathway, but inhibit the expression of and HES1. In vivo experiments revealed that cell proliferation was suppressed in the radiation, pathway inhibitor, and pathway inhibitor + radiation groups, and the pathway inhibitor + radiation group exhibited more active anti-tumor ability when compared with the blank group (all P < 0.05); Numb expression was up-regulated, but Notch1 and HES1 expressions were down-regulated in those three groups, and also, the pathway inhibitor + radiation group exhibited more significant alternation when compared with the blank group (all P < 0.05); cell apoptosis was promoted in those three groups, and the pathway inhibitor + radiation group showed more active apoptosis when compared with the blank group (all P < 0.05). Repression of the Numb/Notch pathway enhances the effects of radiotherapy on the radiosensitivity of the lung cancer cell line H358, and thus the Numb/Notch pathway may be a new target of radiotherapy for lung cancer.
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MESH Headings
- Animals
- Apoptosis/radiation effects
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Blotting, Western
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/radiotherapy
- Cell Movement/radiation effects
- Cell Proliferation/radiation effects
- Gene Expression Regulation, Neoplastic/radiation effects
- Humans
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/radiotherapy
- Membrane Proteins/antagonists & inhibitors
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Nerve Tissue Proteins/antagonists & inhibitors
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Radiation Tolerance
- Radiation, Ionizing
- Real-Time Polymerase Chain Reaction
- Receptors, Notch/antagonists & inhibitors
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Signal Transduction/radiation effects
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Shi-Gang Song
- Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Hong-Yang Yu
- Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Yan-Wei Ma
- Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Feng Zhang
- Department of Radiation Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Xiang-Ying Xu
- Department of Radiation Oncology, The Third Affiliated School of Medicine, Harbin Medical University, No. 150 Haping Road, Nangang District, Harbin, 150001, China.
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Erren T, Morfeld P, Foster R, Reiter R, Groß J, Westermann I. Sleep and cancer: Synthesis of experimental data and meta-analyses of cancer incidence among some 1,500,000 study individuals in 13 countries. Chronobiol Int 2016; 33:325-50. [DOI: 10.3109/07420528.2016.1149486] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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de Assis LVM, Moraes MN, da Silveira Cruz-Machado S, Castrucci AML. The effect of white light on normal and malignant murine melanocytes: A link between opsins, clock genes, and melanogenesis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1119-33. [PMID: 26947915 DOI: 10.1016/j.bbamcr.2016.03.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 02/29/2016] [Accepted: 03/02/2016] [Indexed: 11/26/2022]
Abstract
The skin possesses a photosensitive system comprised of opsins whose function is not fully understood, and clock genes which exert an important regulatory role in skin biology. Here, we evaluated the presence of opsins in normal (Melan-a cells) and malignant (B16-F10 cells) murine melanocytes. Both cell lines express Opn2, Opn4--for the first time reported in these cell types--as well as S-opsin. OPN4 protein was found in a small area capping the cell nuclei of B16-F10 cells kept in constant dark (DD); twenty-four hours after the white light pulse (WLP), OPN4 was found in the cell membrane. Despite the fact that B16-F10 cells expressed less Opn2 and Opn4 than Melan-a cells, our data indicate that the malignant melanocytes exhibited increased photoresponsiveness. The clock gene machinery is also severely downregulated in B16-F10 cells as compared to Melan-a cells. Per1, Per2, and Bmal1 expression increased in B16-F10 cells in response to WLP. Although no response in clock gene expression to WLP was observed in Melan-a cells, gene correlational data suggest a minor effect of WLP. In contrast to opsins and clock genes, melanogenesis is significantly upregulated in malignant melanocytes in comparison to Melan-a cells. Tyrosinase expression increased after WLP only in B16-F10 cells; however no increase in melanin content after WLP was seen in either cell line. Our findings may prove useful in the treatment and the development of new pharmacological approaches of depigmentation diseases and skin cancer.
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Affiliation(s)
- L V M de Assis
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - M N Moraes
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - S da Silveira Cruz-Machado
- Laboratory of Chronopharmacology, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | - A M L Castrucci
- Laboratory of Comparative Physiology of Pigmentation, Department of Physiology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil.
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Chuffa LGA, Alves MS, Martinez M, Camargo ICC, Pinheiro PFF, Domeniconi RF, Júnior LAL, Martinez FE. Apoptosis is triggered by melatonin in an in vivo model of ovarian carcinoma. Endocr Relat Cancer 2016; 23:65-76. [PMID: 26555801 DOI: 10.1530/erc-15-0463] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2015] [Indexed: 12/20/2022]
Abstract
Apoptosis plays an important role in the treatment of cancer, and targeting apoptosis-related molecules in ovarian cancer (OC) is of great therapeutic value. Melatonin (Mel) is an indoleamine displaying several anti-cancer properties and has been reported to modulate apoptosis signaling in multiple tumor subtypes. We investigated OC and the role of Mel therapy on the pro-apoptotic (p53, BAX, caspase-3, and cleaved caspase-3) and anti-apoptotic (Bcl-2 and survivin) proteins in an ethanol (EtOH)-preferring rat model. To induce OC, the left ovary was injected directly with a single dose of 100 μg 7,12-dimethylbenz(a)anthracene dissolved in 10 μl of sesame oil under the bursa. Right ovaries were used as sham-surgery controls. After developing OC, half of the animals received i.p. injections of Mel (200 μg/100 g BW per day) for 60 days. Body weight gain, EtOH consumption, and energy intake were unaffected by the treatments. Interestingly, absolute and relative OC masses showed a significant reduction after Mel therapy, regardless of EtOH consumption. To accomplish OC-related apoptosis, we first observed that p53, BAX, caspase-3, and cleaved caspase-3 were downregulated in OC tissue while Bcl-2 and survivin were overexpressed. Notably, Mel therapy and EtOH intake promoted apoptosis along with the upregulation of p53, BAX, and cleaved caspase-3. Fragmentation of DNA observed by TUNEL-positive nuclei was also enhanced following Mel treatment. In addition, Bcl-2 was downregulated by the EtOH intake and lower survivin levels were observed after Mel therapy. Taken together, these results suggest that Mel induce apoptosis in OC cells of EtOH-preferring animals.
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Affiliation(s)
- Luiz Gustavo A Chuffa
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Michelly S Alves
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Marcelo Martinez
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Isabel Cristina C Camargo
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Patricia F F Pinheiro
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Raquel F Domeniconi
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Luiz Antonio L Júnior
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
| | - Francisco Eduardo Martinez
- Department of AnatomyInstitute of Biosciences of Botucatu, UNESP - Universidade Estadual Paulista, PO Box 18618-970, Rubião Júnior, s/n, Botucatu, São Paulo 510, BrazilDepartment of Morphology and PathologyUFSCar - Universidade Federal de São Carlos, São Carlos, São Paulo 13565-905, BrazilDepartment of Biological SciencesFaculty of Sciences and Letters, UNESP - Universidade Estadual Paulista, Assis, São Paulo 19806-900, Brazil
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Yoshida D, Aoki N, Tanaka M, Aoyama S, Shibata S. The circadian clock controls fluctuations of colonic cell proliferation during the light/dark cycle via feeding behavior in mice. Chronobiol Int 2015; 32:1145-55. [PMID: 26376208 DOI: 10.3109/07420528.2015.1065415] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The mammalian circadian system is controlled not only by the suprachiasmatic nucleus (SCN), but also by the peripheral clocks located in tissues such as liver, kidney, small intestine, and colon, mediated through signals such as hormones. Peripheral clocks, but not the SCN, can be entrained by food intake schedules. While it is known that cell proliferation exhibits a circadian rhythm in the colon epithelium, it is unclear how this rhythm is influenced by food intake schedules. Here, we aimed to determine the relationships between feeding schedules and cell proliferation in the colon epithelium by means of immunochemical analysis, using 5-bromo-2'-deoxyuridine (BrdU), as well as to elucidate how feeding schedules influence the colonic expression of clock and cell cycle genes, using real-time reverse-transcription PCR (qRT-PCR). Cell proliferation in the colonic epithelium of normal mice exhibited a daily fluctuation, which was abrogated in Clock mutant mice. The day/night pattern of cellular proliferation and clock gene expression under daytime and nighttime restricted feeding (RF) schedules showed opposite tendencies. While daytime RF for every 4 h attenuated the day/night pattern of cell proliferation, this was restored to normal in the Clock mutant mice under the nighttime RF schedule. These results suggest that feeding schedules contribute to the establishment of a daily fluctuation of cell proliferation and RF can recover it in Clock mutant mice. Thus, this study demonstrates that the daily fluctuation of cell proliferation in the murine colon is controlled by a circadian feeding rhythm, suggesting that feeding schedules are important for rhythmicity in the proliferation of colon cells.
