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1
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Trang KB, Pahl MC, Pippin JA, Su C, Littleton SH, Sharma P, Kulkarni NN, Ghanem LR, Terry NA, O'Brien JM, Wagley Y, Hankenson KD, Jermusyk A, Hoskins J, Amundadottir LT, Xu M, Brown K, Anderson S, Yang W, Titchenell P, Seale P, Kaestner KH, Cook L, Levings M, Zemel BS, Chesi A, Wells AD, Grant SFA. 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity. eLife 2025; 13:RP95411. [PMID: 39813287 PMCID: PMC11735026 DOI: 10.7554/elife.95411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025] Open
Abstract
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci, we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18, and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.
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Affiliation(s)
- Khanh B Trang
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Matthew C Pahl
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - James A Pippin
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Chun Su
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Sheridan H Littleton
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Genetics, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Prabhat Sharma
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pathology, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Nikhil N Kulkarni
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pathology, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Louis R Ghanem
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Natalie A Terry
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Joan M O'Brien
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Penn Medicine Center for Ophthalmic Genetics in Complex DiseasePhiladelphiaUnited States
| | - Yadav Wagley
- Department of Orthopedic Surgery University of Michigan Medical School Ann ArborAnn ArborUnited States
| | - Kurt D Hankenson
- Department of Orthopedic Surgery University of Michigan Medical School Ann ArborAnn ArborUnited States
| | - Ashley Jermusyk
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesdaUnited States
| | - Jason Hoskins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesdaUnited States
| | - Laufey T Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesdaUnited States
| | - Mai Xu
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesdaUnited States
| | - Kevin Brown
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer InstituteBethesdaUnited States
| | - Stewart Anderson
- Department of Child and Adolescent Psychiatry, Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Psychiatry, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Wenli Yang
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Paul Titchenell
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Physiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Patrick Seale
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Klaus H Kaestner
- Department of Genetics, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Laura Cook
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and ImmunityMelbourneAustralia
- Department of Critical Care, Melbourne Medical School, University of MelbourneMelbourneAustralia
- Division of Infectious Diseases, Department of Medicine, University of British ColumbiaVancouverCanada
| | - Megan Levings
- Department of Surgery, University of British ColumbiaVancouverCanada
- BC Children's Hospital Research InstituteVancouverCanada
- School of Biomedical Engineering, University of British ColumbiaVancouverCanada
| | - Babette S Zemel
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pediatrics, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Alessandra Chesi
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pathology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Andrew D Wells
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pathology, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Pathology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Institute for Immunology, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Struan FA Grant
- Center for Spatial and Functional Genomics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Division of Human Genetics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Department of Genetics, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Pediatrics, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Division Endocrinology and Diabetes, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
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McColl KS, Ajay A, Wang H, Wildey GM, Yoon S, Grubb B, Kopp SR, Joseph PL, Saviana M, Romano G, Nana‐Sinkam P, Peacock CD, Yun Z, Mneimneh W, Lam M, Miyagi M, Kao H, Dowlati A. Identification of HEPACAM2 as a novel and specific marker of small cell carcinoma. Cancer 2025; 131:e35557. [PMID: 39301750 PMCID: PMC11694165 DOI: 10.1002/cncr.35557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Small cell lung cancer (SCLC) is the most aggressive neuroendocrine lung cancer, with a dismal 5-year survival rate. No reliable biomarkers or imaging are available for early SCLC detection. In a search for a specific marker of SCLC, this study identified that hepatocyte cell adhesion molecule 2 (HEPACAM2), a member of the immunoglobulin-like superfamily, is highly and specifically expressed in SCLC. METHODS This study investigated HEPACAM2 expression in patients with SCLC via RNA sequencing and evaluated its relationship to progression-free survival (PFS) and overall survival (OS). Immunofluorescence microscopy was used to assess the cellular location of HEPACAM2 and to conduct in vitro and in vivo studies to understand its expression and functional significance. These findings were integrated with databases of patients with SCLC. RESULTS HEPACAM2 is highly expressed and specific to SCLC. HEPACAM2 levels are inversely correlated with PFS and OS in patients with SCLC and are expressed at all stages. Moreover, HEPACAM2 messenger RNA and its peptides can be detected in the secretomes in cell lines. Positively correlated with ASCL1 expression in SCLC tumors, HEPACAM2 is localized primarily to the plasma membrane and linked to extracellular matrix signaling and cellular migration. A loss of HEPACAM2 in SCLC cells attenuated ASCL1 and MYC expression. Consistent with clinical data, in vitro and in vivo studies suggested that HEPACAM2 promotes cancer cell growth. CONCLUSIONS With its remarkable specificity, high expression, presence in early disease, and extracellular secretion, HEPACAM2 could be a potential diagnostic cell surface biomarker for early SCLC detection. These findings warrant further investigation into its role in the pathobiology of SCLC.
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Affiliation(s)
- Karen S. McColl
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Abhishek Ajay
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
- Department of MedicineInstitute of Computational BiologyCase Western Reserve UniversityClevelandOhioUSA
| | - Han Wang
- Department of BiochemistryCase Western Reserve UniversityClevelandOhioUSA
| | - Gary M. Wildey
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Suzy Yoon
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Brandon Grubb
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Shelby R. Kopp
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Peronne L. Joseph
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Michela Saviana
- Division of Pulmonary Diseases and Critical Care MedicineDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Giulia Romano
- Division of Pulmonary Diseases and Critical Care MedicineDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Patrick Nana‐Sinkam
- Division of Pulmonary Diseases and Critical Care MedicineDepartment of Internal MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Craig D. Peacock
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Zixi Yun
- Department of BiochemistryCase Western Reserve UniversityClevelandOhioUSA
| | - Wadad Mneimneh
- Robert J. Tomsich Pathology & Laboratory Medicine InstituteCleveland Clinic Lerner College of MedicineCase Western Reserve UniversityClevelandOhioUSA
| | - Minh Lam
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Masaru Miyagi
- Department of PharmacologyCase Western Reserve UniversityClevelandOhioUSA
| | - Hung‐Ying Kao
- Department of BiochemistryCase Western Reserve UniversityClevelandOhioUSA
| | - Afshin Dowlati
- Division of Hematology and OncologyUniversity Hospitals Seidman Cancer CenterCase Western Reserve UniversityClevelandOhioUSA
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3
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Trang KB, Pahl MC, Pippin JA, Su C, Littleton SH, Sharma P, Kulkarni NN, Ghanem LR, Terry NA, O’Brien JM, Wagley Y, Hankenson KD, Jermusyk A, Hoskins JW, Amundadottir LT, Xu M, Brown KM, Anderson SA, Yang W, Titchenell PM, Seale P, Cook L, Levings MK, Zemel BS, Chesi A, Wells AD, Grant SF. 3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2023.08.30.23294092. [PMID: 37693606 PMCID: PMC10491377 DOI: 10.1101/2023.08.30.23294092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities of type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts for childhood obesity revealed 19 independent signals for the trait; however, the mechanism of action of these loci remains to be elucidated. To molecularly characterize these childhood obesity loci we sought to determine the underlying causal variants and the corresponding effector genes within diverse cellular contexts. Integrating childhood obesity GWAS summary statistics with our existing 3D genomic datasets for 57 human cell types, consisting of high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, and RNA-seq, we applied stratified LD score regression and calculated the proportion of genome-wide SNP heritability attributable to cell type-specific features, revealing pancreatic alpha cell enrichment as the most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out for genome-wide significant childhood obesity loci and their linkage disequilibrium proxies to implicate effector genes, yielded the most abundant number of candidate variants and target genes at the BDNF, ADCY3, TMEM18 and FTO loci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene, ALKAL2 - an inflammation-responsive gene in nerve nociceptors - was observed at the key TMEM18 locus across multiple immune cell types. Interestingly, this observation was also supported through colocalization analysis using expression quantitative trait loci (eQTL) derived from the Genotype-Tissue Expression (GTEx) dataset, supporting an inflammatory and neurologic component to the pathogenesis of childhood obesity. Our comprehensive appraisal of 3D genomic datasets generated in a myriad of different cell types provides genomic insights into pediatric obesity pathogenesis.
