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Gu M, Jiang H, Ma F, Li S, Guo Y, Zhu L, Shi C, Na R, Wang Y, Zhang W. Multi-Omics Analysis Revealed the Molecular Mechanisms Affecting Average Daily Gain in Cattle. Int J Mol Sci 2025; 26:2343. [PMID: 40076961 PMCID: PMC11900032 DOI: 10.3390/ijms26052343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/25/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
The average daily gain (ADG) is a critical index for evaluating growth rates in cattle and is closely linked to the economic benefits of the cattle industry. Heredity is one of the factors affecting the daily gain of cattle. However, the molecular mechanisms regulating ADG remain incompletely understood. This study aimed to systematically unravel the molecular mechanisms underlying the divergence in ADG between high average daily gain (HADG) and low average daily gain (LADG) Angus cattle through integrated multi-omics analyses (microbiome, metabolome, and transcriptome), hypothesizing that the gut microbiota-host gene-metabolism axis is a key regulatory network driving ADG divergence. Thirty Angus cattle were classified according to their HADG and LADG. Fecal and serum samples were collected for 16S, fecal metabolome, and blood transcriptome analysis. The results showed that compared with the LADG group, the abundance of Firmicutes increased in the HADG group, while the abundance of Bacteroidetes and Proteobacteria decreased. Metabolomics and transcriptomic analysis revealed that KEGG pathways associated with differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) were enriched in bile acid metabolism. Spearman correlation analysis showed that Oscillospira was positively correlated with ZBTB20 and negatively correlated with RADIL. ZBTB20 was negatively correlated with dgA-11_gut_group. This study analyzed the regulatory mechanism of average daily gain of beef cattle from genetic, metabolic, and microbial levels, providing a theoretical basis for analyzing the mechanism of differential daily gain of beef cattle, and has important significance for improving the production performance of beef cattle. The multi-omics network provides biomarker foundations for machine learning-based ADG prediction models, offering potential applications in precision breeding. While these biomarkers show promise for precision breeding, their causal roles require further validation. The conclusions are derived from a single breed (Angus) and gender (castrated males). Future studies should include females and diverse breeds to assess generalizability.
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Affiliation(s)
- Mingjuan Gu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Hongyu Jiang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Fengying Ma
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Shuai Li
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Yaqiang Guo
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Lin Zhu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Caixia Shi
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Risu Na
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
| | - Yu Wang
- College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010010, China
| | - Wenguang Zhang
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot 010010, China; (M.G.); (H.J.); (F.M.); (S.L.); (Y.G.); (L.Z.); (C.S.); (R.N.)
- College of Life Science, Inner Mongolia Agricultural University, Hohhot 010010, China
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Peng X, Lee E, Liang J, Colon T, Tran F, Choi BH, Dai W. KRas plays a negative role in regulating IDO1 expression. Transl Oncol 2025; 51:102167. [PMID: 39550890 PMCID: PMC11615605 DOI: 10.1016/j.tranon.2024.102167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 09/26/2024] [Accepted: 10/27/2024] [Indexed: 11/19/2024] Open
Abstract
Ras proteins are integral to the mediation of signaling cascades to downstream effectors, regulating a multitude of cellular processes. Mutations within Ras and its associated signaling pathways are implicated in various human pathologies, including inflammatory disorders and malignancies. The immune checkpoint proteins, programmed cell death protein 1 (PD-1) and its ligands PD-L1, along with Indoleamine 2,3-dioxygenase-1 (IDO1), are pivotal in facilitating tumor immune escape. While the influence of oncogenic Ras on PD-L1 expression is extensively documented, the regulatory role of KRas in IDO1 expression remains inadequately understood. In the current study, we demonstrate that IDO1 and PD-L1 expressions are differentially regulated in KRas-mutant cancers. Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line. Notably, IDO1 expression was slightly diminished in KRas-mutant patients with lung and pancreatic ductal adenocarcinomas. Experimental data revealed that IFN-γ induces IDO1 expression; however, this induction is attenuated in the presence of constitutively active KRas. These findings suggest that KRas signaling negatively regulates IDO1 expression while enhancing PD-L1 expression. Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.