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Affiliation(s)
- Daisuke Yoshida
- a Laboratory of Physiology and Pharmacology , School of Advanced Sciences and Engineering, Waseda University , Tokyo , Japan
| | - Natsumi Aoki
- a Laboratory of Physiology and Pharmacology , School of Advanced Sciences and Engineering, Waseda University , Tokyo , Japan
| | - Mizuho Tanaka
- a Laboratory of Physiology and Pharmacology , School of Advanced Sciences and Engineering, Waseda University , Tokyo , Japan
| | - Shinya Aoyama
- a Laboratory of Physiology and Pharmacology , School of Advanced Sciences and Engineering, Waseda University , Tokyo , Japan
| | - Shigenobu Shibata
- a Laboratory of Physiology and Pharmacology , School of Advanced Sciences and Engineering, Waseda University , Tokyo , Japan
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Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, Hauch A, Lundberg PW, Summers W, Yuan L, Frasch T, Blask DE. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 2015; 22:R183-204. [PMID: 25876649 PMCID: PMC4457700 DOI: 10.1530/erc-15-0030] [Citation(s) in RCA: 222] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2015] [Indexed: 12/19/2022]
Abstract
The present review discusses recent work on melatonin-mediated circadian regulation, the metabolic and molecular signaling mechanisms that are involved in human breast cancer growth, and the associated consequences of circadian disruption by exposure to light at night (LEN). The anti-cancer actions of the circadian melatonin signal in human breast cancer cell lines and xenografts heavily involve MT1 receptor-mediated mechanisms. In estrogen receptor alpha (ERα)-positive human breast cancer, melatonin suppresses ERα mRNA expression and ERα transcriptional activity via the MT1 receptor. Melatonin also regulates the transactivation of other members of the nuclear receptor superfamily, estrogen-metabolizing enzymes, and the expression of core clock and clock-related genes. Furthermore, melatonin also suppresses tumor aerobic metabolism (the Warburg effect) and, subsequently, cell-signaling pathways critical to cell proliferation, cell survival, metastasis, and drug resistance. Melatonin demonstrates both cytostatic and cytotoxic activity in breast cancer cells that appears to be cell type-specific. Melatonin also possesses anti-invasive/anti-metastatic actions that involve multiple pathways, including inhibition of p38 MAPK and repression of epithelial-mesenchymal transition (EMT). Studies have demonstrated that melatonin promotes genomic stability by inhibiting the expression of LINE-1 retrotransposons. Finally, research in animal and human models has indicated that LEN-induced disruption of the circadian nocturnal melatonin signal promotes the growth, metabolism, and signaling of human breast cancer and drives breast tumors to endocrine and chemotherapeutic resistance. These data provide the strongest understanding and support of the mechanisms that underpin the epidemiologic demonstration of elevated breast cancer risk in night-shift workers and other individuals who are increasingly exposed to LEN.
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Affiliation(s)
- Steven M Hill
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Victoria P Belancio
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Robert T Dauchy
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Shulin Xiang
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Samantha Brimer
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Lulu Mao
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Adam Hauch
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Peter W Lundberg
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Whitney Summers
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Lin Yuan
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Tripp Frasch
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - David E Blask
- Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA Department of Structural and Cellular BiologyTulane University School of Medicine, 1430 Tulane Avenue, SL-49, New Orleans, Louisiana 70112, USADepartment of SurgeryTulane Cancer Center and Louisiana Cancer Research ConsortiumCircadian Cancer Biology GroupTulane Center for Circadian BiologyTulane University School of Medicine, New Orleans, Louisiana 70112, USA
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Belancio VP. LINE-1 activity as molecular basis for genomic instability associated with light exposure at night. Mob Genet Elements 2015; 5:1-5. [PMID: 26442182 DOI: 10.1080/2159256x.2015.1037416] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 03/24/2015] [Accepted: 03/26/2015] [Indexed: 12/29/2022] Open
Abstract
The original hypothesis that exposure to light at night increases risk of breast cancer via suppression of nocturnal melatonin production was proposed over 2 decades ago. In 2007, shift work that involves circadian disruption has been recognized by the World Health Organization as a probable human carcinogen. Our discovery of melatonin-dependent regulation of LINE-1 retrotransposon expression and mobilization is the latest addition to the list of cellular genes and processes that are affected by light exposure at night. This finding establishes an unexpected health relevant connection between this endogenous DNA damaging agent and environmental light exposure. It also offers an appealing hypothesis pertaining to the origin of genomic instability in the genomes of individuals with light at night- or age-associated disruption of melatonin signaling.