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Affiliation(s)
- Khanh B. Trang
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Matthew C. Pahl
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - James A. Pippin
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Chun Su
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Sheridan H. Littleton
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Prabhat Sharma
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Nikhil N. Kulkarni
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Louis R. Ghanem
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, PA, USA
| | - Natalie A. Terry
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, PA, USA
| | - Joan M. O’Brien
- Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA
- Penn Medicine Center for Ophthalmic Genetics in Complex Disease
| | - Yadav Wagley
- Department of Orthopedic Surgery University of Michigan Medical School Ann Arbor, MI, USA
| | - Kurt D. Hankenson
- Department of Orthopedic Surgery University of Michigan Medical School Ann Arbor, MI, USA
| | - Ashley Jermusyk
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Jason W. Hoskins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Laufey T. Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Mai Xu
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Kevin M Brown
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Stewart A. Anderson
- Department of Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Wenli Yang
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul M. Titchenell
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick Seale
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Laura Cook
- Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
- Department of Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia
- Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Megan K. Levings
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
- BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
| | - Babette S. Zemel
- Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alessandra Chesi
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew D. Wells
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Struan F.A. Grant
- Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Division Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Chen Y, Xu X, Wang M, Wang X, Wang Y, Zhang Y, Zhao L, Fan Z, Liu L. Moxifloxacin as a contrast agent of two-photon microscopic imaging for detecting colorectal diseases. JOURNAL OF BIOPHOTONICS 2023; 16:e202200367. [PMID: 36633193 DOI: 10.1002/jbio.202200367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/26/2022] [Accepted: 01/01/2023] [Indexed: 05/17/2023]
Abstract
Since two-photon microscopy (TPM) can obtain high-resolution images at cellular and subcellular level and moxifloxacin has multiphoton fluorescence characteristic, our study aimed to explore the feasibility and diagnostic value of moxifloxacin-assisted TPM in different human colorectal diseases, including low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN) and cancer tissues. Excitation power for TPM imaging with and without moxifloxacin was (2.74 ± 0.16) mW and (0.28 ± 0.02) mW, respectively (p < 0.05). Whether labeled with moxifloxacin or not, images of normal, LGIN, HGIN and cancer tissues all reached the strongest signal at 30 μm from the mucosa. Normalized fluorescence intensity of TPM images with moxifloxacin was approximately 10 times stronger than that without moxifloxacin. Fluorescence signal was differed significantly in normal, LGIN, HGIN and cancer tissues with or without moxifloxacin (p < 0.05). Besides, moxifloxacin-assisted TPM could present variant tissue features with different colorectal diseases, such as the crypt opening, glandular structure, adjacent glandular space and fluorescence distribution.
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Affiliation(s)
- Yingtong Chen
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing, China
| | - Xiaoyi Xu
- National Laboratory of Solid State Microstructure of Nanjing University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Xiang Wang
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yan Wang
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Yong Zhang
- National Laboratory of Solid State Microstructure of Nanjing University, Nanjing, China
| | - Lili Zhao
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Zhining Fan
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Li Liu
- Digestive Endoscopy Department, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, Jiangsu Province Hospital and The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Gusu College of Nanjing Medical University, Suzhou, China
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5
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Cox KE, Liu S, Lwin TM, Hoffman RM, Batra SK, Bouvet M. The Mucin Family of Proteins: Candidates as Potential Biomarkers for Colon Cancer. Cancers (Basel) 2023; 15:1491. [PMID: 36900282 PMCID: PMC10000725 DOI: 10.3390/cancers15051491] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal cancers. MUC1, MUC2, MUC4, MUC5AC, and MUC6 are currently the most widely covered in the literature regarding their role in the progression from normal colonic tissue to cancer.
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Affiliation(s)
- Kristin E. Cox
- Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
| | - Shanglei Liu
- Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
| | - Thinzar M. Lwin
- Department of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Robert M. Hoffman
- Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
- AntiCancer, Inc., San Diego, CA 92111, USA
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael Bouvet
- Department of Surgery, University of California San Diego, La Jolla, CA 92037, USA
- VA San Diego Healthcare System, La Jolla, CA 92161, USA
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6
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Gan Q, Mao L, Shi R, Chang L, Wang G, Cheng J, Chen R. Prognostic Value and Immune Infiltration of HPV-Related Genes in the Immune Microenvironment of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma. Cancers (Basel) 2023; 15:1419. [PMID: 36900213 PMCID: PMC10000937 DOI: 10.3390/cancers15051419] [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: 12/25/2022] [Revised: 02/06/2023] [Accepted: 02/11/2023] [Indexed: 03/12/2023] Open
Abstract
Mounting evidence has highlighted the immune environment as a critical feature in the development of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the relationship between the clinical characteristics of the immune environment and CESC remain unclear. Therefore, the aim of this study was to further characterize the relationship between the tumor and immune microenvironment and the clinical features of CESC using a variety of bioinformatic methods. Expression profiles (303 CESCs and three control samples) and relevant clinical data were obtained from The Cancer Genome Atlas. We divided CESC cases into different subtypes and performed a differential gene expression analysis. In addition, gene ontology (GO) and gene set enrichment analysis (GSEA) were performed to identify potential molecular mechanisms. Furthermore, data from 115 CESC patients from East Hospital were used to help identify the relationship between the protein expressions of key genes and disease-free survival using tissue microarray technology. Cases of CESC (n = 303) were divided into five subtypes (C1-C5) based on their expression profiles. A total of 69 cross-validated differentially expressed immune-related genes were identified. Subtype C4 demonstrated a downregulation of the immune profile, lower tumor immune/stroma scores, and worse prognosis. In contrast, the C1 subtype showed an upregulation of the immune profile, higher tumor immune/stroma scores, and better prognosis. A GO analysis suggested that changes in CESC were primarily enriched nuclear division, chromatin binding, and condensed chromosomes. In addition, GSEA demonstrated that cellular senescence, the p53 signaling pathway, and viral carcinogenesis are critical features of CESC. Moreover, high FOXO3 and low IGF-1 protein expression were closely correlated with decreased clinical prognosis. In summary, our findings provide novel insight into the relationship between the immune microenvironment and CESC. As such, our results may provide guidance for developing potential immunotherapeutic targets and biomarkers for CESC.
