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Fli1⁺ cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis.

ABSTRACT: A network of molecular factors drives the development, differentiation, and maintenance of endothelial cells. Friend leukemia integration 1 transcription factor (FLI1) is a bona fide marker of endothelial cells during early development. In zebrafish Tg( f li1:EGFP) ^y1 , we identified two endothelial cell populations, high-fli1 ⁺ and low-fli1 ⁺, by the intensity of green fluorescent protein signal. By comparing RNA-sequencing analysis of non-fli1 expressing cells (fli1 ^-) with these two (fli1 ⁺) cell populations, we identified several up-regulated genes, not previously recognized as important, during endothelial development. Compared with fli1 ^- and low-fli1 ⁺ cells, high-fli1 ⁺ cells showed up-regulated expression of the zinc finger transcription factor PRDI-BF1 and RIZ homology domain containing 16 (prdm16). Prdm16 knockdown (KD) by morpholino in the zebrafish larva was associated with impaired angiogenesis and increased number of low-fli1 ⁺ cells at the expense of high-fli1 ⁺ cells. In addition, PRDM16 KD in endothelial cells derived from human-induced pluripotent stem cells impaired their differentiation and migration in vitro. Moreover, zebrafish mutants (mut) with loss of function for the oncogene LIM domain only 2 (lmo2) also showed reduced prdm16 gene expression combined with impaired angiogenesis. Prdm16 expression was reduced further in endothelial (CD31⁺) cells compared with CD31^- cells isolated from l mo2-mutants (l mo2-mut) embryos. Chromatin immunoprecipitation-PCR demonstrated that Lmo2 binds to the promoter and directly regulates the transcription of prdm16 This work unveils a mechanism by which prdm16 expression is activated in endothelial cells by Lmo2 and highlights a possible therapeutic pathway by which to modulate endothelial cell growth and repair.

SUBMITTER: Matrone G

PROVIDER: S-EPMC8346798 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Soft tissue sarcoma (STS) is a rare solid malignant cancer, and there are few effective treatment options for advanced disease. Cancer immunotherapy is a promising new strategy for STS treatment. IL-33 is a candidate cytokine for immunotherapy that can activate T lymphocytes and modulate antitumor immunity in some cancers. However, the expression and biological role of IL-33 in STS are poorly understood. In this study, we found that the expression of IL-33 and its receptor ST2 was decreased in STS using real-time PCR assays. By analyzing sarcoma data from The Cancer Genome Atlas, we found that higher transcriptional levels of IL-33 and ST2 were associated with a favorable outcome. There were positive correlations between the expression levels of ST2 and CD3E, CD4, CD8A, CD45RO, FOXP3, CD11B, CD33, and IFN-γ. Strong positive correlations between the expression of IFN-γ and CD3E and CD8A were also observed. Moreover, the expression levels of both IL-33 and ST2 were positively correlated with those of CD3E, CD8A, and chemokines that recruit CD8+ T cells, indicating that the IL-33/ST2 axis may play an important role in recruiting and promoting the immune response of type 1-polarized CD8+ T cells in STS. Meanwhile, we also found that the expression of IL-33 was negatively correlated with that of TGF-β1 and chemokines that recruit regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), indicating that the IL-33/ST2 axis may also contribute to antagonizing Tregs, MDSCs, and TGF-β1-mediated immunosuppression in STS. The correlations between the IL-33/ST2 axis and CD8+ T cells and IFN-γ, as well as Tregs, MDSCs, and TGF-β1 were validated by additional analyses using three other independent GEO datasets of sarcoma. Our results implicate the possible role of the IL-33/ST2 axis in modulating antitumor immunity in STS. IL-33 may not only serve as a useful prognostic biomarker for STS but also as a potential therapeutic target for STS immunotherapy and worth further investigation.

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Fli1⁺ cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis.

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Fli1+ cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis.

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OmicsDI is part of the ELIXIR infrastructure

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Fli1⁺ cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis.