Thyroid Cancer and Circadian Clock Disruption

Thyroid cancer (TC) represents the most common malignancy of the endocrine system, with an increased incidence across continents attributable to both improvement of diagnostic procedures and environmental factors. Among the modifiable risk factors, insulin resistance might influence the development of TC. A relationship between circadian clock machinery disfunction and TC has recently been proposed. The circadian clock machinery comprises a set of rhythmically expressed genes responsible for circadian rhythms. Perturbation of this system contributes to the development of pathological states such as cancer. Several clock genes have been found deregulated upon thyroid nodule malignant transformation. The molecular mechanisms linking circadian clock disruption and TC are still unknown but could include insulin resistance. Circadian misalignment occurring during shift work, jet lag, high fat food intake, is associated with increased insulin resistance. This metabolic alteration, in turn, is associated with a well-known risk factor for TC i.e., hyperthyrotropinemia, which could also be induced by sleep disturbances. In this review, we describe the mechanisms controlling the circadian clock function and its involvement in the cell cycle, stemness and cancer. Moreover, we discuss the evidence supporting the link between circadian clockwork disruption and TC development/progression, highlighting its potential implications for TC prevention, diagnosis and therapy.

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Modulatory Effects of Circadian Rhythms in the Lung Adenocarcinoma Tumor Microenvironment

10.21203/rs.3.rs-838444/v1 ◽

2021 ◽

Author(s):

Qianzhun Huang ◽

Xiaoyang Su ◽

Ning Fang ◽

Jian Huang

Keyword(s):

Tumor Microenvironment ◽

Circadian Rhythms ◽

Lung Adenocarcinoma ◽

Circadian Clock ◽

Drug Sensitivity ◽

Molecular Mechanisms ◽

Clock Genes ◽

Functional Enrichment ◽

Expression Levels ◽

Circadian Clock Genes

Abstract Background: Dysregulated circadian dynamic balance is strongly associated with cancer development. However, biological functions of circadian rhythms in lung adenocarcinoma (LUAD) have not been elucidated. This study aimed at valuating the modulatory effects of circadian rhythms in the LUAD tumor microenvironment.Methods: Multiple open-source bioinformatics research platforms are used to comprehensively elucidate the expression level, prognosis, potential biological function, drug sensitivity, and immune microenvironment of circadian clock genes in LUAD.Results: Most circadian clock genes in LUAD are dysregulated and are strongly correlated with patient prognosis, and missense mutations at splicing sites of these genes. Besides, these genes are closely associated with some well-known cancer-related marker pathways, which are mainly involved in the inhibition of the Apoptosis, Cell cycle, and DNA Damage Response Pathway. Furthermore, functional enrichment analysis revealedthat circadian clock genes regulate transcription factor activities and circadian rhythms in LUAD tissues. As for drug sensitivity, high expression of CLOCK, CRY1, and NR1D2 as well as suppressedPER2 and CRY2 expression levels are associated with drug resistance. The expression levels of circadian clock genes in LUAD correlate with immune infiltration and are involved in the regulation of immunosuppression.Conclusions: Our multi-omics analysis provides a more comprehensive understanding of the molecular mechanisms of the circadian clock genes in LUAD and provides new insights for a more precise screening of prognostic biomarkers and immunotherapy.

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Modeling and analysis of the impacts of jet lag on circadian rhythm and its role in tumor growth

PeerJ ◽

10.7717/peerj.4877 ◽

2018 ◽

Vol 6 ◽

pp. e4877 ◽

Cited By ~ 1

Author(s):

Azka Hassan ◽

Jamil Ahmad ◽

Hufsah Ashraf ◽

Amjad Ali

Keyword(s):