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Affiliation(s)
- Xiandong Peng
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Eunji Lee
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Jialu Liang
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Tania Colon
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Franklin Tran
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Byeong H Choi
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA
| | - Wei Dai
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, 341 East 25th Street, New York, NY 10010, USA.
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Wang F, Zhao D, Xu WY, Liu Y, Sun H, Lu S, Ji Y, Jiang J, Chen Y, He Q, Gong C, Liu R, Su Z, Dong Y, Yan Z, Liu L. Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study. BMC Med 2024; 22:147. [PMID: 38561764 PMCID: PMC10986011 DOI: 10.1186/s12916-024-03368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/22/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy. METHODS This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes. RESULTS The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies. CONCLUSIONS This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.
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Affiliation(s)
- Feihang Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Danyang Zhao
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Wang-Yang Xu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Yiying Liu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Huiyi Sun
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Shanshan Lu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jingjing Jiang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yi Chen
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Qiye He
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | | | - Rui Liu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Zhixi Su
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China.
| | - Yi Dong
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Zhiping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China.
| | - Lingxiao Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China.
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Nordeidet AN, Klevjer M, Wisløff U, Langaas M, Bye A. Exploring shared genetics between maximal oxygen uptake and disease: the HUNT study. Physiol Genomics 2023; 55:440-451. [PMID: 37575066 DOI: 10.1152/physiolgenomics.00026.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 07/25/2023] [Accepted: 08/07/2023] [Indexed: 08/15/2023] Open
Abstract
Low cardiorespiratory fitness, measured as maximal oxygen uptake (V̇o2max), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured V̇o2max and disease. We believe that identifying the mechanisms explaining how low V̇o2max is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study approach to test for shared genetics. A total of 64,479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants previously linked to V̇o2max were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, and cancer as well as clinical measurements and biomarkers from HUNT. In the total population, three single-nucleotide polymorphisms (SNPs) in and near the follicle-stimulating hormone receptor gene (FSHR) were found to be associated (false discovery rate < 0.05) with serum creatinine levels and one intronic SNP in the Rap-associating DIL domain gene (RADIL) with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in the PBX/knotted homeobox 2 gene (PKNOX2) were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance; the associations with the lowest P values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between V̇o2max and disease. However, further effort should be put into investigating the potential shared genetics between inborn V̇o2max and disease in larger cohorts to increase statistical power.NEW & NOTEWORTHY To our knowledge, this is the first genetic association study exploring how genes linked to cardiorespiratory fitness (CRF) relate to disease risk. By investigating shared genetics, we found indications that genetic variants linked to directly measured CRF also affect the level of blood creatinine, risk of diabetes, and endocarditis. Less certain findings showed that genetic variants of high CRF might cause lower body mass index, healthier HDL cholesterol, and lower resting heart rate.
