High Expression of FGF2/SDC1 Signaling Contributes to Poor Clinical Outcome in Hodgkin Lymphoma Patients and SDC1 siRNA Suppresses Proliferation, Migration, and Invasion in Hodgkin Lymphoma Cells (2017)

Abstract Our recent studies have shown that Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) expressions are upregulated, by 45- and 24-fold respectively, in CD30+ cells from tissues of relapsed versus relapsed-free Hodgkin lymphoma (HL) patients (p Among eleven HL cell lines examined, HD-MyZ represented the best model for relapsed/refractory HL due to its highest cell proliferation rate (35 hour doubling time) and overexpression of FGF2 and SDC1, by 60- and 150-fold respectively, when compared with the B lymphoblast cell line, C1RB7. Immunofluorescence and co-immunoprecipitation studies in normal fibroblasts and HL cells demonstrate that FGF2 and SDC1 are co-localized on the cell membrane and bind together as ligand and receptor. Additionally, FGF2 binds to FGFRs in HL cells with lower affinity than in normal fibroblasts with predominant binding to FGFR1, suggesting that FGF2 signaling largely involves both SDC1 and FGFR1. Fluorescence microscopy studies showed that FGFR1 is constitutively phosphorylated in HL cells, and it stimulates cell proliferation by an autocrine pathway. Treatment with exogenous FGF2 in the absence of serum resulted in phosphorylation of both AKT and ERK, thereby activating FGF2-mediated cell proliferation. FGF2 induction also upregulated mRNA expressions of SDC1 (12-fold), proliferation marker- CCND1 (242-fold) and metastatic marker- MMP9 (67-fold) compared to unstimulated cells. To examine the molecular mechanism, whereby SDC1 is involved in the proliferation and metastasis of HL cells, SDC1 knockdown (KD) was achieved near 100% with 1nM siRNA after 48 hours of transfection. The SDC1 KD condition did not affect cell morphology but significantly attenuated cell proliferation by two-fold (p In conclusion, our results provide evidence that increased FGF2/SDC1 expression and signaling may drive and maintain the hyperproliferation of HL cells, thereby contributing to disease progression and poor prognosis in HL patients. Therefore, a novel method to inhibit altered FGF2/SDC1 signaling offers an excellent potential for treating high-risk and refractory HL patient populations. Download : Download high-res image (142KB) Download : Download full-size image Disclosures Goy: Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics / JJ Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feldman: Janssen: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Speakers Bureau. Leslie: KITE pharma: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Pecora: COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.