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Affiliation(s)
- Qiyu Gan
- Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Luning Mao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100021, China
| | - Rui Shi
- Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Linlin Chang
- Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Guozeng Wang
- Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Jingxin Cheng
- Department of Gynecology and Obstetrics, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Rui Chen
- Department of Gynecology, Shanghai United Family Hospital, Shanghai 200120, China
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7
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Exploring Core Genes by Comparative Transcriptomics Analysis for Early Diagnosis, Prognosis, and Therapies of Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15051369. [PMID: 36900162 PMCID: PMC10000172 DOI: 10.3390/cancers15051369] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/16/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers with a high mortality rate. Early diagnosis and therapies for CRC may reduce the mortality rate. However, so far, no researchers have yet investigated core genes (CGs) rigorously for early diagnosis, prognosis, and therapies of CRC. Therefore, an attempt was made in this study to explore CRC-related CGs for early diagnosis, prognosis, and therapies. At first, we identified 252 common differentially expressed genes (cDEGs) between CRC and control samples based on three gene-expression datasets. Then, we identified ten cDEGs (AURKA, TOP2A, CDK1, PTTG1, CDKN3, CDC20, MAD2L1, CKS2, MELK, and TPX2) as the CGs, highlighting their mechanisms in CRC progression. The enrichment analysis of CGs with GO terms and KEGG pathways revealed some crucial biological processes, molecular functions, and signaling pathways that are associated with CRC progression. The survival probability curves and box-plot analyses with the expressions of CGs in different stages of CRC indicated their strong prognostic performance from the earlier stage of the disease. Then, we detected CGs-guided seven candidate drugs (Manzamine A, Cardidigin, Staurosporine, Sitosterol, Benzo[a]pyrene, Nocardiopsis sp., and Riccardin D) by molecular docking. Finally, the binding stability of four top-ranked complexes (TPX2 vs. Manzamine A, CDC20 vs. Cardidigin, MELK vs. Staurosporine, and CDK1 vs. Riccardin D) was investigated by using 100 ns molecular dynamics simulation studies, and their stable performance was observed. Therefore, the output of this study may play a vital role in developing a proper treatment plan at the earlier stages of CRC.
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8
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Yang M, Zhang Q, Ge Y, Tang M, Zhang X, Song M, Ruan G, Zhang X, Zhang K, Shi H. Glucose to lymphocyte ratio predicts prognoses in patients with colorectal cancer. Asia Pac J Clin Oncol 2022. [DOI: 10.1111/ajco.13904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 10/11/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022]
Affiliation(s)
- Ming Yang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Qi Zhang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Yizhong Ge
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China
| | - Meng Tang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Xi Zhang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Mengmeng Song
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Guotian Ruan
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Xiaowei Zhang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Kangping Zhang
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
| | - Hanping Shi
- Department of Gastrointestinal Surgery/Department of Clinical Nutrition Beijing Shijitan Hospital Capital Medical University Beijing China
- Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition Beijing China
- Key Laboratory of Cancer FSMP for State Market Regulation Beijing China
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9
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Urh K, Zidar N, Boštjančič E. Bioinformatics Analysis of RNA-seq Data Reveals Genes Related to Cancer Stem Cells in Colorectal Cancerogenesis. Int J Mol Sci 2022; 23:ijms232113252. [PMID: 36362041 PMCID: PMC9654446 DOI: 10.3390/ijms232113252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Cancer stem cells (CSC) play one of the crucial roles in the pathogenesis of various cancers, including colorectal cancer (CRC). Although great efforts have been made regarding our understanding of the cancerogenesis of CRC, CSC involvement in CRC development is still poorly understood. Using bioinformatics and RNA-seq data of normal mucosa, colorectal adenoma, and carcinoma (n = 106) from GEO and TCGA, we identified candidate CSC genes and analyzed pathway enrichment analysis (PEI) and protein–protein interaction analysis (PPI). Identified CSC-related genes were validated using qPCR and tissue samples from 47 patients with adenoma, adenoma with early carcinoma, and carcinoma without and with lymph node metastasis and were compared to normal mucosa. Six CSC-related genes were identified: ANLN, CDK1, ECT2, PDGFD, TNC, and TNXB. ANLN, CDK1, ECT2, and TNC were differentially expressed between adenoma and adenoma with early carcinoma. TNC was differentially expressed in CRC without lymph node metastases whereas ANLN, CDK1, and PDGFD were differentially expressed in CRC with lymph node metastases compared to normal mucosa. ANLN and PDGFD were differentially expressed between carcinoma without and with lymph node metastasis. Our study identified and validated CSC-related genes that might be involved in early stages of CRC development (ANLN, CDK1, ECT2, TNC) and in development of metastasis (ANLN, PDGFD).
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10
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Bayrak T, Çetin Z, Saygılı Eİ, Ogul H. Identifying the tumor location-associated candidate genes in development of new drugs for colorectal cancer using machine-learning-based approach. Med Biol Eng Comput 2022; 60:2877-2897. [DOI: 10.1007/s11517-022-02641-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/28/2022] [Indexed: 02/07/2023]
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11
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Yang M, Zhang Q, Ge YZ, Tang M, Hu CL, Wang ZW, Zhang X, Song MM, Ruan GT, Zhang XW, Liu T, Xie HL, Zhang HY, Zhang KP, Li QQ, Li XR, Liu XY, Lin SQ, Shi HP. Prognostic Roles of Glucose to Lymphocyte Ratio and Modified Glasgow Prognosis Score in Patients With Non-small Cell Lung Cancer. Front Nutr 2022; 9:871301. [PMID: 35619963 PMCID: PMC9127733 DOI: 10.3389/fnut.2022.871301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/04/2022] [Indexed: 11/21/2022] Open
Abstract
Background Non-small cell lung cancer (NSCLC) is among the most prevalent malignancies worldwide. Previous studies have shown that the status of inflammation, nutrition and immune are closely related to overall survival (OS) of patients with NSCLC, but little is known about their interactive and combined roles. Hence, we chose glucose to lymphocyte ratio (GLR) and modified Glasgow Prognosis Score (mGPS) as prognostic factors and assessed the prognostic values of them for patients with NSCLC. Methods Baseline clinicopathologic and laboratory characteristics of 862 patients with NSCLC were obtained from a multicenter prospective cohort. The Cox proportional hazard regression models were used to determine prognostic values of the clinical factors. A nomogram was also constructed integrating the clinical factors with clinical significance or independent prognostic values. Concordance index (C-index) was utilized to evaluate the prediction accuracy of the TNM stage and the nomogram. Results Multivariate analyses demonstrated that GLR [Hazard ratio (HR) = 1.029, 95% confidence interval (CI) = 1.004–1.056, P = 0.023] and mGPS (score of 1: HR = 1.404, 95% CI = 1.143–1.726, P = 0.001; score of 2: HR = 1.515, 95% CI = 1.159–1.980, P = 0.002) were independent prognostic factors for patients with NSCLC. The C-indexes of the TNM stage and the nomogram were 0.642 (95% CI = 0.620–0.663) and 0.694 (95% CI = 0.671–0.717), respectively. Conclusion GLR and mGPS were independent prognostic factors for patients with NSCLC. Moreover, our constructed nomogram might be superior in predicting prognosis of patients with NSCLC compared with the TNM stage.
