scholarly journals Elevated EDAR signalling promotes mammary gland tumourigenesis with squamous metaplasia

Oncogene ◽  
2021 ◽  
Author(s):  
Rebecca Williams ◽  
Stephanie Jobling ◽  
Andrew H. Sims ◽  
Chunyan Mou ◽  
Lorna Wilkinson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oestrogen Receptor ◽  
Squamous Metaplasia ◽  
Death Receptor ◽  
Hair Follicles ◽  
Receptor Expression ◽  
Tumour Necrosis Factor Receptor ◽  
High Incidence ◽  
Tnfr Superfamily ◽  
Necrosis Factor

AbstractEctodysplasin A receptor (EDAR) is a death receptor in the Tumour Necrosis Factor Receptor (TNFR) superfamily with roles in the development of hair follicles, teeth and cutaneous glands. Here we report that human Oestrogen Receptor (ER) negative breast carcinomas which display squamous differentiation express EDAR strongly. Using a mouse model with a high Edar copy number, we show that elevated EDAR signalling results in a high incidence of mammary tumours in breeding female mice. These tumours resemble the EDAR-high human tumours in that they are characterised by a lack of oestrogen receptor expression, contain extensive squamous metaplasia, and display strong β-catenin transcriptional activity. In the mouse model, all of the tumours carry somatic deletions of the third exon of the CTNNB1 gene that encodes β-catenin. Deletion of this exon yields unconstrained β-catenin signalling activity. We also demonstrate that β-catenin activity is required for transformed cell growth, showing that increased EDAR signalling creates an environment in which β-catenin activity can readily promote tumourigenesis. Together, this work identifies a novel death receptor oncogene in breast cancer, whose mechanism of transformation is based on the interaction between the WNT and Ectodysplasin A (EDA) pathways.

scholarly journals Tumour necrosis factor receptor-associated factors: interacting protein with forkhead-associated domain inhibition decreases inflammatory cell infiltration and cardiac remodelling after acute myocardial infarction

2020 ◽  
Vol 31 (1) ◽  
pp. 85-92 ◽  
Author(s):  
Yicheng Jiang ◽  
Xue Li ◽  
Hai Xu ◽  
Yang Gu ◽  
Feiya Shi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mouse Model ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cardiac Remodelling ◽  
Tumour Necrosis Factor Receptor ◽  
Tumour Necrosis Factor Α ◽  
Interacting Protein ◽  
Factor Α ◽  
Necrosis Factor

Abstract OBJECTIVES Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Post-AMI cardiac remodelling is closely related to the prognosis of AMI. The excess inflammatory responses could promote cardiac remodelling. Tumour necrosis factor receptor-associated factor-interacting protein with forkhead-associated domain (TIFA) has been identified as a nuclear factor (NF)-κB activator, which plays a key role in the activation of the NF-κB signalling pathway. The goal of this research was to investigate the expression and the underlying mechanism of TIFA in an AMI mouse model. METHODS The AMI mouse model was induced by ligation of the left coronary artery. TIFA and NF-κB knockdown were established by lentivirus transduction. The expression levels of associated proteins were analysed by a western blot or an enzyme-linked immunosorbent assay. Histological characteristics were evaluated by haematoxylin–eosin staining. RESULTS The TIFA level was elevated in our AMI mouse model. The production of interleukin-1β and tumour necrosis factor-α increased markedly in the mice with AMI. TIFA knockdown inhibited the infiltration of inflammatory cells, production of pro-inflammatory mediators (interleukin-1β and tumour necrosis factor-α), NF-κB activation and cardiac remodelling (matrix metallopeptidase 9) post-AMI. In addition, NF-κB knockdown could also alleviate cardiac remodelling after AMI. CONCLUSIONS The preceding results indicated that TIFA inhibition could ameliorate cardiac remodelling after AMI partly through inactivation of NF-κB. This study provides insights into further research of cardiac remodelling and AMI from bench to clinic.

Activity of Mangosteen Xanthones and Teleocidin A-2 in Death Receptor Expression Enhancement and Tumor Necrosis Factor Related Apoptosis-Inducing Ligand Assays#

2010 ◽  
Vol 73 (3) ◽  
pp. 452-455 ◽  
Author(s):  
Hiroyuki Kikuchi ◽  
Takashi Ohtsuki ◽  
Takashi Koyano ◽  
Thaworn Kowithayakorn ◽  
Toshiyuki Sakai ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Death Receptor ◽  
Receptor Expression ◽  
Necrosis Factor

scholarly journals The Role of Costimulatory Receptors of the Tumour Necrosis Factor Receptor Family in Atherosclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Ricardo F. Antunes ◽  
Juan Carlos Kaski ◽  
Ingrid E. Dumitriu
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Adaptive Immune System ◽  
Chronic Inflammatory Disease ◽  
Tumour Necrosis Factor Receptor ◽  
Adaptive Immune ◽  
Tnfr Superfamily ◽  
Necrosis Factor

Atherosclerosis is a chronic inflammatory disease that is mediated by both the innate and adaptive immune responses. T lymphocytes, that together with B cells are the cellular effectors of the adaptive immune system, are currently endowed with crucial roles in the development and progression of atherosclerosis. Costimulatory receptors are a class of molecules expressed by T lymphocytes that regulate the activation of T cells and the generation of effector T-cell responses. In this review we present the roles of costimulatory receptors of the tumour necrosis factor receptor (TNFR) superfamily in atherosclerosis and discuss the implications for future therapies that could be used to specifically modulate the immune response of pathogenic T cells in this disease.

Prognostic significance of Dicer expression in ovarian cancer—link to global microRNA changes and oestrogen receptor expression

2009 ◽  
pp. n/a-n/a ◽  
Author(s):  
Areeg Faggad ◽  
Jan Budczies ◽  
Oleg Tchernitsa ◽  
Silvia Darb-Esfahani ◽  
Jalid Sehouli ◽  
...  
Keyword(s):  
Oestrogen Receptor ◽  
Prognostic Significance ◽  
Receptor Expression ◽  
Dicer Expression

Prolonged atrazine exposure beginning in utero and adult uterine morphology in mice

2021 ◽  
pp. 1-10
Author(s):  
Meaghan J. Griffiths ◽  
Amy L. Winship ◽  
Jessica M. Stringer ◽  
Elyse O. Swindells ◽  
Alesia P. Harper ◽  
...  
Keyword(s):  
Drinking Water ◽  
Oestrogen Receptor ◽  
Endometrial Hyperplasia ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Metabolism ◽  
In Utero ◽  
Receptor Expression ◽  
Mesenchymal Transition ◽  
Pregnant Mice ◽  
Emt Markers

Abstract Through drinking water, humans are commonly exposed to atrazine, a herbicide that acts as an endocrine and metabolic disruptor. It interferes with steroidogenesis, including promoting oestrogen production and altering cell metabolism. However, its precise impact on uterine development remains unknown. This study aimed to determine the effect of prolonged atrazine exposure on the uterus. Pregnant mice (n = 5/group) received 5 mg/kg body weight/day atrazine or DMSO in drinking water from gestational day 9.5 until weaning. Offspring continued to be exposed until 3 or 6 months of age (n = 5–9/group), when uteri were collected for morphological and molecular analyses and steroid quantification. Endometrial hyperplasia and leiomyoma were evident in the uteri of atrazine-exposed mice. Uterine oestrogen concentration, oestrogen receptor expression, and localisation were similar between groups, at both ages (P > 0.1). The expression and localisation of key epithelial-to-mesenchymal transition (EMT) genes and proteins, critical for tumourigenesis, remained unchanged between treatments, at both ages (P > 0.1). Hence, oestrogen-mediated changes to established EMT markers do not appear to underlie abnormal uterine morphology evident in atrazine exposure mice. This is the first report of abnormal uterine morphology following prolonged atrazine exposure starting in utero, it is likely that the abnormalities identified would negatively affect female fertility, although mechanisms remain unknown and require further study.

