CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth.
| العنوان: | CXCR2 expression during melanoma tumorigenesis controls transcriptional programs that facilitate tumor growth. |
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| المؤلفون: | Yang J, Bergdorf K, Yan C, Luo W, Chen SC, Ayers D, Liu Q, Liu X, Boothby M, Groves SM, Oleskie AN, Zhang X, Maeda DY, Zebala JA, Quaranta V, Richmond A |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Mar 04. Date of Electronic Publication: 2023 Mar 04. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Background: Though the CXCR2 chemokine receptor is known to play a key role in cancer growth and response to therapy, a direct link between expression of CXCR2 in tumor progenitor cells during induction of tumorigenesis has not been established. Methods: To characterize the role of CXCR2 during melanoma tumorigenesis, we generated tamoxifen-inducible tyrosinase-promoter driven Braf V600E /Pten -/- /Cxcr2 -/- and NRas Q61R /INK4a -/- /Cxcr2 -/- melanoma models. In addition, the effects of a CXCR1/CXCR2 antagonist, SX-682, on melanoma tumorigenesis were evaluated in Braf V600E /Pten -/- and NRas Q61R /INK4a -/- mice and in melanoma cell lines. Potential mechanisms by which Cxcr2 affects melanoma tumorigenesis in these murine models were explored using RNAseq, mMCP-counter, ChIPseq, and qRT-PCR; flow cytometry, and reverse phosphoprotein analysis (RPPA). Results: Genetic loss of Cxcr2 or pharmacological inhibition of CXCR1/CXCR2 during melanoma tumor induction resulted in key changes in gene expression that reduced tumor incidence/growth and increased anti-tumor immunity. Interestingly, after Cxcr2 ablation, Tfcp2l1 , a key tumor suppressive transcription factor, was the only gene significantly induced with a log Conclusions: Here, we provide novel mechanistic insight revealing how loss of Cxcr2 expression/activity in melanoma tumor progenitor cells results in reduced tumor burden and creation of an anti-tumor immune microenvironment. This mechanism entails an increase in expression of the tumor suppressive transcription factor, Tfcp2l1, along with alteration in the expression of genes involved in growth regulation, tumor suppression, stemness, differentiation, and immune modulation. These gene expression changes are coincident with reduction in the activation of key growth regulatory pathways, including AKT and mTOR. |
| التعليقات: | Update in: Mol Cancer. 2023 Jun 3;22(1):92. (PMID: 37270599) |
| تواريخ الأحداث: | Date Created: 20230303 Latest Revision: 20230609 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9980137 |
| DOI: | 10.1101/2023.02.22.529548 |
| PMID: | 36865260 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.02.22.529548 |
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