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1.
Genome Biol ; 24(1): 267, 2023 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-38001542

RESUMEN

BACKGROUND: RNA editing has been described as promoting genetic heterogeneity, leading to the development of multiple disorders, including cancer. The cytosine deaminase APOBEC3B is implicated in tumor evolution through DNA mutation, but whether it also functions as an RNA editing enzyme has not been studied. RESULTS: Here, we engineer a novel doxycycline-inducible mouse model of human APOBEC3B-overexpression to understand the impact of this enzyme in tissue homeostasis and address a potential role in C-to-U RNA editing. Elevated and sustained levels of APOBEC3B lead to rapid alteration of cellular fitness, major organ dysfunction, and ultimately lethality in mice. Importantly, RNA-sequencing of mouse tissues expressing high levels of APOBEC3B identifies frequent UCC-to-UUC RNA editing events that are not evident in the corresponding genomic DNA. CONCLUSIONS: This work identifies, for the first time, a new deaminase-dependent function for APOBEC3B in RNA editing and presents a preclinical tool to help understand the emerging role of APOBEC3B as a driver of carcinogenesis.


Asunto(s)
Neoplasias , Edición de ARN , Humanos , Animales , Ratones , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Mutación , Neoplasias/patología , Antígenos de Histocompatibilidad Menor/genética , Antígenos de Histocompatibilidad Menor/metabolismo , ADN/metabolismo
2.
Cancer Res ; 82(23): 4414-4428, 2022 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-36200806

RESUMEN

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature; this was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment. SIGNIFICANCE: Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.


Asunto(s)
Neoplasias Ováricas , Macrófagos Asociados a Tumores , Humanos , Femenino , Ratones , Animales , Células Endoteliales/patología , Carcinoma Epitelial de Ovario/genética , Neoplasias Ováricas/patología , Microambiente Tumoral , Endotelio/metabolismo , Colesterol , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/genética
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