Circadian Rhythms ◽

Circadian Clock ◽

Clock Genes ◽

Damage Control ◽

Vital Role ◽

Biochemical Networks ◽

Jet Lag ◽

Peripheral Tissues ◽

Modeling And Analysis ◽

Circadian Clock Proteins

Circadian rhythms maintain a 24 h oscillation pattern in metabolic, physiological and behavioral processes in all living organisms. Circadian rhythms are organized as biochemical networks located in hypothalamus and peripheral tissues. Rhythmicity in the expression of circadian clock genes plays a vital role in regulating the process of cell division and DNA damage control. The oncogenic protein, MYC and the tumor suppressor, p53 are directly influenced by the circadian clock. Jet lag and altered sleep/wake schedules prominently affect the expression of molecular clock genes. This study is focused on developing a Petri net model to analyze the impacts of long term jet lag on the circadian clock and its probable role in tumor progression. The results depict that jet lag disrupts the normal rhythmic behavior and expression of the circadian clock proteins. This disruption leads to persistent expression of MYC and suppressed expression of p53. Thus, it is inferred that jet lag altered circadian clock negatively affects the expressions of cell cycle regulatory genes and contribute in uncontrolled proliferation of tumor cells.

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Achilles-Mediated and Sex-Specific Regulation of Circadian mRNA Rhythms in Drosophila

Journal of Biological Rhythms ◽

10.1177/0748730419830845 ◽

2019 ◽

Vol 34 (2) ◽

pp. 131-143 ◽

Cited By ~ 3

Author(s):

Jiajia Li ◽

Renee Yin Yu ◽

Farida Emran ◽

Brian E. Chen ◽

Michael E. Hughes

Keyword(s):

Circadian Clock ◽

Molecular Mechanisms ◽

Rna Binding ◽

Clock Genes ◽

Peripheral Tissues ◽

Knock Down ◽

Rhythmic Expression ◽

The Core ◽

Physiological Processes ◽

Specific Regulation

The circadian clock is an evolutionarily conserved mechanism that generates the rhythmic expression of downstream genes. The core circadian clock drives the expression of clock-controlled genes, which in turn play critical roles in carrying out many rhythmic physiological processes. Nevertheless, the molecular mechanisms by which clock output genes orchestrate rhythmic signals from the brain to peripheral tissues are largely unknown. Here we explored the role of one rhythmic gene, Achilles, in regulating the rhythmic transcriptome in the fly head. Achilles is a clock-controlled gene in Drosophila that encodes a putative RNA-binding protein. Achilles expression is found in neurons throughout the fly brain using fluorescence in situ hybridization (FISH), and legacy data suggest it is not expressed in core clock neurons. Together, these observations argue against a role for Achilles in regulating the core clock. To assess its impact on circadian mRNA rhythms, we performed RNA sequencing (RNAseq) to compare the rhythmic transcriptomes of control flies and those with diminished Achilles expression in all neurons. Consistent with previous studies, we observe dramatic upregulation of immune response genes upon knock-down of Achilles. Furthermore, many circadian mRNAs lose their rhythmicity in Achilles knock-down flies, suggesting that a subset of the rhythmic transcriptome is regulated either directly or indirectly by Achilles. These Achilles-mediated rhythms are observed in genes involved in immune function and in neuronal signaling, including Prosap, Nemy and Jhl-21. A comparison of RNAseq data from control flies reveals that only 42.7% of clock-controlled genes in the fly brain are rhythmic in both males and females. As mRNA rhythms of core clock genes are largely invariant between the sexes, this observation suggests that sex-specific mechanisms are an important, and heretofore under-appreciated, regulator of the rhythmic transcriptome.

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SPF45-related splicing factor for phytochrome signaling promotes photomorphogenesis by regulating pre-mRNA splicing in Arabidopsis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1706379114 ◽

2017 ◽

Vol 114 (33) ◽

pp. E7018-E7027 ◽

Cited By ~ 18

Author(s):

Ruijiao Xin ◽

Ling Zhu ◽

Patrice A. Salomé ◽

Estefania Mancini ◽

Carine M. Marshall ◽

...

