Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages

Bencheikh, Laura; Diop, M’Boyba; Rivière, Julie; Imanci, Aygun; Pierron, Gérard; Souquère, Sylvie; Naimo, Audrey; Morabito, Margot; Dussiot, Michaël; Leeuw, Frédéric De; Lobry, Camille; Solary, Éric; Droin, Nathalie

doi:10.1038/s41467-019-09970-9

Cited by 32 publications

(26 citation statements)

References 42 publications

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“…Also after ectopic expression of CSF1R_L301S , a constitutively active form of CSF1R, which was described previously, 37 the expression of pri-miR-34a was downregulated in DLD1 CRC cells ( Figure 7 B ). Furthermore, inhibition of CSF1R by the small molecule inhibitor GW2580 38 resulted in an upregulation of pri-miR-34a in SW480 and SW620 cells ( Figure 7 C and D ). Because GSEAs showed a positive correlation between CSF1R expression and the IL6_JAK_STAT3 pathway hallmark gene signature ( Figures 3 D and 7 E ), we asked whether STAT3 activation may mediate the repression of miR-34a after CSF1R activation.…”

Section: Resultsmentioning

confidence: 95%

Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer

Shi

Kaller

Rokavec

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims The miR-34a gene is a direct target of p53 and is commonly silenced in colorectal cancer (CRC). Here we identified the receptor tyrosine kinase CSF1R as a direct miR-34a target and characterized CSF1R as an effector of p53/miR-34a-mediated CRC suppression. Methods Analyses of TCGA-COAD and three other CRC cohorts for association of mRNA expression and signatures with patient survival and molecular subtypes. Bioinformatics identification and experimental validation of miRNA and transcription factor targets. Functional analysis of factors/pathways in the regulation of epithelial-mesenchymal transition (EMT), invasion, migration, acquired chemo-resistance and metastasis. Analyses of protein expression and CpG methylation within primary human colon cancer samples. Results In primary CRCs increased CSF1R, CSF1 and IL34 expression was associated with poor patient survival and a mesenchymal-like subtype. CSF1R displayed an inverse correlation with miR-34a expression. This was explained by direct inhibition of CSF1R by miR-34a. Furthermore, p53 repressed CSF1R via inducing miR-34a , whereas SNAIL induced CSF1R both directly and indirectly via repressing miR-34a in a coherent feed-forward loop. Activation of CSF1R induced EMT, migration, invasion and metastasis of CRC cells via STAT3-mediated down-regulation of miR-34a . 5-FU resistance of CRC cells was mediated by CpG-methylation of miR-34a and the resulting elevated expression of CSF1R . In primary CRCs elevated expression of CSF1R was detected at the tumor invasion front and was associated with CpG methylation of the miR-34a promoter as well as distant metastasis. Conclusions The reciprocal inhibition between miR-34a and CSF1R and its loss in tumor cells may be relevant for therapeutic and prognostic approaches towards CRC management.

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Section: Resultsmentioning

confidence: 95%

Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer

Shi

Kaller

Rokavec

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…Amongst others, LRRs are found in molecules such as adhesion molecules, enzymes, or tyrosine kinase receptors (RTKs). Despite the localization of RTKs at the cell surface, several are also found in the nucleus [29] being responsible for protein–protein interactions. Whether this is transferable for the intranuclear role of GARP in tumor cells as well as in Treg will be analyzed in more detail in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…For example, RTKs, proteins containing LRRs similar to GARP protein, are mainly localized at the cell surface. Nevertheless, several RTKs, such as colony stimulating factor 1 receptor (CSF-1R), are also found in the nucleus [29] where they interact with transcription factors regulation cell proliferation, survival, and migration. These full-length proteins translocate from the cell surface to the nucleus via the Golgi apparatus and the endoplasmatic reticulum.…”

Section: Discussionmentioning

confidence: 99%

GARP as an Immune Regulatory Molecule in the Tumor Microenvironment of Glioblastoma Multiforme

