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MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling
Jino Park1,2, Soojin Kim1,2, Joongho Joh1
1James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Abstract:
Constitutive STAT3 activation by tyrosine phosphorylation of mutated or amplified tyrosine kinases (pYSTAT3) is critical for cancer initiation, progression, invasion, and motility of carcinoma cells. We showed that AF1q is associated with STAT3 signaling in breast cancer cells. In xenograft models, enhanced AF1q expression activated STAT3 and promoted tumor growth and metastasis in immunodeficient NSG mice. The cytokine secretory phenotype of MDA-MB-231LN breast cancer cells with altered AF1q expression revealed changes in expression of platelet-derived growth factor subunit B (PDGF-B). AF1q-induced PDGF-B stimulated motility, migration, and invasion of MDA-MB-231LN cells, and AF1q up-regulated platelet-derived growth factor receptor (PDGFR) signaling. Further, AF1q-induced PDGFR signaling enhanced STAT3 activity through Src kinase activation, which could be blocked by the Src kinase inhibitor PP1. Moreover, AF1q up-regulated tyrosine kinase signaling through PDGFR signaling, which was blockable by imatinib. In conclusion, we demonstrated that enhanced AF1q expression contributes to persistent and oncogenic pYSTAT3 levels in invasive carcinoma cells by activating Src kinase through activation of the PDGF-B/PDGFR cascade. Therefore, AF1q plays an essential role as a cofactor in PDGF-B-driven STAT3 signaling.
Insights
AF1q enhances cancer growth and metastasis by activating STAT3 signaling. This occurs through the PDGF-B/PDGFR pathway, which involves Src kinase, leading to persistent oncogenic signaling in invasive carcinoma cells.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Constitutive STAT3 activation (pYSTAT3) drives cancer progression.
- AF1q has been observed to associate with STAT3 signaling in breast cancer.
Purpose of the Study:
- To elucidate the role of AF1q in STAT3 signaling and its impact on breast cancer progression.
- To investigate the molecular mechanisms by which AF1q influences tumor growth, metastasis, and cell motility.
Main Methods:
- Utilized xenograft models with immunodeficient NSG mice to assess tumor growth and metastasis.
- Analyzed cytokine secretory phenotype and gene expression changes (e.g., PDGF-B) in breast cancer cells with altered AF1q expression.
- Investigated the involvement of platelet-derived growth factor receptor (PDGFR) and Src kinase signaling pathways using specific inhibitors (PP1, imatinib).
Main Results:
- Enhanced AF1q expression promoted tumor growth and metastasis in vivo.
- AF1q modulated platelet-derived growth factor subunit B (PDGF-B) expression, stimulating cell motility, migration, and invasion.
- AF1q-induced PDGFR signaling activated STAT3 via Src kinase, a process inhibitable by PP1 and imatinib.
Conclusions:
- Enhanced AF1q expression drives persistent, oncogenic pYSTAT3 levels in invasive carcinoma.
- AF1q acts as a cofactor in PDGF-B-driven STAT3 signaling by activating Src kinase through the PDGF-B/PDGFR cascade.
- AF1q plays a critical role in promoting invasion and motility of carcinoma cells.
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