Park Jino, Kim Soojin, Joh Joongho, Remick Scot C, Miller Donald M, Yan Jun, Kanaan Zeyad, Chao Ju-Hsien, Krem Maxwell M, Basu Soumit K, Hagiwara Shotaro, Kenner Lukas, Moriggl Richard, Bunting Kevin D, Tse William
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.
Oncotarget. 2016 Jul 12;7(28):43960-43973. doi: 10.18632/oncotarget.9759.
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.
通过突变或扩增的酪氨酸激酶的酪氨酸磷酸化而导致的组成型STAT3激活（pYSTAT3）对于癌细胞的起始、进展、侵袭和运动至关重要。我们发现AF1q与乳腺癌细胞中的STAT3信号传导相关。在异种移植模型中，增强的AF1q表达激活了STAT3，并促进了免疫缺陷NSG小鼠的肿瘤生长和转移。AF1q表达改变的MDA-MB-231LN乳腺癌细胞的细胞因子分泌表型显示血小板衍生生长因子亚基B（PDGF-B）的表达发生了变化。AF1q诱导的PDGF-B刺激了MDA-MB-231LN细胞的运动、迁移和侵袭，并且AF1q上调了血小板衍生生长因子受体（PDGFR）信号传导。此外，AF1q诱导的PDGFR信号传导通过Src激酶激活增强了STAT3活性，这可被Src激酶抑制剂PP1阻断。而且，AF1q通过PDGFR信号传导上调了酪氨酸激酶信号传导，这可被伊马替尼阻断。总之，我们证明增强的AF1q表达通过激活PDGF-B/PDGFR级联反应来激活Src激酶，从而导致侵袭性癌细胞中持续存在致癌性pYSTAT3水平。因此，AF1q作为PDGF-B驱动的STAT3信号传导中的辅助因子发挥着重要作用。
