MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling
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Jino Park1,2, Soojin Kim1,2, Joongho Joh1, Scot C. Remick3, Donald M. Miller1, Jun Yan1,4, Zeyad Kanaan1, Ju-Hsien Chao1,2, Maxwell M. Krem1,2, Soumit K. Basu1,2, Shotaro Hagiwara5, Lukas Kenner6,7,8, Richard Moriggl6,9, Kevin D. Bunting10, William Tse1,2
1James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
2Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
3Maine Medical Center Research Institute, Portland, ME, USA
4Department of Medicine and Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA
5Division of Hematology, Internal Medicine, National Center for Global Health and Medicine, Shinjuku, Japan
6Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
7Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria
8Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria
9Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria
10Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA
William Tse, email: email@example.com
Keywords: AF1q, STAT3, PDGF, PDGFR, Src
Received: December 07, 2015 Accepted: April 29, 2016 Published: June 01, 2016
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.
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