Local growth hormone facilitates aging of the colon epithelial microenvironment
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ABSTRACT:
PROVIDER: PRJNA1218809 | ENA |
REPOSITORIES: ENA
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Project description:Aging is associated with appearance of senescent cells secreting the senescence-associated secretome facilitating a milieu favoring age-related changes in microenvironment. Previously, we showed accumulation and secretion of local non-pituitary growth hormone (npGH) in senescent colon epithelial cells. Here, we elucidate mechanisms underlying npGH action in the non-tumorous colon tissue microenvironment. We demonstrate autocrine npGH action in normal human colon cells (hNCC) infected with lentivirus expressing hGH (lentiGH), as well as paracrine npGH action in hNCC cocultured with lentiGH hNCC and in intact human 3-dimensional intestinal organoids co-cultured with organoids infected with lentiGH. Enriched gene ontology and pathway analysis of intact organoids exposed to paracrine npGH identified distorted extracellular matrix (ECM) and focal adhesion pathways concurrent with altered expression of ECM and cytoskeletal proteins. Significant phosphoprotein changes associated with cytoskeleton and cell migration pathway occurred in GH-exposed hNCC. Paracrine npGH triggers these changes by activating epithelial-mesenchymal transition, as shown by suppression of E-cadherin and induction of Twist2 in cellular models, as well as in the colon of nude mice harboring GH-secreting xenografts. These changes are consistent with observed increased migration of hNCC overexpressing lentiGH, or in those co-cultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. Furthermore, whole exome sequencing detected increased cell copy number alterations in intact organoids co-cultured with lentiGH-infected organoids, likely as a consequence of GH-mediated suppressed DNA damage repair thereby favoring cell transformation. Our results indicate that accumulated npGH in aging tissue enables a microenvironment landscape favoring age-associated pro-proliferative changes.
2025-01-08 | MSV000096807 | MassIVE
Project description:We elucidate mechanisms underlying loca non-pituitary GH (npGH) action in the non-tumorous colon tissue microenvironment. We demonstrate autocrine npGH action in normal human colon cells (hNCC) infected with lentivirus-expressing hGH (lentiGH), as well as paracrine npGH action in hNCC co-cultured with lentiGH hNCC and in intact human 3-dimensional intestinal organoids co-cultured with organoids infected with lentiGH. Enriched gene ontology and pathway analysis of intact organoids exposed to paracrine npGH identified distorted extracellular matrix (ECM) and focal adhesion pathways concurrent with altered expression of ECM and cytoskeletal proteins. Significant phosphoprotein changes associated with cytoskeleton and cell migration pathway occurred in GH-exposed hNCC. Paracrine npGH triggers these changes by activating epithelial-mesenchymal transition, as shown by suppression of E-cadherin and induction of Twist2 in cellular models, as well as in the colon of nude mice inoculated with GH-secreting xenografts. These changes are consistent with observed increased migration of hNCC overexpressing lentiGH, or in those co-cultured with GH-secreting hNCC or with GH-secreting normal colon fibroblasts. Furthermore, whole exome sequencing detected increased structural variation in intact organoids co-cultured with lentiGH-infected organoids, likely as a consequence of GH-mediated suppressed DNA damage repair, thereby favoring cell transformation.
2025-07-30 | GSE288661 | GEO
Project description:Microenvironmental factors modulating age-related DNA damage are unclear. Non-pituitary growth hormone (npGH) is induced in human colon, non-transformed human colon cells, and fibroblasts, and in 3-dimensional intestinal organoids with age-associated DNA damage. Autocrine/paracrine npGH suppresses p53 and attenuates DNA damage response (DDR) by inducing TRIM29 and reducing ATM phosphorylation, leading to reduced DNA repair and DNA damage accumulation. Organoids cultured up to 4 months exhibit aging markers, p16, and SA-β-galactosidase and decreased telomere length, as well as DNA damage accumulation, with increased npGH, suppressed p53, and attenuated DDR. Suppressing GH in aged organoids increases p53 and decreases DNA damage. WT mice exhibit age-dependent colon DNA damage accumulation, while in aged mice devoid of colon GH signaling, DNA damage remains low, with elevated p53. As age-associated npGH induction enables a pro-proliferative microenvironment, abrogating npGH signaling could be targeted as anti-aging therapy by impeding DNA damage and age-related pathologies.
| S-EPMC8716125 | biostudies-literature
Project description:MYC oncogene reprograms the local tissue microenvironment during prostate carcinogenesis
| PRJNA952229 | ENA
Project description:Background. Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the source of hormone. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet addresses whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a recent genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging. Conclusions. Reduced juvenile hormone alone is sufficient to extend lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of reproductive. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity. Four genotypes were analyzed. They are CA knockout (CAKO), wildtype (wDah/w1118 ), CAKO with OvoD1 mutation and control (wDah/w1118) with OvoD1 mutation. Three biological replicates for each genotype.