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Affiliation(s)
- Ming Yang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Qi Zhang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Yi-Zhong Ge
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China.,The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Meng Tang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Chun-Lei Hu
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Zi-Wen Wang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Xi Zhang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Meng-Meng Song
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Guo-Tian Ruan
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Xiao-Wei Zhang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Tong Liu
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Hai-Lun Xie
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - He-Yang Zhang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Kang-Ping Zhang
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Qin-Qin Li
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Xiang-Rui Li
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Xiao-Yue Liu
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
| | - Shi-Qi Lin
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China.,The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Han-Ping Shi
- Department of Gastrointestinal Surgery / Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.,Beijing International Science and Technology Cooperation Base for Cancer Metabolism and Nutrition, Beijing, China.,Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China
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12
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A New Algorithm for Multivariate Genome Wide Association Studies Based on Differential Evolution and Extreme Learning Machines. MATHEMATICS 2022. [DOI: 10.3390/math10071024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies (GWAS) are observational studies of a large set of genetic variants, whose aim is to find those that are linked to a certain trait or illness. Due to the multivariate nature of these kinds of studies, machine learning methodologies have been already applied in them, showing good performance. This work presents a new methodology for GWAS that makes use of extreme learning machines and differential evolution. The proposed methodology was tested with the help of the genetic information (370,750 single-nucleotide polymorphisms) of 2049 individuals, 1076 of whom suffer from colorectal cancer. The possible relationship of 10 different pathways with this illness was tested. The results achieved showed that the proposed methodology is suitable for detecting relevant pathways for the trait under analysis with a lower computational cost than other machine learning methodologies previously proposed.
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13
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The Regulatory Role of Neuropeptide Gene Glucagon in Colorectal Cancer: A Comprehensive Bioinformatic Analysis. DISEASE MARKERS 2022; 2022:4262600. [PMID: 35340411 PMCID: PMC8956438 DOI: 10.1155/2022/4262600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 11/26/2022]
Abstract
Background Colorectal cancer is highly prevalent and causes high global mortality, and glucagon axis has been implicated in colon cancer. The present study is aimed at investigating the regulating mechanisms of glucagon involvement in colorectal cancer. Methods Publicly available data from the TCGA database was utilized to explore the expression pattern and regulating role of glucagon (GCG) in colorectal cancer (COADREAD) including colon adenocarcinomas (COAD) and rectum adenocarcinomas (READ). Statistical analyses were performed using the R software packages and public web servers. The expression pattern and prognostic significance of GCG gene in pan-cancer and TCGA-COADREAD data were investigated by performing unpaired and paired sample analyses. The association of GCG expression with clinical characteristics was investigated using logistic regression analysis. Univariate cox regression analysis was performed to test the prognostic value of GCG expression for overall survival in COADREAD patients. GCG-significantly correlated genes were obtained. Biological functions and signaling pathways were identified by performing functional enrichment analysis and Gene Set Enrichment Analysis (GSEA). Additionally, the potential involvement of GCG in tumor immunity was researched by investigating the correlation between GCG expression and 24 tumor infiltrating immune cells. Results GCG was found to be significantly downregulated in COADREAD tumor samples compared with healthy control samples. GCG gene was shown to be associated with the prognostic outcomes of COADREAD, whereby its upregulation predicted improved survival outcomes. Functional enrichment analysis showed that the top 100 positively and top 100 negatively GCG-correlated genes were mainly enriched in three signaling pathways including ribosome, nitrogen metabolism, and proximal tubule bicarbonate reclamation. The GSEA showed that GCG-significantly correlated genes were mainly enriched in cell cycle-related pathways (reactome cell cycle, reactome cell cycle mitotic, reactome cell cycle checkpoints, reactome M phase, Reactome G2 M DNA damage checkpoint, and Reactome G2 M checkpoints), neuropeptide ligand receptor interaction, RHO GTPases signaling, WNT signaling, RUNX1 signaling, NOTCH signaling, ESR signaling, HCMV infection, and oxidative stress-related signaling. GCG was positively correlated with Th17 cells, pDC, macrophages, TFH cells, iDC, Tem, B cells, dendritic cells, neutrophils, mast cells, and eosinophils and was negatively associated with NK cells. Conclusions GCG dysregulation with high prognostic value in COADREAD was noted. Several tumor progression-related pathways and tumor immune-modulatory cells were linked to GCG expression in COADREAD. Therefore, GCG may be regarded as a potential therapeutic target for treating colorectal cancer.
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14
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Zhou X, Zhang S, Liu D, Qian H, Zhang D, Liu Q. The differences between fecal microbiota and intestinal fluid microbiota in colon polyps: An observational study. Medicine (Baltimore) 2021; 100:e28028. [PMID: 34967350 PMCID: PMC8718174 DOI: 10.1097/md.0000000000028028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/11/2021] [Indexed: 01/05/2023] Open
Abstract
Generally, intestinal microbiota can be classified into intestinal cavity microbiota and mucosal microbiota, among which, the former is the default type. This study aimed to identify the differences between fecal microbiota and intestinal fluid microbiota in colon polys.This study enrolled patients with colon polys who met the Rome-III criteria to carry out 16s rDNA gene sequencing. Then, both fresh feces as well as intestinal fluid was sampled. Thereafter, α/β diversities, together with the heterogeneities with regard to microbial function and structure were assessed among those intestinal fluid and fresh feces samples collected.According to bioinformatics analysis, difference in α-diversity was not statistically significant between intestinal fluid microbiota and fecal microbiota among patients with colorectal polyps (CPs). Non-metric multidimensional scaling analysis of β-diversity revealed that differences were of statistical significance between both groups. In addition, linear discriminant analysis effect size analysis displayed great heterogeneities in intestinal microbiota of both groups, including Firmicutes, Clostridia, and Phascolarctobacterium. At the phylum level, difference (P = .016) in Spirochaetes was statistically significant between the intestinal fluid group and fecal group. At the family level, differences in Bacteroidaceae, Micrococcaceae, F16, Spirocheatacae, Enterobacteriaceae, Cardiobacteriaceae, Turkish Spirobacteriaceae, Bifidobacteriaceae, and Dethiosulfovibrionaceae were statistically significant between the 2 groups. At the genus level, there were statistical differences between the 2 groups in terms of Bacteroidetes, Rothia, Actinobacillus, F16, Treponema, Oscillospira, Turicibacter, Sharpea, Heamophilus, Veillonella, and Cardiobacterium.There are statistical differences in the composition between intestinal microbiota and fecal microbiota in CP patients, both of which are equally important and indispensable for analyzing the intestinal microbiota in CP patients.
