Vigilin, a nucleocytoplasmic shuttling protein, post-transcriptionally suppresses proto-oncogene c-fms expression (encoding CSF-1R) in breast cancer by binding to a 69 nt cis-acting 3-UTR element in CSF-1R mRNA. CSF-1R is an important mediator of breast cancer development, metastasis, and survival. We confirm that vigilin decreases in vitro reporter luciferase activity as well as the translation rate of target mRNAs. We further explore the mechanism of suppression of CSF-1R. We show that the 69 nt binding element has profound effects on translation efficiency of CSF-1R mRNA, not seen in the presence of mutation of the element. Also, mutation of the 69 nt element in the CSF-1R mRNA 3'UTR both interferes with direct vigilin binding and obviates effect of vigilin overexpression on translational repression of CSF-1R. We show that stable vigilin binding requires the full length 69 nt CSF-1R element, including the 26 nt pyrimidine-rich core. Furthermore, titration of endogenous vigilin and other proteins which bind the 69 nt element, by exogenously introduced CSF-1R mRNA 3'UTR containing the pyrimidine-rich sequence, increases the adhesion, motility, and invasion of breast cancer cells. This phenotypic effect is not seen when the 69 nt element is deleted. Lastly, we are the first to show that human breast tissues exhibit strong vigilin expression in normal breast epithelium. Our pilot data suggest decreased vigilin protein expression, along with shift from the nucleus to the cytoplasmic location, in the transition to ductal carcinoma in situ.
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http://dx.doi.org/10.1016/j.tranon.2018.09.012 | DOI Listing |
Blood
December 2024
University of Michigan, Ann Arbor, Michigan, United States.
The transcription factor GATA-3 and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCL), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAM) within their tumor microenvironment (TME). Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor.
View Article and Find Full Text PDFVet Comp Oncol
December 2024
Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA.
Canine osteosarcoma (OSA) is a malignancy that has been shown to modulate the host immune system. Macrophage colony-stimulating factor (M-CSF; CSF1) and interleukin-34 (IL-34; IL34) are both ligands of colony stimulating factor 1 receptor (CSF-1R), and may play a role in the pathogenesis of a variety of human cancers, including OSA. This study aimed to, (1) assess M-CSF and IL-34 expression in canine OSA cell lines and tissue samples, and (2) determine any correlations between M-CSF and IL-34 expression and immune cell infiltrates within canine OSA tissues.
View Article and Find Full Text PDFZhonghua Kou Qiang Yi Xue Za Zhi
June 2023
Department of Prosthodontics and Implant Dentistry, School and Hospital of Stomatology, Guizhou Medical University, Guiyang 550004, China.
To investigate the effects of colony-stimulating factor 1 receptor (CSF-1R) inhibitor pexidartinib (PLX3397) on the senescence of bone marrow-derived macrophages (BMDM) stimulated by lipopolysaccharide (LPS). BMDM were isolated and cultured from femurs and tibiae of 10 male C57BL/6 mice aged 6-8 weeks (obtained from Laboratory Animal Center of Guizhou Medical University). They were divided into blank control group, LPS group (treated with 1 μg/ml LPS for 24 h) as well as low, medium and high concentration PLX3397 pretreatment groups (treated with 100, 500 and 1 000 nmol/L PLX3397 for 4 h respectively followed by 1 μg/ml LPS for 24 h).
View Article and Find Full Text PDFCancers (Basel)
November 2021
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada.
Colony-stimulating factor-1 receptor (CSF-1R) signaling promotes an immune suppressive microenvironment enriched in M2 macrophages. Given that CSF-1R inhibitors are under investigation in clinical trials, including in breast cancer, CSF-1R expression and association with immune biomarkers could identify patients who derive greater benefit from combination with immunotherapies. TIMER2.
View Article and Find Full Text PDFAutoimmunity
September 2021
Department of Thoracic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, People's Republic of China.
Background: Oesophageal squamous cell carcinoma (ESCC) is a malignant tumour of the digestive system that is associated with high morbidity and mortality rates worldwide. With the increased use of immunotherapy in cancer treatment, there is an urgent need to elucidate the immune-related mechanisms in ESCC and other digestive system carcinomas.
Methods: In our study, single-sample gene set enrichment analysis (ssGSEA) was first performed to analyse the expression profile downloaded from the NCBI Gene Expression Omnibus (GEO) database.
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