Keyword(s):

Gene Expression ◽

Circadian Clock ◽

Molecular Mechanisms ◽

Fluorescent Protein ◽

Clock Genes ◽

Mrna Processing ◽

Mrna Splicing ◽

Splicing Factor ◽

Light Signaling ◽

Small Nuclear Ribonucleoprotein

Light signals regulate plant growth and development by controlling a plethora of gene expression changes. Posttranscriptional regulation, especially pre-mRNA processing, is a key modulator of gene expression; however, the molecular mechanisms linking pre-mRNA processing and light signaling are not well understood. Here we report a protein related to the human splicing factor 45 (SPF45) named splicing factor for phytochrome signaling (SFPS), which directly interacts with the photoreceptor phytochrome B (phyB). In response to light, SFPS-RFP (red fluorescent protein) colocalizes with phyB-GFP in photobodies. sfps loss-of-function plants are hyposensitive to red, far-red, and blue light, and flower precociously. SFPS colocalizes with U2 small nuclear ribonucleoprotein-associated factors including U2AF65B, U2A′, and U2AF35A in nuclear speckles, suggesting SFPS might be involved in the 3′ splice site determination. SFPS regulates pre-mRNA splicing of a large number of genes, of which many are involved in regulating light signaling, photosynthesis, and the circadian clock under both dark and light conditions. In vivo RNA immunoprecipitation (RIP) assays revealed that SFPS associates with EARLY FLOWERING 3 (ELF3) mRNA, a critical link between light signaling and the circadian clock. Moreover, PHYTOCHROME INTERACTING FACTORS (PIFs) transcription factor genes act downstream of SFPS, as the quadruple pif mutant pifq suppresses defects of sfps mutants. Taken together, these data strongly suggest SFPS modulates light-regulated developmental processes by controlling pre-mRNA splicing of light signaling and circadian clock genes.

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Modern concepts of the molecular pathogenesis of thyroid cancer

Advances in molecular oncology ◽

10.17650/2313-805x-2021-8-2-8-22 ◽

2021 ◽

Vol 8 (2) ◽

pp. 8-22

Author(s):

A. A. Mikhailova ◽

A. V. Shestakov ◽

K. A. Chubakova ◽

E. V. Kolokolova ◽

V. Yu. Eliseev ◽

...

Keyword(s):

Thyroid Cancer ◽

Tumor Markers ◽

Molecular Mechanisms ◽

Thyroid Nodules ◽

Gene Mutations ◽

Endocrine System ◽

Nodular Goiter ◽

Micro Rna ◽

Diagnostic Methods ◽

Patient Treatment

Thyroid cancer remains the most common malignancy of the endocrine system worldwide. The indicators of its morbidity and mortality rates have been increasing rapidly over the last decades. Most cases of differentiated thyroid cancer (follicular and papillary histotypes) are clinically manifested by nodular goiter frequently combined with uncertain results of cytological diagnosis (categories III and IV according to the Bethesda (Bethesda System for Reporting Thyroid Cytopathology) classification). All of that makes it difficult to choose a proper tactic for patient treatment. It is known that the development, progression, invasion, and metastasis of cancer cells are regulated by a variety of molecular mechanisms. This review describes several molecular aspects of thyroid nodules oncogenesis, as well as its most promising diagnostic tumor markers. Following molecular pathways are described in particular: gene mutations, protein tumor markers, and epigenetic effects of micro-RNA, histones, as well as DNA methylation. The study of the pathogenesis of this disease has a prognostic value and contributes to the search for effective therapeutic and diagnostic methods and their improvement. That is why we also reviewed modern test panels aimed at preoperative differential diagnosis of thyroid nodules. Summarizing the results of world research on this topic allows us not only to expand the understanding of the fundamental processes of oncogenesis, but also to outline promising areas for future experimental research projects. All of that together will contribute to developing new prognostic, diagnostic and therapeutic technologies, and as a result, will improve the quality of medical care for patients with thyroid cancer.

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Comparative physiological and transcriptomic analysis of pear leaves under distinct training systems

Scientific Reports ◽

10.1038/s41598-020-75794-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Zheng Liu ◽

Liyuan An ◽

Shihua Lin ◽

Tao Wu ◽

Xianming Li ◽

...