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Affiliation(s)
- Ada N Nordeidet
- Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Marie Klevjer
- Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Ulrik Wisløff
- Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Centre for Research on Exercise, Physical Activity and Health, School of Human Movement and Nutrition Sciences, University of Queensland, Brisbane, Queensland, Australia
| | - Mette Langaas
- Department of Mathematical Sciences, Faculty of Information Technology and Electrical Engineering, Norwegian University of Science and Technology, Trondheim, Norway
| | - Anja Bye
- Department of Circulation and Medical Imaging, Cardiac Exercise Research Group, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
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Nolan A, Raso C, Kolch W, von Kriegsheim A, Wynne K, Matallanas D. Proteomic Mapping of the Interactome of KRAS Mutants Identifies New Features of RAS Signalling Networks and the Mechanism of Action of Sotorasib. Cancers (Basel) 2023; 15:4141. [PMID: 37627169 PMCID: PMC10452836 DOI: 10.3390/cancers15164141] [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: 07/14/2023] [Revised: 08/14/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
RAS proteins are key regulators of cell signalling and control different cell functions including cell proliferation, differentiation, and cell death. Point mutations in the genes of this family are common, particularly in KRAS. These mutations were thought to cause the constitutive activation of KRAS, but recent findings showed that some mutants can cycle between active and inactive states. This observation, together with the development of covalent KRASG12C inhibitors, has led to the arrival of KRAS inhibitors in the clinic. However, most patients develop resistance to these targeted therapies, and we lack effective treatments for other KRAS mutants. To accelerate the development of RAS targeting therapies, we need to fully characterise the molecular mechanisms governing KRAS signalling networks and determine what differentiates the signalling downstream of the KRAS mutants. Here we have used affinity purification mass-spectrometry proteomics to characterise the interactome of KRAS wild-type and three KRAS mutants. Bioinformatic analysis associated with experimental validation allows us to map the signalling network mediated by the different KRAS proteins. Using this approach, we characterised how the interactome of KRAS wild-type and mutants is regulated by the clinically approved KRASG12C inhibitor Sotorasib. In addition, we identified novel crosstalks between KRAS and its effector pathways including the AKT and JAK-STAT signalling modules.
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Affiliation(s)
- Aoife Nolan
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
| | - Cinzia Raso
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
| | - Walter Kolch
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
- Conway Institute of Biomolecular and Biomedical Research, University College Dublin, D04 V1W8 Dublin, Ireland
| | - Alex von Kriegsheim
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
- Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Kieran Wynne
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
| | - David Matallanas
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland; (A.N.); (C.R.); (W.K.); (A.v.K.); (K.W.)
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Junk P, Kiel C. Structure-based prediction of Ras-effector binding affinities and design of "branchegetic" interface mutations. Structure 2023; 31:870-883.e5. [PMID: 37167973 DOI: 10.1016/j.str.2023.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/28/2023] [Accepted: 04/14/2023] [Indexed: 05/13/2023]
Abstract
Ras is a central cellular hub protein controlling multiple cell fates. How Ras interacts with a variety of potential effector proteins is relatively unexplored, with only some key effectors characterized in great detail. Here, we have used homology modeling based on X-ray and AlphaFold2 templates to build structural models for 54 Ras-effector complexes. These models were used to estimate binding affinities using a supervised learning regressor. Furthermore, we systematically introduced Ras "branch-pruning" (or branchegetic) mutations to identify 200 interface mutations that affect the binding energy with at least one of the model structures. The impacts of these branchegetic mutants were integrated into a mathematical model to assess the potential for rewiring interactions at the Ras hub on a systems level. These findings have provided a quantitative understanding of Ras-effector interfaces and their impact on systems properties of a key cellular hub.
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Affiliation(s)
- Philipp Junk
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland.
| | - Christina Kiel
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland; Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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Tran F, Lee E, Cuddapah S, Choi BH, Dai W. MicroRNA-Gene Interactions Impacted by Toxic Metal(oid)s during EMT and Carcinogenesis. Cancers (Basel) 2022; 14:5818. [PMID: 36497298 PMCID: PMC9741118 DOI: 10.3390/cancers14235818] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Chronic environmental exposure to toxic metal(loid)s significantly contributes to human cancer development and progression. It is estimated that approximately 90% of cancer deaths are a result of metastasis of malignant cells, which is initiated by epithelial-mesenchymal transition (EMT) during early carcinogenesis. EMT is regulated by many families of genes and microRNAs (miRNAs) that control signaling pathways for cell survival, death, and/or differentiation. Recent mechanistic studies have shown that toxic metal(loid)s alter the expression of miRNAs responsible for regulating the expression of genes involved in EMT. Altered miRNA expressions have the potential to be biomarkers for predicting survival and responses to treatment in cancers. Significantly, miRNAs can be developed as therapeutic targets for cancer patients in the clinic. In this mini review, we summarize key findings from recent studies that highlight chemical-miRNA-gene interactions leading to the perturbation of EMT after exposure to toxic metal(loid)s including arsenic, cadmium, nickel, and chromium.