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Affiliation(s)
- Victoria P Belancio
- Department of Structural and Cellular Biology; Tulane Cancer Center; Tulane Cancer for Aging; Tulane Center for Circadian Biology; Tulane University ; New Orleans, LA USA
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Belancio VP, Blask DE, Deininger P, Hill SM, Jazwinski SM. The aging clock and circadian control of metabolism and genome stability. Front Genet 2015; 5:455. [PMID: 25642238 PMCID: PMC4294216 DOI: 10.3389/fgene.2014.00455] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 12/11/2014] [Indexed: 11/13/2022] Open
Abstract
It is widely accepted that aging is characterized by a gradual decline in the efficiency and accuracy of biological processes, leading to deterioration of physiological functions and development of age-associated diseases. Age-dependent accumulation of genomic instability and development of metabolic syndrome are well-recognized components of the aging phenotype, both of which have been extensively studied. Existing findings strongly support the view that the integrity of the cellular genome and metabolic function can be influenced by light at night (LAN) and associated suppression of circadian melatonin production. While LAN is reported to accelerate aging by promoting age-associated carcinogenesis in several animal models, the specific molecular mechanism(s) of its action are not fully understood. Here, we review literature supporting a connection between LAN-induced central circadian disruption of peripheral circadian rhythms and clock function, LINE-1 retrotransposon-associated genomic instability, metabolic deregulation, and aging. We propose that aging is a progressive decline in the stability, continuity, and synchronization of multi-frequency oscillations in biological processes to a temporally disorganized state. By extension, healthy aging is the ability to maintain the most consistent, stable, and entrainable rhythmicity and coordination of these oscillations, at the molecular, cellular, and systemic levels.
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Affiliation(s)
- Victoria P Belancio
- Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane University New Orleans, LA, USA ; Tulane Cancer Center, Tulane Center for Aging, and Tulane Center for Circadian Biology New Orleans, LA, USA
| | - David E Blask
- Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane University New Orleans, LA, USA ; Tulane Cancer Center, Tulane Center for Aging, and Tulane Center for Circadian Biology New Orleans, LA, USA
| | - Prescott Deininger
- Tulane Cancer Center, Tulane Center for Aging, and Tulane Center for Circadian Biology New Orleans, LA, USA ; Department of Epidemiology, Tulane University New Orleans, LA, USA
| | - Steven M Hill
- Department of Structural and Cellular Biology, Tulane School of Medicine, Tulane University New Orleans, LA, USA ; Tulane Cancer Center, Tulane Center for Aging, and Tulane Center for Circadian Biology New Orleans, LA, USA
| | - S Michal Jazwinski
- Tulane Cancer Center, Tulane Center for Aging, and Tulane Center for Circadian Biology New Orleans, LA, USA ; Department of Medicine, Tulane University New Orleans, LA, USA
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Yang SL, Yu C, Jiang JX, Liu LP, Fang X, Wu C. Hepatitis B virus X protein disrupts the balance of the expression of circadian rhythm genes in hepatocellular carcinoma. Oncol Lett 2014; 8:2715-2720. [PMID: 25360177 PMCID: PMC4214404 DOI: 10.3892/ol.2014.2570] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 09/11/2014] [Indexed: 01/09/2023] Open
Abstract
The human circadian rhythm is controlled by at least eight circadian clock genes and disruption of the circadian rhythm is associated with cancer development. The present study aims to elucidate the association between the expression of circadian clock genes and the development of hepatocellular carcinoma (HCC), and also to reveal whether the hepatitis B virus X protein (HBx) is the major regulator that contributes to the disturbance of circadian clock gene expression. The mRNA levels of circadian clock genes in 30 HCC and the paired peritumoral tissues were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A stable HBx-expressing cell line, Bel-7404-HBx, was established through transfection of HBx plasmids. The mRNA level of circadian clock genes was also detected by RT-qPCR in these cells. Compared with the paired peritumoral tissues, the mRNA levels of the Per1, Per2, Per3 and Cry2 genes in HCC tissue were significantly lower (P<0.05), while no significant difference was observed in the expression levels of CLOCK, BMAL1, Cry1 and casein kinase 1ɛ (CK1ɛ; P>0.05). Compared with Bel-7404 cells, the mRNA levels of the CLOCK, Per1 and Per2 genes in Bel-7404-HBx cells were significantly increased, while the mRNA levels of the BMAL1, Per3, Cry1, Cry2 and CKIɛ genes were decreased (P<0.05). Thus, the present study identified that disturbance of the expression of circadian clock genes is common in HCC. HBx disrupts the expression of circadian clock genes and may, therefore, induce the development of HCC.
