Regulation ot TAM gene expression by ABCA1 and ABCG1 (4 Cre- and 4 Cre+)
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ABSTRACT:
PROVIDER: PRJNA520922 | ENA |
REPOSITORIES: ENA
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Project description:Gene expression was analyzed in TAM from mice injected with ID8 ovarian cancer cells intraperitoneally in ABC a1/g1 fl/fl-LysM-Cre mice. Tumor-associated macrophages (TAM) have been shown to have important roles in the malignant progression of various cancers. However, macrophages also posses intrinsic tumoricidal activity and can promote the activity of cytotoxic lymphocytes, but they rapidly adopt an alternative phenotype within tumors, associated with immune-suppression and trophic functions that support tumor growth. The mechanisms that promote TAM polarization in the tumor-microenvironment remain poorly understood, these mechanisms may represent important therapeutic targets to block the tumor-promoting functions of TAM and restore their anti-tumor potential. Here we have characterized TAM in a mouse model of metastatic ovarian cancer. We show that ovarian cancer cells promote membrane-cholesterol efflux and the depletion of lipid rafts from macrophages. Increased cholesterol efflux promoted IL-4 mediated reprogramming while inhibiting IFNg-induced gene expression. These studies reveal an unexpected role for tumor-induced membrane-cholesterol efflux in driving the IL-4 signaling and the tumor-promoting functions of TAM, while rendering them refractory to pro-inflammatory stimuli. Thus, preventing cholesterol efflux in TAM could represent a novel therapeutic strategy to block pro-tumor functions and restore anti-tumor immunity.
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Project description:The COX-2 antisense lncRNA PACERR interacts with discrete RNA binding proteins to mediate a cell specific COX-2 response to HDL. PACERR exerts its action both in cis and in trans, controlling the expression of COX-2 in macrophages, while also regulating the levels of macrophage ABCA1 and ABCG1, cholesterol transport genes involved in maintaining cholesterol homeostasis. When cells are exposed to HDL, PACERR is transcribed, leading to the release of bound histone acetyltransferase p300 and its relocation to the promoter of COX-2 which is then transcribed, leading to PG formation. In concert, PACERR also releases heterogeneous nuclear ribonucleoprotein L (hnRNPL) which relocates to the ABCA1 and ABCG1 gene loci, controlling mRNA alternative splicing and subsequent cholesterol efflux to HDL. A strong hnRNPL binding site motif is found in PACERR RNA and when this was deleted, the interaction between PACERR RNA and hnRNPL is abrogated both at baseline and following HDL treatment of macrophages. THP-1 macrophages stably overexpressing PACERR (P1-3) or deleted of the hnRNPL binding site (Delta1-3) from the PACERR sequence. In delta cells, PACERR no longer binds to hnRNPL but is free to bind to ABCA1 and ABCG1 impacting their transcription. In summary, we found that PACERR controls the levels of the cholesterol transporters through its interaction with the splicing factor, hnRNPL. It is released from PACERR RNA in response to HDL where it relocates to introns of cholesterol transporters determining the alternative splicing fate of transcripts required for cholesterol efflux. Through use of the delta cells, we have Illustrated the specificity for the interaction between hnRNPL and PACERR.
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