Hypoxia induced ATF3 escalates breast cancer invasion by increasing collagen deposition
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ABSTRACT:
PROVIDER: PRJNA1148531 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30255672_1.fastq.gz | Fastqsanger.gz | |||
| SRR30255672_2.fastq.gz | Fastqsanger.gz | |||
| SRR30255673_1.fastq.gz | Fastqsanger.gz | |||
| SRR30255673_2.fastq.gz | Fastqsanger.gz |
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Project description:Activating transcription factors (ATFs), members of the adaptive-response gene family, participate in cellular processes to aid adaptations in response to extra- and/or intracellular changes. In this study, we observed that one of the ATFs Activating transcription factor 3 (ATF3) is upregulated under hypoxia via alterations in the epigenetic landscape of its promoter, followed by transcriptional upregulation. Under hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1ɑ) alleviates methylation at the ATF3 promoter by recruiting TET1 and induces ATF3 transcription. Additionally, our RNA-seq analysis showed that ATF3 globally affects transcription under hypoxia and controls the processes of EMT and cancer invasion by stimulating the transcription of Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1), an enzyme which enhances invasion conducive extracellular matrix (ECM) under hypoxic condition. Prolyl hydroxylases play a critical role in the hydroxylation and deposition of collagen in the extracellular matrix (ECM) during the evolution of cancer, which is necessary for metastasis. Importantly, P4HA1 undergoes alternative splicing under hypoxia, where the inclusion of exon 9a is increased. It is interesting to note that ATF3's involvement in P4HA1 splicing was also evident, as binding of ATF3 at intron 9a led to demethylation of this DNA region via recruitment of TET1. Further, we also show that the demethylated DNA region of intron 9a then becomes accessible to CTCF. Thus, a cascade of demethylation via ATF3 recruited TET1, followed by increased RNA PolII pause via CTCF at the intron 9a leads to inclusion of exon 9a. The P4HA1 9a isoform leads to enhanced invasion under hypoxic conditions by increasing deposition of collagen in the ECM. These results provide a novel hypoxia-induced HIF1ɑ-ATF3-P4HA1 axis which can be potentially exploited as a therapeutic target to impede EMT and ultimately breast cancer invasion.
2024-12-31 | GSE274936 | GEO
Project description:Mutant collagen COL11A1 enhances cancerous invasion
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Project description:Pathological fibrosis, an excessive accumulation of collagen, compromises tissue architecture, impedes its function and represents a medical complication. Properties of the amniotic membrane have demonstrated potential to regulate fibrotic processes. RNA sequencing analysis evaluated the effects of dehydrated human amnion/chorion membrane (DHACM) on fibrotic events using in vitro macromolecular crowding to mimic a physiologically relevant microenvironment. Functional enrichment with Reactome pathway analysis indicated that the function of a subset of these dysregulated genes was associated with the composition and function of the extracellular matrix. Further use of macromolecular crowding in vitro was used to evaluate the effects of DHACM and a lyophilized human amnion/chorion membrane (LHACM) on type 1 collagen production and deposition under profibrotic conditions (addition of TGFβ1). In the continued presence of TGFβ1, LHACM and DHACM regulated the intracellular production and extracellular deposition of type 1 collagen. In addition, results suggest that the effect on collagen deposition could in part be modulated through the regulation of proteins responsible for the extracellular post-translational modifications of collagen. These observations may support the use of DHACM and LHACM in the regulation collagen production/deposition in profibrotic environments.
2024-05-06 | GSE247237 | GEO
Project description:Mutant collagen COL11A1 enhances cancerous invasion [RNA-seq]
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Project description:Human Amniotic membrane modulates collagen production and deposition in vitro
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Project description:Endometriosis (EMs) is a common infertility-related disease in women of reproductive age. Impaired endometrial decidualization is one of the most important factors contributing to the embryo implantation failure EMs patients. However, the exact mechanism remains unclear. Previous studies have shown collagen I deposition in the eutopic endometrium of EMs patients, which may lead to impaired endometrial decidualization. The level of collagen I in eutopic endometrium of EMs was analyzed. We performed a proteomic analysis of ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) and extracellular vesicles derived from endometrial stromal cells in the endometrium of control patients (CTL-EVs). An endometrial transcriptional profiles of EMs patients and normal controls in the mid-secretory phase of menstrual cycle was compared. Endometrial stromal cells (ESCs) were stimulated with chloroquine or rapamycin to evaluate the association between autophagy and collagen I. The expression of PKM2 in EMs-EVs and serum extracellular vesicles from EMs patients were examined by western blotting. PKM2 was overexpressed or knockdown in ESCs to investigate the level of autophagy and collagen I. ESCs were treated with ectopic ESC-derived extracellular vesicles with highly expressed PKM2 protein, and the potential molecular mechanisms were further confirmed through western blotting and immunohistochemical analysis. We found that endometrial collagen I expression during the mid-secretory phase was increased in the EMs group. We demonstrated that autophagy is defective in eutopic endometrial stromal cells (ESCs) of EMs patients. In ESCs, pharmacological inhibition of autophagy by chloroquine (CQ) promoted collagen I deposition. Ectopic endometrial stromal cell-derived extracellular vesicles (EMs-EVs) inhibited autophagy of ESCs and promoted collagen I deposition in vivo and in vitro. Mechanistically, EMs-EVs encapsulating PKM2 impair eutopic endometrial autophagy via Akt/mTOR signaling pathway. Together, we demonstrated that EMs-EVs encapsulating PKM2 impaired endometrial autophagy inducing collagen I deposition in EMs, which provided a potential target for therapeutic implications.
2025-02-22 | GSE278827 | GEO
Project description:Background Reduced endometrial receptivity is a major factor for impaired fertility in endometriosis (EMS). Endometrial deposition of collagen I proteins may account for poor endometrial receptivity in endometriosis. Methods We investigated the expression of collagen I expression in endometrium of endometriosis patients and in constructed EMS mice model. Effect of collagen I on ESCs was evaluated. Co-culture of exosomes with ESCs was conducted to evaluate the uptake of exosomes by different endometrial cell lines and the effect on decidualization of eutopic ESCs and embryo implantation. MiRNA expression profiles were compared between ectopic ESC derived exosomes and eutopic ESC derived exosomes. Luciferase reporter and its mutant plasmids were applied to confirm the direct target of miR-25-3p. Findings Here we found endometrial collagen I deposition with impaired decidualization in endometriosis patients and EMS mice model. Treatment of collagen I with ESCs contributed to impaired decidualization and inhibited BLS expansion in vitro. Endometriotic stromal cell-derived exosomes were detected in eutopic endometrium and the ectopic endometrial stromal cell derived exosomes were more taken-up by the same cell line in eutopic endometrium. Treatment of endometriotic stromal cell-derived exosomes increased the expression of endometrial collagen I in vitro and in vivo, while inhibited BLS expansion. Exosomal miR-25-3p was significantly increased in endometriotic stromal cell-derived exosomes compared with control group, and PTEN is a certain target of miR-25-3p. The promotion of endometrial miR-25-3p significantly increased collagen I expression in vitro through the PTEN/Akt pathway. Interpretation These results suggested that endometriotic stromal cell-derived exosomal miR-25-3p played key role in inducing endometrial collagen I deposition to impair embryo expansion in endometriosis via PTEN/Akt pathway. Funding National Nature Science Foundation of China (82271702), National Natural Science Foundation of China (81771537). Keywords: endometriosis; exosome; collagen I; miRNA; collagen deposition
2025-01-28 | GSE222432 | GEO
Project description:Nf1 Deficiency Increases Mammary Collagen Deposition and Restricts Adipocyte Differentiation Before Tumor Formation
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Project description:Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven pro-inflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3-/- neutrophil recruitment to wild type lungs. In vitro, ATF3-/- neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3-/- neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3-/- and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production, but promotion of neutrophil chemotaxis. Ly6G+ neutrophils were purified by magnetic beads from WT or ATF3 KO bone marrow and RNA was immediately isolated for global gene expression using microarrays.
2014-04-05 | E-GEOD-53973 | biostudies-arrayexpress
Project description:BACKGROUND: The NF1 tumor suppressor gene is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1) – a tumor predisposition syndrome caused by a germline NF1 mutation – have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanisms by which NF1 mutation leads to breast cancer tumorigenesis are not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. METHODS: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development and develops highly penetrant breast cancer. RESULTS: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient rat mammary mature adipocytes have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation but flow cytometry analysis did not show a change mammary adipose-derived mesenchymal stem cell abundance. CONCLUSION: Collectively, these studies uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary gland will create a foundation for developing early detection strategies of breast cancer among NF1 patients.
2023-05-08 | GSE231603 | GEO