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Affiliation(s)
| | | | | | - Byeong Hyeok Choi
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
| | - Wei Dai
- Division of Environmental Medicine, Department of Medicine, Grossman School of Medicine, New York University, New York, NY 10010, USA
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Tian T, Li Y, Li J, Zhang G, Wang J, Wan C, Fang J, Wu D, Zhou Y, Qin Y, Zhu H, Liu D, Zhu W. Genetic influence on brain volume alterations related to self-reported childhood abuse. Front Neurosci 2022; 16:1019718. [PMID: 36203798 PMCID: PMC9530554 DOI: 10.3389/fnins.2022.1019718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
As an important predictor of adulthood psychopathology, self-reported childhood abuse appears heritable and is associated with brain abnormalities. However, the specific genetic mechanisms behind these brain alterations remain largely unknown. This study recruited young adults who reported different degrees of childhood abuse from the community. In order to fully understand the influence of genes on brain changes related to self-reported childhood abuse, various experiments were conducted in this study. Firstly, volume changes of gray matter and white matter related to childhood abuse were investigated by using advanced magnetic resonance imaging techniques. After sequencing the whole exons, we further investigated the relationship between polygenic risk score, brain volume alterations, and childhood abuse score. Furthermore, transcription-neuroimaging association analysis was used to identify risk genes whose expressions were associated with brain volume alterations. The gray matter volumes of left caudate and superior parietal lobule, and white matter volumes of left cerebellum and right temporal lobe-basal ganglia region were significantly correlated with the childhood abuse score. More importantly, brain volume changes mediated the influence of polygenic risk on self-reported childhood abuse. Additionally, transcription-neuroimaging association analysis reported 63 risk genes whose expression levels were significantly associated with childhood abuse-related brain volume changes. These genes are involved in multiple biological processes, such as nerve development, synaptic transmission, and cell construction. Combining data from multiple perspectives, our work provides evidence of brain abnormalities associated with childhood abuse, and further indicates that polygene genetic risk and risk gene expression may affect the occurrence of childhood abuse by brain regulation, which provides insights into the molecularpathology and neuromechanism of childhood adversity. Paying attention to the physical and mental health of high-risk children may be a fundamental way to prevent childhood abuse and promote lifelong mental health.
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A proteomic approach identifies isoform-specific and nucleotide-dependent RAS interactions. Mol Cell Proteomics 2022; 21:100268. [PMID: 35839996 PMCID: PMC9396065 DOI: 10.1016/j.mcpro.2022.100268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 06/28/2022] [Accepted: 07/07/2022] [Indexed: 11/22/2022] Open
Abstract
Active mutations in the RAS genes are found in ∼30% of human cancers. Although thought to have overlapping functions, RAS isoforms show preferential activation in human tumors, which prompted us to employ a comparative and quantitative proteomics approach to generate isoform-specific and nucleotide-dependent interactomes of the four RAS isoforms, KRAS4A, KRAS4B, HRAS, and NRAS. Many isoform-specific interacting proteins were identified, including HRAS-specific CARM1 and CHK1 and KRAS-specific PIP4K2C and IPO7. Comparing the interactomes of WT and constitutively active G12D mutant of RAS isoforms, we identified several potential previously unknown effector proteins of RAS, one of which was recently reported while this article was in preparation, RADIL. These interacting proteins play important roles as knockdown or pharmacological inhibition leads to potent inhibition of cancer cells. The HRAS-specific interacting protein CARM1 plays a role in HRAS-induced senescence, with CARM1 knockdown or inhibition selectively increasing senescence in HRAS-transformed cells but not in KRAS4B-transformed cells. By revealing new isoform-specific and nucleotide-dependent RAS interactors, the study here provides insights to help understand the overlapping functions of the RAS isoforms.
RAS interactome uncovers isoform-specific and nucleotide-dependent interactors. Potential novel RAS effector proteins are introduced. RAS interactors are possible new targets for RAS-driven cancer cells.
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