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Affiliation(s)
- Xi Zhou
- Department of Anorectal Surgery, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuoqiu Zhang
- Department of Anorectal Surgery, Nanjing University of Chinese Medicine, Nanjing, China
| | - Dan Liu
- Department of Medical Cosmetic, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haihua Qian
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Dan Zhang
- Department of Anorectal Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, China
| | - Qiuhui Liu
- Department of Intensive Care Unit, Affiliated Hospital of Nanjing University of Chinese Medicine, Wujin Traditional Chinese Medicine Hospital, Changzhou, China
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15
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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Yang Y, Gu X, Li Z, Zheng C, Wang Z, Zhou M, Chen Z, Li M, Li D, Xiang J. Whole-exome sequencing of rectal cancer identifies locally recurrent mutations in the Wnt pathway. Aging (Albany NY) 2021; 13:23262-23283. [PMID: 34642262 PMCID: PMC8544332 DOI: 10.18632/aging.203618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 09/29/2021] [Indexed: 12/29/2022]
Abstract
Locally recurrent rectal cancer (LRRC) leads to a poor prognosis and appears as a clinically predominant pattern of failure. In this research, whole-exome sequencing (WES) was performed on 21 samples from 8 patients to search for the molecular mechanisms of LRRC. The data was analyzed by bioinformatics. Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) were performed to validate the candidate genes. Immunohistochemistry was used to detect the protein expression of LEF1 and CyclinD1 in LRRC, primary rectal cancer (PRC), and non-recurrent rectal cancer (NRRC) specimens. The results showed that LRRC, PRC, and NRRC had 668, 794, and 190 specific genes, respectively. FGFR1 and MYC have copy number variants (CNVs) in PRC and LRRC, respectively. LRRC specific genes were mainly enriched in positive regulation of transcription from RNA polymerase II promoter, plasma membrane, and ATP binding. The specific signaling pathways of LRRC were Wnt signaling pathway, gap junction, and glucagon signaling pathway, etc. The transcriptional and translational expression levels of genes including NFATC1, PRICKLE1, SOX17, and WNT6 related to Wnt signaling pathway were higher in rectal cancer (READ) tissues than normal rectal tissues. The PRICKLE1 mutation (c.C875T) and WNT6 mutation (c.G629A) were predicted as “D (deleterious)”. Expression levels of LEF1 and cytokinin D1 proteins: LRRC > PRC > NRRC > normal rectal tissue. Gene variants in the Wnt signaling pathway may be critical for the development of LRRC. The present study may provide a basis for the prediction of LRRC and the development of new therapeutic drugs.
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Affiliation(s)
- Yi Yang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Xiaodong Gu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zhenyang Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Chuang Zheng
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zihao Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Minwei Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zongyou Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Mengzhen Li
- MyGene Diagnostics Co., Ltd, Guangzhou 510000, China
| | - Dongbing Li
- MyGene Diagnostics Co., Ltd, Guangzhou 510000, China
| | - Jianbin Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
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17
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Hong Q, Li B, Cai X, Lv Z, Cai S, Zhong Y, Wen B. Transcriptomic Analyses of the Adenoma-Carcinoma Sequence Identify Hallmarks Associated With the Onset of Colorectal Cancer. Front Oncol 2021; 11:704531. [PMID: 34458146 PMCID: PMC8387103 DOI: 10.3389/fonc.2021.704531] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
The concept of the adenoma-carcinoma sequence in colorectal cancer (CRC) is widely accepted. However, the relationship between the characteristics of the transcriptome and the adenoma-carcinoma sequence in CRC remains unclear. Here, the transcriptome profiles of 15 tissue samples from five CRC patients were generated by RNAseq. Six specific dynamic expression patterns of differentially expressed genes (DEGs) were generated by mFuzz. Weighted correlation network analysis showed that DEGs in cluster 4 were associated with carcinoma tissues, and those in cluster 6 were associated with non-normal tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified metabolic dysregulation as a consistent finding throughout the transition process, whereas downregulation of the immune response occurred during normal to adenoma transition, and the upregulation of canonical pathways was associated with adenoma to carcinoma transition. Overall survival analysis of patients in cluster 6 identified TPD52L1 as a marker of poor prognosis, and cell proliferation, colony formation, wound healing, and Transwell invasion assays showed that high expression levels of TPD52L1 promoted malignant behaviors. In total, 70 proteins were identified as potential partners of hD53 by mass spectrometry. CRC formation was associated with three cancer hallmarks: dysregulation of metabolism, inactivation of the immune response, and activation of canonical cancer pathways. The TPD52L1 gene was identified as a potential marker to track tumor formation in CRC and as an indicator of poor patient prognosis.
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Affiliation(s)
- Qin Hong
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Bing Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiumei Cai
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhengtao Lv
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shilun Cai
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunshi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bo Wen
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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18
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Yin TF, Zhao DY, Zhou YC, Wang QQ, Yao SK. Identification of the circRNA-miRNA-mRNA regulatory network and its prognostic effect in colorectal cancer. World J Clin Cases 2021; 9:4520-4541. [PMID: 34222420 PMCID: PMC8223824 DOI: 10.12998/wjcc.v9.i18.4520] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/26/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored. AIM To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis. METHODS CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork. RESULTS We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs (CA2, ITLN1 and LRRC19) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC. CONCLUSION We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.
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Affiliation(s)
- Teng-Fei Yin
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Dong-Yan Zhao
- Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Yuan-Chen Zhou
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Qian-Qian Wang
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Shu-Kun Yao
- Graduate school, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
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19
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Comprehensive Analysis of Differentially Expressed Long Noncoding RNA-mRNA in the Adenoma-Carcinoma Sequence of DNA Mismatch Repair Proficient Colon Cancer. JOURNAL OF ONCOLOGY 2021; 2021:9977695. [PMID: 34211553 PMCID: PMC8208869 DOI: 10.1155/2021/9977695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 05/08/2021] [Indexed: 12/24/2022]
Abstract
DNA proficient mismatch repair colon cancer (pMMR CC) is the most common subtype of sporadic CC. We aimed to investigate the role of long noncoding RNAs (lncRNAs) in pMMR CC carcinogenesis. In the present study, we conducted transcriptomic analysis of lncRNAs-mRNAs in five low-grade intraepithelial neoplasia (LGIN), five high-grade intraepithelial neoplasia (HGIN), four pMMR CC, and five normal control (NC) tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway, and coexpression network analyses were performed to elucidate the functions of lncRNAs and mRNAs as well as their interactions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate five dysregulated lncRNAs in a large set of colon tissues. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the candidate lncRNAs. A set of 5783 differentially expressed lncRNAs and 4483 differentially expressed mRNAs were detected among the LGIN, HGIN, pMMR CC, and NC samples. These differentially expressed lncRNAs and mRNAs were assigned to 275 significant GO terms and 179 significant KEGG enriched pathways. qRT-PCR confirmed that the expression of five selected lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, NR_026543, and ENST00000545920) were consistent with the microarray data. ROC analysis showed that four lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, and NR_026543) had larger area under the ROC curve (AUC) values compared to serum carcinoembryonic antigens, thereby distinguishing NC from pMMR CC. In conclusion, several lncRNAs play various roles in the adenoma-carcinoma sequence and may serve as potential biomarkers for the early diagnosis of pMMR CC.