Keyword(s):

Circadian Clock ◽

Molecular Mechanisms ◽

Clock Genes ◽

Light Availability ◽

Photosynthetic Performance ◽

Canopy Architecture ◽

Training Systems ◽

Carbohydrate Derivative ◽

Circadian Clock Genes ◽

Architectural Traits

Abstract Canopy architecture is critical in determining the light interception and distribution, and subsequently the photosynthetic efficiency and productivity. However, the physiological responses and molecular mechanisms by which pear canopy architectural traits impact on photosynthesis remain poorly understood. Here, physiological investigations coupled with comparative transcriptomic analyses were performed in pear leaves under distinct training systems. Compared with traditional freestanding system, flat-type trellis system (DP) showed higher net photosynthetic rate (PN) levels at the most time points throughout the entire monitored period, especially for the interior of the canopy in sunny side. Gene ontology analysis revealed that photosynthesis, carbohydrate derivative catabolic process and fatty acid metabolic process were over-represented in leaves of DP system with open-canopy characteristics. Weighted gene co-expression network analysis uncovered a significant network module positive correlated with PN value. The hub genes (PpFKF1 and PpPRR5) of the module were enriched in circadian rhythm pathway, suggesting a functional role for circadian clock genes in mediating photosynthetic performance under distinct training systems. These results draw a link between pear photosynthetic response and specific canopy architectural traits, and highlight light harvesting and circadian clock network as potential targets for the input signals from the fluctuating light availability under distinct training systems.

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Non-Coding RNAs: Uncharted Mediators of Thyroid Cancer Pathogenesis

Cancers ◽

10.3390/cancers12113264 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3264

Author(s):

Hossein Tabatabaeian ◽

Samantha Peiling Yang ◽

Yvonne Tay

Keyword(s):

Thyroid Cancer ◽

Cancer Patients ◽

Molecular Mechanisms ◽

Endocrine System ◽

Circular Rnas ◽

Poor Overall Survival ◽

Cancer Pathogenesis ◽

Critical Issues ◽

Non Coding Rnas

Thyroid cancer is the most prevalent malignancy of the endocrine system and the ninth most common cancer globally. Despite the advances in the management of thyroid cancer, there are critical issues with the diagnosis and treatment of thyroid cancer that result in the poor overall survival of undifferentiated and metastatic thyroid cancer patients. Recent studies have revealed the role of different non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) that are dysregulated during thyroid cancer development or the acquisition of resistance to therapeutics, and may play key roles in treatment failure and poor prognosis of the thyroid cancer patients. Here, we systematically review the emerging roles and molecular mechanisms of ncRNAs that regulate thyroid tumorigenesis and drug response. We then propose the potential clinical implications of ncRNAs as novel diagnostic and prognostic biomarkers for thyroid cancer.

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Machine Learning and In-Vivo Expression Analyses Reveal Circadian Clock Features Predictive of Anxiety in Humans

10.21203/rs.3.rs-1190238/v1 ◽

2021 ◽

Author(s):

Aziz Zafar ◽

Rebeccah Overton ◽

Ziad Attia ◽

Ahmet Ay ◽

Krista Ingram

Keyword(s):

