MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling.
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.
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Jino
J
Park
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Soojin
S
Kim
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Joongho
J
Joh
Maine Medical Center Research Institute, Portland, ME, USA.
Scot C
SC
Remick
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Donald M
DM
Miller
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Department of Medicine and Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA.
Jun
J
Yan
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Zeyad
Z
Kanaan
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Ju-Hsien
JH
Chao
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Maxwell M
MM
Krem
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Soumit K
SK
Basu
Division of Hematology, Internal Medicine, National Center for Global Health and Medicine, Shinjuku, Japan.
Shotaro
S
Hagiwara
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria.|Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria.
Lukas
L
Kenner
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria.
Richard
R
Moriggl
Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
Kevin D
KD
Bunting
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.|Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
William
W
Tse
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D006801:Humans; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000067492:RNAi Therapeutics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D019061:src-Family Kinases / Q000378:metabolism*
C091736:MLLT11 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases
AF1q; PDGF; PDGFR; STAT3; Src