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20
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Velasco A, Tokat F, Bonde J, Trim N, Bauer E, Meeney A, de Leng W, Chong G, Dalstein V, Kis LL, Lorentzen JA, Tomić S, Thwaites K, Putzová M, Birnbaum A, Qazi R, Primmer V, Dockhorn-Dworniczak B, Hernández-Losa J, Soares FA, Gertler AA, Kalman M, Wong C, Carraro DM, Sousa AC, Reis RM, Fox SB, Fassan M, Brevet M, Merkelbach-Bruse S, Colling R, Soilleux E, Teo RYW, D'Haene N, Nolet S, Ristimäki A, Väisänen T, Chapusot C, Soruri A, Unger T, Wecgowiec J, Biscuola M, Frattini M, Long A, Campregher PV, Matias-Guiu X. Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer. Virchows Arch 2021; 478:851-863. [PMID: 33170334 PMCID: PMC8099763 DOI: 10.1007/s00428-020-02962-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/14/2020] [Accepted: 10/30/2020] [Indexed: 12/24/2022]
Abstract
Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
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Affiliation(s)
- Ana Velasco
- Departments of Pathology and Molecular Genetics, Hospital U Arnau de Vilanova and Hospital U de Bellvitge, University of Lleida, IRBLLEIDA, IDIBELL, CIBERONC, Av. Alcalde Rovira Roure, 80 25198, Lleida, Spain.
| | - Fatma Tokat
- Department of Pathology, Acıbadem Mehmet Ali Aydınlar University, Istanbul, Turkey
| | - Jesper Bonde
- Molecular Pathology Laboratory, Department of Pathology, afs. 134, Hvidovre Hospital, Hvidovre, Denmark
| | - Nicola Trim
- Molecular Pathology Diagnostic Service, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Elisabeth Bauer
- Städtisches Klinikum Karlsruhe gGmbH, Institut für Pathologie, Karlsruhe, Germany
| | - Adam Meeney
- Ophthalmic Pathology Laboratory Histopathology, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK
| | - Wendy de Leng
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - George Chong
- Molecular Pathology Centre, Jewish General Hospital-McGill University, Montreal, Quebec, Canada
| | - Véronique Dalstein
- Laboratoire de Biopathologie, Unité INSERM UMR-S 1250, CHU Reims, Reims, France
| | - Lorand L Kis
- Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
| | - Jon A Lorentzen
- Molecular Pathology Unit, Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Snjezana Tomić
- Department of Pathology, Forensic Medicine and Cytology, University Hospital Split, Split, Croatia
| | - Keeley Thwaites
- Histopathology Department, Barking, Havering and Redbridge University Hospitals NHS Trust, Queen's Hospital, Romford, UK
| | - Martina Putzová
- Bioptická laboratoř s.r.o., Laboratory of Molecular Genetics, Plzeň, Czech Republic
- ÚBLG FN Motol, Praha, Czech Republic
- LF UK, Plzeň, Czech Republic
| | | | - Romena Qazi
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Johr Town, Lahore, Pakistan
| | - Vanessa Primmer
- Pathologisch-Bakteriologisches Institut Kaiser-Franz-Josef-Spital, Vienna, Austria
| | | | - Javier Hernández-Losa
- Department of Pathology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Madrid, Spain
| | | | - Asaf A Gertler
- Department of Pathology, Hadassah Medical Center, Jerusalem, Israel
| | - Michal Kalman
- Department of Pathologic Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovak Republic
- Martin's Biopsy Center Ltd., Martin, Slovak Republic
| | - Chris Wong
- Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong Special Administrative Region of the People's Republic of China, Hong Kong, People's Republic of China
| | - Dirce M Carraro
- Genomics and Molecular Biology Group, International Research Center/CIPE, A. C. Camargo Cancer Center, São Paulo, SP, Brazil
| | - Ana C Sousa
- GenoMed, Diagnósticos de Medicina Molecular, SA, Lisbon, Portugal
| | - Rui M Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Stephen B Fox
- Pathology, Peter MacCallum Cancer Centre and University of Melbourne, Vic, Australia
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Marie Brevet
- Department of Pathology, Hospices Civils de Lyon, Université Lyon 1, Bron, France & Cypath, Villeurbanne, France
| | | | - Richard Colling
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | | | - Ryan Yee Wei Teo
- Department of Pathology, Tan Tock Seng Hospital, Novena, Republic of Singapore
| | - Nicky D'Haene
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Serge Nolet
- Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, Québec, Canada
| | - Ari Ristimäki
- Department of Pathology, Research Programs Unit and HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Timo Väisänen
- Oulu University Hospital and Department of Pathology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
| | | | - Afsaneh Soruri
- Institut für Pathologie und Molekularpathologie, Pforzheim, Germany
| | - Tina Unger
- Institut für Pathologie, University of Leipzig, Leipzig, Germany
| | - Johanna Wecgowiec
- Institut für Pathologie, Evangelisches Krankenhaus BETHESDA Zu Duisburg GmbH, Duisburg, Germany
| | - Michele Biscuola
- Department of Pathology, Molecular Pathology Laboratory, Hospital Universitario Virgen del Rocío-IBIS, Seville, Spain
| | - Milo Frattini
- Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland
| | - Anna Long
- Cellular Pathology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | | | - Xavier Matias-Guiu
- Departments of Pathology and Molecular Genetics, Hospital U Arnau de Vilanova and Hospital U de Bellvitge, University of Lleida, IRBLLEIDA, IDIBELL, CIBERONC, Av. Alcalde Rovira Roure, 80 25198, Lleida, Spain
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21
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GASVeM: A New Machine Learning Methodology for Multi-SNP Analysis of GWAS Data Based on Genetic Algorithms and Support Vector Machines. MATHEMATICS 2021. [DOI: 10.3390/math9060654] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genome-wide association studies (GWAS) are observational studies of a large set of genetic variants in an individual’s sample in order to find if any of these variants are linked to a particular trait. In the last two decades, GWAS have contributed to several new discoveries in the field of genetics. This research presents a novel methodology to which GWAS can be applied to. It is mainly based on two machine learning methodologies, genetic algorithms and support vector machines. The database employed for the study consisted of information about 370,750 single-nucleotide polymorphisms belonging to 1076 cases of colorectal cancer and 973 controls. Ten pathways with different degrees of relationship with the trait under study were tested. The results obtained showed how the proposed methodology is able to detect relevant pathways for a certain trait: in this case, colorectal cancer.
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22
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Li WK, Wang Y, Wang YD, Liu KL, Guo CM, Su H, Liu H, Wu J. Diagnostic value of novel retroflexion colonoscopy in the right colon: A randomized controlled trial. World J Gastrointest Oncol 2020; 12:1336-1345. [PMID: 33250965 PMCID: PMC7667455 DOI: 10.4251/wjgo.v12.i11.1336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/27/2020] [Accepted: 10/15/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Colonoscopy is the accepted gold standard for the detection of colorectal cancer. However, colonoscopy is less effective in preventing colon cancer in the right side compared with the left side.
AIM To investigate the feasibility of a novel type of retroflexion colonoscope, EC-3490Ti colonoscope, for detection of proximal colon lesions.
METHODS In this prospective trial, we recruited patients who underwent colonoscopy for screening or surveillance. When the endoscopists could not grasp the whole observation of the right-side colon mucosa in the forward view (FV), insertion and withdrawal were repeatedly performed in the FV group with the EC38-i10F colonoscope while retroflexion was performed in the retroflexed view (RV) group with the EC-3490Ti colonoscope. Adenoma detection rate, the total number of adenomas per positive participant, the success rate of retroflexion, and endoscope withdrawal time were recorded and compared.
