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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Park, J; Kim, S; Joh, J; Remick, SC; Miller, DM; Yan, J; Kanaan, Z; Chao, JH; Krem, MM; Basu, SK; Hagiwara, S; Kenner, L; Moriggl, R; Bunting, KD; Tse, W

Title: MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling.

Source: Oncotarget. 2016; 7(28):43960-43973



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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.

Keywords Pubmed: Animals
Breast Neoplasmsgeneticsmetabolismpathology
Cell Line
Cell Line, Tumor
Cell Movementgenetics
Female
Humans
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Neoplasm Invasiveness
Neoplasm Proteinsgeneticsmetabolism
Proto-Oncogene Proteinsgeneticsmetabolism
RNAi Therapeutics
Receptors, Platelet-Derived Growth Factormetabolism
STAT3 Transcription Factormetabolism
Signal Transduction
Xenograft Model Antitumor Assaysmethods
src-Family Kinasesmetabolism

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