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Affiliation(s)
- Sheng-Li Yang
- Department of General Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
| | - Chao Yu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, P.R. China
| | - Jian-Xin Jiang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, P.R. China
| | - Li-Ping Liu
- Department of Hepatobiliary and Pancreatic Surgery, Shenzhen People's Hospital, Second Clinical Medical College, Jinan University, Shenzhen, Guangdong 518000, P.R. China
| | - Xiefan Fang
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Chao Wu
- Department of General Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
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Wirth MD, Burch JB, Hébert JR, Kowtal P, Kapoor A, Steck SE, Hurley TG, Gupta PC, Pednekar MS, Youngstedt SD, Zhang H, Sarin R. Case-control study of breast cancer in India: Role of PERIOD3 clock gene length polymorphism and chronotype. Cancer Invest 2014; 32:321-9. [PMID: 24903750 PMCID: PMC4100474 DOI: 10.3109/07357907.2014.919305] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND This study examined a PERIOD3 (PER3) gene variable number tandem repeat polymorphism and chronotype as potential BrCA risk factors among Indian women. METHODS This case-control study included sporadic, histologically confirmed BrCA cases (n = 255) and controls (n = 249) from India with data collection from 2010-2012. RESULTS Women with the 4/5 or 5/5 PER3 genotype had a nonstatistically significant 33% increased odds of BrCA. Cases were more likely to have a morning (OR = 2.43, 95% CI = 1.23-4.81) or evening (OR = 2.55, 95% CI = 1.19-5.47) chronotype. CONCLUSIONS Findings are consistent with the possibility that extremes in chronotype may elicit circadian desynchronization, resulting in increased BrCA susceptibility.
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Affiliation(s)
- Michael D. Wirth
- South Carolina Statewide Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - James B. Burch
- South Carolina Statewide Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- WJB Dorn VA Medical Center, Columbia, SC, USA
| | - James R. Hébert
- South Carolina Statewide Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Pradnya Kowtal
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Aparna Kapoor
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Susan E. Steck
- South Carolina Statewide Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Thomas G. Hurley
- South Carolina Statewide Cancer Prevention and Control Program, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Prakash C. Gupta
- Healis - Sekhsaria Institute for Public Health, Navi Mumbai, India
| | | | - Shawn D. Youngstedt
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- WJB Dorn VA Medical Center, Columbia, SC, USA
| | - Hongmei Zhang
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis
| | - Rajiv Sarin
- Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
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Pluquet O, Dejeans N, Chevet E. Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. Ann Med 2014; 46:233-43. [PMID: 24491143 DOI: 10.3109/07853890.2013.874664] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
In the past 20 years both the circadian clock and endoplasmic reticulum (ER) stress signaling have emerged as major players in oncogenesis and cancer development. Although several lines of evidence have established functional links between these two molecular pathways, their interconnection and the subsequent functional implications in cancer development remain to be fully characterized. Herein, we provide an extensive review of the literature depicting the molecular connectivity linking ER stress signaling and the circadian clock and elaborate on the potential use of these functional interactions in cancer therapeutics.