RESULTS The total adenoma detection rate (39.3% vs 37.7%, P = 0.646) did not show any significant difference between the two groups. However, the polyp detection rate (59.6% vs 51.0%, P = 0.002), adenoma detection rate in the right colon (21.6% vs 14.4%, P = 0.012), and the total number of adenomas per positive participant (2.1 vs 1.7, P = 0.011) reached statistical significance. Retroflexion was achieved in 91.7% of our cohort. Compared with the FV group, the withdrawal time was significantly prolonged in the RV group (586.1 ± 124.4 s vs 508.8 ± 129.6 s, P < 0.001). In contrast, the proportion of additional ancillary pressure decreased (27.4% vs 45.7%, P < 0.001), and the visual analog scale pain scores did not increase (2.7 ± 1.4 vs 2.8 ± 1.4, P = 0.377).
CONCLUSION Retroflexion in the proximal colon could be performed successfully and safely with the EC-3490Ti colonoscope. This maneuver could detect more adenomas effectively.
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Affiliation(s)
- Wen-Kun Li
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Yun Wang
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Ya-Dan Wang
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Kui-Liang Liu
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Chun-Mei Guo
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Hui Su
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Hong Liu
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Peking University Ninth School of Clinical Medicine, Beijing 100038, China
| | - Jing Wu
- Department of Gastroenterology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China
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Mangalaparthi KK, Patel K, Khan AA, Manoharan M, Karunakaran C, Murugan S, Gupta R, Gupta R, Khanna-Gupta A, Chaudhuri A, Kumar P, Nair B, Kumar RV, Prasad TSK, Chatterjee A, Pandey A, Gowda H. Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort. Front Oncol 2020; 10:1457. [PMID: 32974170 PMCID: PMC7469928 DOI: 10.3389/fonc.2020.01457] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 07/09/2020] [Indexed: 12/18/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as TP53, CSMD3, SYNE1, PIK3CA, and NOTCH1 were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in PIK3CA-NOTCH1, DNAH5-ZFHX4, MUC16-FAT1, and ZFHX4-NOTCH1 gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in PIK3CA making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.
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Affiliation(s)
- Kiran K. Mangalaparthi
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Krishna Patel
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Aafaque A. Khan
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | | | | | | | - Ravi Gupta
- Medgenome Labs Pvt. Ltd., Bangalore, India
| | | | | | | | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
| | - Bipin Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Rekha V. Kumar
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - T. S. Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
- Manipal Academy of Higher Education, Manipal, India
- Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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24
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Gao Y, Zhang S, Zhang Y, Qian J. Identification of MicroRNA-Target Gene-Transcription Factor Regulatory Networks in Colorectal Adenoma Using Microarray Expression Data. Front Genet 2020; 11:463. [PMID: 32508878 PMCID: PMC7248367 DOI: 10.3389/fgene.2020.00463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/15/2020] [Indexed: 12/18/2022] Open
Abstract
Objective The aim of the study was to find the key genes, microRNAs (miRNAs) and transcription factors (TFs) and construct miRNA-target gene-TF regulatory networks to investigate the underlying molecular mechanism in colorectal adenoma (CRA). Methods Four mRNA expression datasets and one miRNA expression dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DEMs) and differentially expressed genes (DEGs) were identified between CRA and normal samples. Moreover, functional enrichment analysis for DEGs was carried out utilizing the Cytoscape-plugin, known as ClueGO. These DEGs were mapped to STRING database to construct a protein-protein interaction (PPI) network. Then, a miRNA-target gene regulatory network was established to screen key DEMs. In addition, similar workflow of the analyses were also performed comparing the CRC samples with CRA ones to screen key DEMs. Finally, miRNA-target gene-TF regulatory networks were constructed for these key DEMs using iRegulon plug-in in Cytoscape. Results We identified 514 DEGs and 167 DEMs in CRA samples compared to healthy samples. Functional enrichment analysis revealed that these DEGs were significantly enriched in several terms and pathways, such as regulation of cell migration and bile secretion pathway. A PPI network was constructed including 325 nodes as well as 890 edges. A total of 59 DEGs and 65 DEMs were identified in CRC samples compared to CRA ones. In addition, Two key DEMs in CRA samples compared to healthy samples were identified, such as hsa-miR-34a and hsa-miR-96. One key DEM, hsa-miR-29c, which was identified when we compared the differentially expressed molecules found in the comparison CRA versus normal samples to the ones obtained in the comparison CRC versus CRA, was also identified in CRC samples compared to CRA ones. The miRNA-target gene-TF regulatory networks for these key miRNAs included two TFs, one TF and five TFs, respectively. Conclusion These identified key genes, miRNA, TFs and miRNA-target gene-TF regulatory networks associated with CRA, to a certain degree, may provide some hints to enable us to better understand the underlying pathogenesis of CRA.
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Affiliation(s)
- Yadong Gao
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Shenglai Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Yan Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
| | - Junbo Qian
- Department of Gastroenterology, The Second Affiliated Hospital of Nantong University, Nantong, China.,Department of Gastroenterology, The First People's Hospital of Nantong, Nantong, China
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25
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Qin L, Zeng J, Shi N, Chen L, Wang L. Application of weighted gene co‑expression network analysis to explore the potential diagnostic biomarkers for colorectal cancer. Mol Med Rep 2020; 21:2533-2543. [PMID: 32323816 PMCID: PMC7185270 DOI: 10.3892/mmr.2020.11047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant diseases in the world. Although mechanistic studies have been conducted on the pathogenesis of CRC, the molecular mechanism of CRC tumorigenesis remains unclear. In the present study, the weighted gene co-expression network analysis was performed for the Gene Expression Omnibus (GEO) dataset GSE87211, in order to analyze the key modules involved in the pathogenesis of CRC. Next, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the key module genes to analyze the functional pathways involved. The hub genes were screened using the Cytoscape platform and verified by a second GEO dataset, GSE21510. Finally, 10 hub genes were identified in 2 key modules (the green and brown modules) as the genes most significantly associated with the tumorigenesis of CRC. The 5 hub genes from the green module included collagen type I α1 chain, collagen type XII α1 chain, collagen triple helix repeat containing 1, inhibin subunit βa (INHBA) and chromobox 2 (CBX2), while the 5 hub genes from the brown module included bestrophin 2 (BEST2), carbonic anhydrase 2, glucagon, solute carrier family 4 member 4 and gliomedin. The 2 key modules with the 10 hub genes identified may regulate the occurrence and development of CRC through the extracellular matrix pathway, PI3K-Akt and chemokine signaling pathways, thus providing a reference for understanding the complex mechanism of tumorigenesis in CRC. Of note, few studies have reported the pathogenesis of CRC with the 3 identified hub genes, INHBA, CBX2 and BEST2. Further investigation of the molecular mechanism of these genes in CRC is recommended.
