Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors

AbstractNeuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p < 0.05) OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. These results suggest opportunities for better treatment strategies for NETs based on molecular features.

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Differential methylation of G-protein coupled receptor signaling genes in gastrointestinal neuroendocrine tumors

10.21203/rs.3.rs-224809/v1 ◽

2021 ◽

Author(s):

Seyoun Byun ◽

Kajsa E. Affolter ◽

Angela K. Snow ◽

Karen Curtin ◽

Austin R. Cannon ◽

...

Keyword(s):

Small Intestine ◽

Neuroendocrine Tumors ◽

Patient Survival ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Treatment Strategies ◽

Molecular Features ◽

Differentially Methylated Genes ◽

Chromosomal Changes ◽

Approved Drugs

Abstract Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Whole genome methylation and chromosomal copy number varation (CNV) of NETs from the small intestine and appendix was measured Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), MultiCNV, and NoCNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes which are over represented with sevenG-protein coupled receptor (GPCR) pathways and the gene encoding somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p-<0.05) OR2S2, SMILR, RNU6-653P and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identifiedin high versus low methylation of 24 genes. The most significant is TRHR (p < 0.01), a GPCR with multiple FDA-approved drugs. By separating NETs into different molecular subtypes based on chromosomal changes, we find that multiple GPCRs and their ligands appear to be regulated through methylation and correlated with survival. Opportunities for better treatment strategies based on molecular features exist for NETs.

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Human G Protein–Coupled Receptor Gpr-9-6/Cc Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-Expressed Chemokine–Mediated Chemotaxis

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1241 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1241-1256 ◽

Cited By ~ 352

Author(s):

Brian A. Zabel ◽

William W. Agace ◽

James J. Campbell ◽

Heidi M. Heath ◽

David Parent ◽

...

Keyword(s):

Small Intestine ◽

T Lymphocytes ◽

G Protein ◽

Chemokine Receptor ◽

Chemokine Receptors ◽

Intraepithelial Lymphocytes ◽

Mucosal Immune Response ◽

G Protein Coupled Receptor ◽

Cc Chemokine ◽

G Protein Coupled

TECK (thymus-expressed chemokine), a recently described CC chemokine expressed in thymus and small intestine, was found to mediate chemotaxis of human G protein–coupled receptor GPR-9-6/L1.2 transfectants. This activity was blocked by anti–GPR-9-6 monoclonal antibody (mAb) 3C3. GPR-9-6 is expressed on a subset of memory α4β7high intestinal trafficking CD4 and CD8 lymphocytes. In addition, all intestinal lamina propria and intraepithelial lymphocytes express GPR-9-6. In contrast, GPR-9-6 is not displayed on cutaneous lymphocyte antigen–positive (CLA+) memory CD4 and CD8 lymphocytes, which traffic to skin inflammatory sites, or on other systemic α4β7−CLA− memory CD4/CD8 lymphocytes. The majority of thymocytes also express GPR-9-6, but natural killer cells, monocytes, eosinophils, basophils, and neutrophils are GPR-9-6 negative. Transcripts of GPR-9-6 and TECK are present in both small intestine and thymus. Importantly, the expression profile of GPR-9-6 correlates with migration to TECK of blood T lymphocytes and thymocytes. As migration of these cells is blocked by anti–GPR-9-6 mAb 3C3, we conclude that GPR-9-6 is the principal chemokine receptor for TECK. In agreement with the nomenclature rules for chemokine receptors, we propose the designation CCR-9 for GPR-9-6. The selective expression of TECK and GPR-9-6 in thymus and small intestine implies a dual role for GPR-9-6/CCR-9, both in T cell development and the mucosal immune response.

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Gustducin couples fatty acid receptors to GLP-1 release in colon

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00471.2012 ◽

2013 ◽

Vol 304 (6) ◽

pp. E651-E660 ◽

Cited By ~ 26

Author(s):

Yan Li ◽

Zaza Kokrashvili ◽

Bedrich Mosinger ◽

Robert F. Margolskee

Keyword(s):

Small Intestine ◽

Fatty Acid ◽

G Protein ◽

Lithocholic Acid ◽

Taste Receptor ◽

Sweet Taste ◽

Enteroendocrine Cells ◽

G Protein Coupled Receptor ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled

Sweet taste receptor subunits and α-gustducin found in enteroendocrine cells of the small intestine have been implicated in release of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in response to glucose and noncaloric sweeteners. α-Gustducin has also been found in colon, although its function there is unclear. We examined expression of α-gustducin, GLP-1, and GIP throughout the intestine. The number of α-gustducin-expressing cells and those coexpressing α-gustducin together with GLP-1 and/or GIP increased from small intestine to colon. α-Gustducin also was coexpressed with fatty acid G protein-coupled receptor (GPR) 40, GPR41, GPR43, GPR119, GPR120, and bile acid G protein-coupled receptor TGR5 in enteroendocrine cells of the colon. In colon, GPR43 was coexpressed with GPR119 and GPR120, but not with TGR5. Treatment of colonic mucosa isolated from wild-type mice with acetate, butyrate, oleic acid, oleoylethanolamide, or lithocholic acid stimulated GLP-1 secretion. However, GLP-1 release in response to these fatty acids was impaired in colonic tissue from α-gustducin knockout mice.

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