2013-07-26 | E-GEOD-48145 | biostudies-arrayexpress
Project description:Epidemiological studies highlight a strong association between obesity and colorectal cancer (CRC). This association appears stronger in men and a role for sex hormones is indicated by epidemiological studies. Especially estrogen is protective against CRC and correlated to several aspects of the metabolic syndrome. Anti-inflammatory and anti-tumorigenic effects of estrogen in colon have been demonstrated to act via estrogen receptor beta (ERβ). This led us to hypothesize that estrogenic signaling, through both systemic and local effects might modulate the colon microenvironment during HFD-induced obesity. In order to test our hypothesis mice were fed a control diet or a high fat diet (HFD) for 3 weeks and treated with different estrogenic ligands. In the present study, we demonstrate that there are sex-differences in the response to HFD-induced obesity and in the colon transcriptome. Both sexes develop obesity with an impaired circadian rhythm but the male metabolic profile is more sensitive to HFD and increased the colon epithelial cell proliferation. Females were resistant to impaired glucose metabolism, but HFD-feeding increased the infiltration of macrophages. Estrogen signaling in males, via ERα, presented anti-obesogenic effects. However, systemic and/or local activation of both ERα and ERβ restored the circadian rhythm in the males. In females, systemic activation of ERα restored the circadian rhythm, however, systemic and/or local activation of ERβ down-regulated the expression of macrophage markers. These results suggest that estrogen signaling through systemic and/or local activation of ERβ can regulate the colon microenvironment during HFD-induced obesity.
2020-10-07 | GSE149811 | GEO
Project description:Optimized ChIP-seq procedure facilitates hormone receptor profiling in human tumors
| PRJNA472620 | ENA
Project description:Background. Juvenile hormone (JH) has been demonstrated to control adult lifespan in a number of non-model insects where surgical removal of the corpora allata eliminates the hormone’s source. In contrast, little is known about how juvenile hormone affects adult Drosophila melanogaster. Previous work suggests that insulin signaling may modulate Drosophila aging in part through its impact on juvenile hormone titer, but no data yet addresses whether reduction of juvenile hormone is sufficient to control Drosophila life span. Here we adapt a recent genetic approach to knock out the corpora allata in adult Drosophila melanogaster and characterize adult life history phenotypes produced by reduction of juvenile hormone. With this system we test potential explanations for how juvenile hormone modulates aging. Conclusions. Reduced juvenile hormone alone is sufficient to extend lifespan of Drosophila melanogaster. Reduced juvenile hormone limits reproduction by inhibiting the production of yolked eggs, and this may arise because juvenile hormone is required for the post-eclosion development of vitellogenin-producing adult fat body. Our data do not support a mechanism for juvenile hormone control of longevity simply based on reducing the physiological costs of reproductive. Nor does the longevity benefit appear to function through mechanisms by which dietary restriction extends longevity. We identify transcripts that change in response to juvenile hormone independent of reproductive state and suggest these represent somatically expressed genes that could modulate how juvenile hormone controls persistence and longevity.
2013-07-26 | GSE48145 | GEO
Project description:The impact of chirality on immune response has attracted great interest in cancer vaccine research recently. However, the study of chiral synthetic polypeptide hydrogels as cancer vaccines as well as of the impact of biomaterials itself for antitumor immunotherapy has rarely been reported. Herein, we demonstrated the key role of residue chirality of polypeptides hydrogels in antitumor immunity and local immune microenvironment regulation. Compared to poly(γ-ethyl-L-glutamate)-based hydrogels (L-Gel), poly(γ-ethyl-D-glutamate)-based hydrogels (D-Gel) induced greater immune cell infiltration. Unexpectedly, D-Gel caused higher levels of suppressive markers on antigen-presenting cells and even induced stronger T cells exhaustion than L-Gel. Finally, D-Gel established a local chronic inflamed and immunosuppressive microenvironment and showed insufficient anti-tumor effects. Conversely, the milder host immune responses induced by L-Gel led to more effective tumor inhibition. This study provides new insights on the role of residue chirality in the regulation of local immune microenvironment and affecting antitumor immune response.
2024-03-14 | GSE261299 | GEO
Project description:scRNA-seq reveals tumor microenvironment remodeling induced by local intervention-based immunotherapy
| PRJNA633139 | ENA