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Affiliation(s)
- Liping Qin
- Molecular Laboratory, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China
| | - Jianping Zeng
- Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 311121, P.R. China
| | - Nannan Shi
- Molecular Laboratory, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China
| | - Liu Chen
- Molecular Laboratory, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China
| | - Li Wang
- Molecular Laboratory, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 311121, P.R. China
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26
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Li J, Wang Y, Wang X, Yang Q. CDK1 and CDC20 overexpression in patients with colorectal cancer are associated with poor prognosis: evidence from integrated bioinformatics analysis. World J Surg Oncol 2020; 18:50. [PMID: 32127012 PMCID: PMC7055103 DOI: 10.1186/s12957-020-01817-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 02/17/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies of the digestive system, which causes severe financial burden worldwide. However, the specific mechanisms involved in CRC are still unclear. METHODS To identify the significant genes and pathways involved in the initiation and progression of CRC, the microarray dataset GSE126092 was downloaded from Gene Expression Omnibus (GEO) database, and then, the data was analyzed to identify differentially expressed genes (DEGs). Subsequently, the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on these DEGs using the DAVID database, and the protein-protein interaction (PPI) network was constructed using the STRING database and analyzed using the Cytoscape software. Finally, hub genes were screened, and the survival analysis was performed on these hub genes using the Kaplan-Meier curves in the cBioPortal database. RESULTS In total, 937 DEGs were obtained, including 316 upregulated genes and 621 downregulated genes. GO analysis revealed that the DEGs were mostly enriched in terms of nuclear division, organelle fission, cell division, and cell cycle process. KEGG pathway analysis showed that the DEGs were mostly enriched in cell cycle, oocyte meiosis, cytokine-cytokine receptor interaction, and cGMP-PKG signaling pathway. The PPI network comprised 608 nodes and 3100 edges, and 4 significant modules and 10 hub genes with the highest degree were identified using the Cytoscape software. Finally, survival analysis showed that overexpression of CDK1 and CDC20 in patients with CRC were statistically associated with worse overall survival. CONCLUSIONS This bioinformatics analysis revealed that CDK1 and CDC20 might be candidate targets for diagnosis and treatment of CRC, which provided valuable clues for CRC.
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Affiliation(s)
- Jianxin Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Yinchun Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Xin Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China
| | - Qingqiang Yang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People's Republic of China.
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Cai P, Lu Z, Jiang T, Wang Z, Yang Y, Zheng L, Zhao J. Syndecan-4 involves in the pathogenesis of rheumatoid arthritis by regulating the inflammatory response and apoptosis of fibroblast-like synoviocytes. J Cell Physiol 2020; 235:1746-1758. [PMID: 31309562 DOI: 10.1002/jcp.29093] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/27/2019] [Indexed: 12/28/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the pathogenesis of RA is still unknown. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) are of significance in the pathogenesis of RA. In this study, three microarray profiles (GSE55457, GSE55584, and GSE55235) of human joint FLSs from 33 RA patients and 20 normal controls were extracted from the Gene Expression Omnibus Dataset and analyzed to investigate the underlying pathogenesis of RA. As analyzed by the differently expressed genes, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction network analysis, syndecan-4 (SDC4), a receptor of multiple cytokines and chemokines, which played a key role in the regulation of inflammatory response, was found to be an essential regulator in RA. To further validate these results, the levels of SDC4, reactive oxygen species (ROS), nitric oxide (NO), inflammation, and apoptosis in RA-FLSs were examined. SDC4-silenced RA-FLSs were also used. The results demonstrated that SDC4 and the level of ROS, NO, and inflammation were highly expressed while the apoptosis was decreased in RA-FLSs compared with normal FLSs. SDC4 silencing significantly suppressed the levels of ROS, NO, and inflammation; elevated the expression of nuclear factor erythroid 2-related factor 2; and promoted the apoptosis of RA-FLSs. Collectively, our results demonstrated a new mechanism of SDC4 in initiating the inflammation and inhibiting the apoptosis of RA-FLSs and that a potential target for the diagnosis and treatment of RA in the clinic might be developed.
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Affiliation(s)
- Peian Cai
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhenhui Lu
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tongmeng Jiang
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zetao Wang
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Pharmaceutical College, Guangxi Medical University, Nanning, China
| | - Yifeng Yang
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Zheng
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jinmin Zhao
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Cai P, Jiang T, Li B, Qin X, Lu Z, Le Y, Shen C, Yang Y, Zheng L, Zhao J. Comparison of rheumatoid arthritis (RA) and osteoarthritis (OA) based on microarray profiles of human joint fibroblast-like synoviocytes. Cell Biochem Funct 2019; 37:31-41. [PMID: 30468518 DOI: 10.1002/cbf.3370] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/15/2018] [Accepted: 10/30/2018] [Indexed: 12/22/2022]
Abstract
The purpose of the present study was to investigate the underlying molecular mechanism of osteoarthritis (OA) and rheumatoid arthritis (RA) based on microarray profiles. Three human joint fibroblast-like synoviocytes (FLSs) microarray profiles including 26 OA samples, 33 RA samples, and 20 healthy control (HC) samples were downloaded from the GEO database. Differentially expressed genes (DEGs) between OA and HC (DEGsOA) and RA and HC (DEGsRA) were identified. Co-expressed and specific genes were analysed between DEGsOA and DEGsRA. Gene ontology, KEGG pathway enrichment, PPI network, and GSEA were performed to predict the function of DEGs. Two hundred seventy-six and 410 differential genes in DEGsOA and DEGsRA were observed. One hundred fifty coexpressed genes and 126 OA-specific genes (SELE, SERPINE1, and NFKBIA were the key genes) between DEGsOA and DEGsRA were enriched in the tumour necrosis factor (TNF) signalling pathway. However, 260 RA-specific genes of which the key genes were CCR5, CCR7, CXCR4, CCL5, and CCR4 were enriched in chemokine signalling pathway. Therefore, FLSs might exert an inflammatory effect by regulating TNF signalling pathway, targeting SELE, SERPINE1, and NFKBIA during the process of OA. Although TNF signalling pathway was also involved in the synovitis of RA, chemokine signalling pathway played the key role in RA FLSs mediating cell migration, invasion, and release of chemotaxis. In addition, CCR5, CCR7, CXCR4, CCL5, and CCR4 might be hub genes in RA. The different biomarkers and pathways identified in OA and RA may provide references for further study. SIGNIFICANCE OF THE STUDY: This study revealed the similar and different mechanisms of FLSs and different biomarkers that might with important regulatory effects on RA and OA. In OA, FLSs played an inflammatory role through TNF signalling pathway, targeting SELE, SERPINE1, and NFKBIA. Although TNF signalling pathway was also involved in the synovitis of RA, chemokine signalling pathway was a crucial pathway in mediating FLSs migration, invasion, and release of chemotaxis. CCR5, CCR7, CXCR4, CCL5, and CCR4 might be keys genes in RA. We expect that our results will bring more comprehensively understanding between RA and OA for researchers.
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Affiliation(s)
- Peian Cai
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tongmeng Jiang
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bo Li
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiong Qin
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhenhui Lu
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yiguan Le
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chong Shen
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yifeng Yang
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Li Zheng
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jinmin Zhao
- Guangxi Engineering Center in Biomedical Materials for Tissue and Organ Regeneration, Guangxi Collaborative Innovation Center for Biomedicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Orthopaedics Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Regenerative Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Sun G, Li Y, Peng Y, Lu D, Zhang F, Cui X, Zhang Q, Li Z. Identification of a five‐gene signature with prognostic value in colorectal cancer. J Cell Physiol 2018; 234:3829-3836. [PMID: 30132881 DOI: 10.1002/jcp.27154] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/10/2018] [Indexed: 12/26/2022]
Affiliation(s)
- Guangwei Sun
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Yalun Li
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Yangjie Peng
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Dapeng Lu
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Fuqiang Zhang
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Xueyang Cui
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Qingyue Zhang
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
| | - Zhuang Li
- Department of Anorectal Surgery The First Hospital of China Medical University Shenyang China
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