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

Document Type

Article

Publication Date

7-12-2016

Institution/Department

MMCRI

Journal Title

Oncotarget

MeSH Headings

Animals, Breast Neoplasms, Cell Line, Cell Line, Tumor, Cell Movement, Female, Humans, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Neoplasm Invasiveness, Neoplasm Proteins, Proto-Oncogene Proteins, RNAi Therapeutics, Receptors, Platelet-Derived Growth Factor, STAT3 Transcription Factor, Signal Transduction, Xenograft Model Antitumor Assays, src-Family Kinases

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.

ISSN

1949-2553

First Page

43960

Last Page

43973

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