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Affiliation(s)
- Olivier Pluquet
- Institut de Biologie de Lille, CNRS UMR8161/Universités Lille 1 et Lille 2/Institut Pasteur de Lille , 1, rue du Pr. Calmette, BP 447, 59021 Lille , France
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Couto P, Miranda D, Vieira R, Vilhena A, De Marco L, Bastos-Rodrigues L. Association between CLOCK, PER3 and CCRN4L with non‑small cell lung cancer in Brazilian patients. Mol Med Rep 2014; 10:435-40. [PMID: 24821610 DOI: 10.3892/mmr.2014.2224] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 03/24/2014] [Indexed: 11/06/2022] Open
Abstract
Circadian rhythms comprise of daily oscillations in a variety of biological processes and are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer progression, and understanding natural oscillations in cellular growth control, tumor suppression and cancer treatment, may reveal how clock and clock‑controlled genes are regulated in normal physiological functioning. To investigate the association between clock genes and non‑small cell lung cancer (NSCLC), we genotyped three tag SNPs (rs938836, rs17050680, rs3805213) in the Nocturnin gene (CCRN4L), five SNPs (rs228727, rs228644, rs228729, rs707467, rs104620202) in the period 3 (PER3) gene and one SNP (rs6855837) in the CLOCK gene, in 78 Brazilian patients with NSCLC. One tag SNP in CCRN4L (rs3805213) and another tag SNP from PER3 (rs228729) demonstrated a significant correlation with genotype and allele frequency in lung cancer (P=4.4x10‑3 and P=5.7x10‑2; P=0.004 and P=0.02, respectively). The results of our study suggest these polymorphisms in the CCRN4L and PER3 genes may represent a risk factor in the occurrence and development of NSCLC in Brazilian patients.
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Affiliation(s)
- Patricia Couto
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130‑100, Brazil
| | - Debora Miranda
- Department of Pediatrics, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130‑100, Brazil
| | - Renalice Vieira
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130‑100, Brazil
| | - Alyne Vilhena
- Hospital Julia Kubitscheck, Belo Horizonte, MG 30620‑470, Brazil
| | - Luiz De Marco
- Department of Surgery, Universidade Federal de Minas Gerais, Belo Horizonte, MG 30130‑100, Brazil
| | - Luciana Bastos-Rodrigues
- Basic Department ‑ Health Area, Universidade Federal de Juiz de Fora, Campus Governador Valadares, Governador Valadares, MG 35010‑177, Brazil
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Mazzoccoli G, Vinciguerra M, Papa G, Piepoli A. Circadian clock circuitry in colorectal cancer. World J Gastroenterol 2014; 20:4197-4207. [PMID: 24764658 PMCID: PMC3989956 DOI: 10.3748/wjg.v20.i15.4197] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 11/18/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the most prevalent among digestive system cancers. Carcinogenesis relies on disrupted control of cellular processes, such as metabolism, proliferation, DNA damage recognition and repair, and apoptosis. Cell, tissue, organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery. Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis, and altered expression of clock genes has been found in cancer patients. Epidemiological studies have shown that circadian disruption, that is, alteration of bodily temporal organization, is a cancer risk factor, and an increased incidence of colorectal neoplastic disease is reported in shift workers. In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer.
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50
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Zhao X, Zhu X, Cheng S, Xie Y, Wang Z, Liu Y, Jiang Z, Xiao J, Guo H, Wang Y. MiR-29a/b/c regulate human circadian gene hPER1 expression by targeting its 3'UTR. Acta Biochim Biophys Sin (Shanghai) 2014; 46:313-7. [PMID: 24578160 DOI: 10.1093/abbs/gmu007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Several essential biological progresses in mammals are regulated by circadian rhythms. Though the molecular mechanisms of oscillating these circadian rhythms have been uncovered, the specific functions of the circadian genes are not very clear. It has been reported that knocking down circadian genes by microRNA is a useful strategy to explore the function of the circadian rhythms. In this study, through a forward bioinformatics screening approach, we identified miR-29a/b/c as potent inhibitors for the human circadian gene hPER1. We further found that miR-29a/b/c could directly target hPER1 3'untranslated region (UTR) and down-regulate hPER1 at both mRNA and protein expression levels in human A549 cells. Thus, our findings suggested that the expression of hPER1 is regulated by miR-29a/b/c, which may also provide a new clue for the function of hPER1.
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Affiliation(s)
- Xiyan Zhao
- Health Ministry Key Laboratory of Chronobiology, Pre-clinic and Forensic Medical School, Sichuan University, Chengdu 610041, China
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