Zimmer

Kim

Sprang

et al. 2019

IJMS

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Glycoprotein A repetition predominant (GARP), a specific surface molecule of activated regulatory T cells, has been demonstrated to significantly contribute to tolerance in humans by induction of peripheral Treg and regulatory M2-macrophages and by inhibition of (tumorantigen-specific) T effector cells. Previous work identified GARP on Treg, and also GARP on the surface of several malignant tumors, as well as in a soluble form being shedded from their surface, contributing to tumor immune escape. Preliminary results also showed GARP expression on brain metastases of malignant melanoma. On the basis of these findings, we investigated whether GARP is also expressed on primary brain tumors. We showed GARP expression on glioblastoma (GB) cell lines and primary GB tissue, as well as on low-grade glioma, suggesting an important influence on the tumor micromilieu and the regulation of immune responses also in primary cerebral tumors. This was supported by the finding that GB cells led to a reduced, in part GARP-dependent effector T cell function (reduced proliferation and reduced cytokine secretion) in coculture experiments. Interestingly, GARP was localized not only on the cell surface but also in the cytoplasmatic, as well as nuclear compartments in tumor cells. Our findings reveal that GARP, as an immunoregulatory molecule, is located on, as well as in, tumor cells of GB and low-grade glioma, inhibiting effector T cell function, and thus contributing to the immunosuppressive tumor microenvironment of primary brain tumors. As GARP is expressed on activated Treg, as well as on brain tumors, it may be an interesting target for new immunotherapeutic approaches using antibody-based strategies as this indication.

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“…Monocytes and macrophages are abundant in the marrow of AML patients, and the tumor-associated macrophages (TAMs) are crucial for tumor cell survival and proliferation. Tumor-infiltrating macrophages can be targeted via CSF-1R inhibitors [ 45 , 46 ]. PTK2B is a member of the FAK family of tyrosine kinases and is activated by BCR-ABL during CML pathogenesis [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology‐Based Strategy

Han

Song²,

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Background. Yisui Qinghuang powder (YSQHP) is an effective traditional Chinese medicinal formulation used for the treatment of myelodysplastic syndromes (MDS). However, its pharmacological mechanism of action is unclear. Materials and Methods. In this study, the active compounds of YSQHP were screened using the traditional Chinese medicine systems pharmacology (TCMSP) and HerDing databases, and the putative target genes of YSQHP were predicted using the STITCH and DrugBank databases. Then, we further screened the correlative biotargets of YSQHP and MDS. Finally, the compound-target-disease (C-T-D) network was conducted using Cytoscape, while GO and KEGG analyses were conducted using R software. Furthermore, DDI-CPI, a web molecular docking analysis tool, was used to verify potential targets and pathways. Finally, binding site analysis was performed to identify core targets using MOE software. Results. Our results identified 19 active compounds and 273 putative target genes of YSQHP. The findings of the C-T-D network revealed that Rb1, CASP3, BCL2, and MAPK3 showed the most number of interactions, whereas indirubin, tryptanthrin, G-Rg1, G-Rb1, and G-Rh2 showed the most number of potential targets. The GO analysis showed that 17 proteins were related with STPK activity, PUP ligase binding, and kinase regulator activity. The KEGG analysis showed that PI3K/AKT, apoptosis, and the p53 pathways were the main pathways involved. DDI-CPI identified the top 25 proteins related with PI3K/AKT, apoptosis, and the p53 pathways. CASP8, GSK3B, PRKCA, and VEGFR2 were identified as the correlative biotargets of DDI-CPI and PPI, and their binding sites were found to be indirubin, G-Rh2, and G-Rf. Conclusion. Taken together, our results revealed that YSQHP likely exerts its antitumor effects by binding to CASP8, GSK3B, PRKCA, and VEGFR2 and by regulating the apoptosis, p53, and PI3K/AKT pathways.

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Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages

Cited by 32 publications

References 42 publications

Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer

Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer

GARP as an Immune Regulatory Molecule in the Tumor Microenvironment of Glioblastoma Multiforme

Deciphering the Key Pharmacological Pathways and Targets of Yisui Qinghuang Powder That Acts on Myelodysplastic Syndromes Using a Network Pharmacology‐Based Strategy

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