scholarly journals TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

2021 ◽  
pp. annrheumdis-2020-219262
Author(s):  
Cecilia Ansalone ◽  
John Cole ◽  
Sabarinadh Chilaka ◽  
Flavia Sunzini ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
Epigenetic Modification ◽  
Human Peripheral Blood ◽  
Joint Destruction ◽  
Receptor Expression ◽  
Skeletal Health ◽  
Flow Cytometric ◽  
Human Osteoclast ◽  
The Relationship ◽  
Pathological Consequence ◽  
Necrosis Factor

ObjectivesCirculating myeloid precursors are responsible for post-natal osteoclast (OC) differentiation and skeletal health, although the exact human precursors have not been defined. Enhanced osteoclastogenesis contributes to joint destruction in rheumatoid arthritis (RA) and tumour necrosis factor (TNF) is a well-known pro-osteoclastogenic factor. Herein, we investigated the interplay between receptor activator of nuclear factor kappa-Β ligand (RANK-L), indispensable for fusion of myeloid precursors and the normal development of OCs, and TNF in directing the differentiation of diverse pre-OC populations derived from human peripheral blood.MethodsFlow cytometric cell sorting and analysis was used to assess the potential of myeloid populations to differentiate into OCs. Transcriptomic, epigenetic analysis, receptor expression and inhibitor experiments were used to unravel RANK-L and TNF signalling hierarchy.ResultsTNF can act as a critical homoeostatic regulator of CD14+ monocyte (MO) differentiation into OCs by inhibiting osteoclastogenesis to favour macrophage development. In contrast, a distinct previously unidentified CD14−CD16−CD11c+ myeloid pre-OC population was exempt from this negative regulation. In healthy CD14+ MOs, TNF drove epigenetic modification of the RANK promoter via a TNFR1-IKKβ-dependent pathway and halted osteoclastogenesis. In a subset of patients with RA, CD14+ MOs exhibited an altered epigenetic state that resulted in dysregulated TNF-mediated OC homoeostasis.ConclusionsThese findings fundamentally re-define the relationship between RANK-L and TNF. Moreover, they have identified a novel pool of human circulating non-MO OC precursors that unlike MOs are epigenetically preconditioned to ignore TNF-mediated signalling. In RA, this epigenetic preconditioning occurs in the MO compartment providing a pathological consequence of failure of this pathway.

scholarly journals A Mouse Model for Studying Stem Cell Effects on Regeneration of Hair Follicle Outer Root Sheaths

2020 ◽  
Vol 15 (1) ◽  
pp. 41-50
Author(s):  
Jingxu Guo ◽  
Shuwei Li ◽  
Hongyang Wang ◽  
Tinghui Wu ◽  
Zhenhui Wu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mouse Model ◽  
Hair Follicle ◽  
Smooth Muscle Actin ◽  
Hair Follicles ◽  
Alpha Smooth Muscle Actin ◽  
Papillary Structure ◽  
Glass Membrane

AbstractObjectiveStem cells hold promise for treating hair loss. Here an in vitro mouse model was developed using outer root sheaths (ORSs) isolated from hair follicles for studying stem cell-mediated dermal papillary regeneration.MethodsUnder sterile conditions, structurally intact ORSs were isolated from hair follicles of 3-day-old Kunming mice and incubated in growth medium. Samples were collected daily for 5 days. Stem cell distribution, proliferation, differentiation, and migration were monitored during regeneration.ResultsCell proliferation began at the glass membrane periphery then spread gradually toward the membrane center, with the presence of CD34 and CD200 positive stem cells involved in repair initiation. Next, CD34 positive stem cells migrated down the glass membrane, where some participated in ORS formation, while other CD34 cells and CD200 positive cells migrated to hair follicle centers. Within the hair follicle matrix, stem cells divided, grew, differentiated and caused outward expansion of the glass membrane to form a dermal papillary structure containing alpha-smooth muscle actin. Neutrophils attracted to the wound site phagocytosed bacterial and cell debris to protect regenerating tissue from infection.ConclusionIsolated hair follicle ORSs can regenerate new dermal papillary structures in vitro. Stem cells and neutrophils play important roles in the regeneration process.

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