Machine Learning ◽

Circadian Rhythms ◽

Circadian Clock ◽

Clock Gene ◽

Molecular Mechanisms ◽

Clock Genes ◽

Anxiety Symptoms ◽

Circadian Phase ◽

Functional Studies

Abstract Mood disorders, including anxiety, are associated with disruptions in circadian rhythms and are linked to polymorphisms in circadian clock genes. Molecular mechanisms underlying these connections may be direct—via transcriptional activity of clock genes on downstream mood pathways in the brain, or indirect—via clock gene influences on the phase and amplitude of circadian rhythms which, in turn, modulate physiological processes influencing mood. Employing machine learning combined with statistical approaches, we explored clock genotype combinations that predict risk for anxiety symptoms in a deeply phenotyped population. We identified multiple novel circadian genotypes predictive of anxiety, with the PER3B-AG/CRY1-CG genotype being the strongest predictor of anxiety risk in males. Molecular chronotyping, using clock gene expression oscillations, revealed that advanced circadian phase and robust circadian amplitudes are associated with high levels of anxiety symptoms. Further analyses revealed that individuals with advanced phases and pronounced circadian misalignment were at higher risk for severe anxiety symptoms. Our results support both direct and indirect influences of clock gene variants on mood: while sex-specific clock genotype combinations predictive of anxiety symptoms suggest direct effects on mood pathways, the mediation of PER3B effects on anxiety via diurnal preference measures and the association of circadian phase with anxiety symptoms provide evidence for indirect effects of the molecular clockwork on mood. Unraveling the complex molecular mechanisms underlying the links between circadian physiology and mood is essential to identifying the core clock genes to target in future functional studies, thereby advancing the development of non-invasive treatments for anxiety-related disorders.

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Genomic basis of circannual rhythm in the european corn borer moth

10.1101/633362 ◽

2019 ◽

Author(s):

Genevieve M. Kozak ◽

Crista B. Wadsworth ◽

Shoshanna C. Kahne ◽

Steven M. Bogdanowicz ◽

Richard G. Harrison ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Circadian Clock ◽

European Corn Borer ◽

Molecular Mechanisms ◽

Clock Genes ◽

Clock Cycle ◽

Physiological Role ◽

Genomic Variation ◽

Circannual Rhythm ◽

Corn Borer

ABSTRACTGenetic variation in life-history timing allows populations to synchronize with seasonal cycles but little is known about the molecular mechanisms that produce differences in circannual rhythm in nature. Changes in diapause timing in the European corn borer moth (Ostrinia nubilalis) have facilitated rapid response to shifts in winter length encountered during range expansion and from climate change, with some populations emerging from diapause earlier to produce an additional generation per year. We identify genomic variation associated with changes in the time spent in winter diapause and show evidence that the circadian clock genes period (per) and pigment dispersing factor receptor (Pdfr) interact to underlie this adaptive polymorphism in circannual rhythm. Per and Pdfr are located within two epistatic QTL, strongly differ in allele frequency among individuals that pupate earlier or later, have the highest linkage disequilibrium among gene pairs in the QTL regions despite separation by > 4 megabases, and possess amino-acid changes likely to affect function. One per mutation in linkage disequilibrium with Pdfr creates a novel putative clock-cycle binding site found exclusively in populations that pupate later. We find associated changes in free-running daily circadian rhythm, with longer daily rhythms in individuals that end diapause early. These results support a modular connection between circadian and circannual timers and provide testable hypotheses about the physiological role of the circadian clock in seasonal synchrony. Winter length is expected to continually shorten from climate warming and we predict these gene candidates will be targets of selection for future adaptation and population persistence.

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Early birds, late owls, and the ecological role of intra-population chronotype variation

10.1101/2020.08.09.243261 ◽

2020 ◽

Author(s):

Ella Royzrakh-Pasternak ◽

Tamar Dayan ◽

Ofir Levy ◽

Noga Kronfeld-Schor

Keyword(s):

Circadian Clock ◽

Molecular Mechanisms ◽

Clock Genes ◽

Period Length ◽

Population Variation ◽

Energetic Cost ◽

Foraging Activity ◽

Clock Period ◽

Proximate Cause ◽

Selective Forces

AbstractWhile the molecular mechanisms underlying variation in chronotypes within populations have been studied extensively, the ultimate selective forces governing it are poorly understood. The proximate cause is variation in clock genes and protein expression, which produces variation in tau (period length of the circadian clock), with early individuals having shorter tau. We studied within-population variation in foraging activity times of two Acomys species in the field. This variation manifested in a regular and consistent sequence of individual foraging activity that is positively and strongly correlated with variation in tau. Thus, variation in circadian clock period length (tau) appears to be the mechanism underlying the regular pattern of intraspecific temporal partitioning. Late chronotypes also spent more time torpid than earlier ones, suggesting an energetic cost to this strategy and possible tradeoffs. We suggest that variation in tau is an adaptive mechanism to reduce competition between individuals within a population.

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