title: Regulation of metastasis of pediatric multiple myeloma by MMP13.
abstract: The molecular mechanism underlying metastasis of pediatric multiple myeloma (MM) remains elusive. Here, we showed that the levels of MMP13 are significantly higher in MM from young patients than those from adult patients. Moreover, a strong correlation of the MMP13 and phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels was detected in MM from young patients. To prove a causal link between activation of fibroblast growth factor receptors (FGFR) signaling pathway and MMP13 expression, we used a human MM line, RPMI-8226 (8226), to study the underlying molecular basis. We found that FGF1-induced FGFR4 phosphorylation in 8,226 cells resulted in significant activation of MMP13, and consequently, an increase in cancer invasiveness. FGFR4 inhibition in 8,226 cells abolished FGF1-stimulated MMP13 expression, suggesting that activation of FGFR signaling pathway in MM may promote cancer metastasis by inducing MMP13 expression. To define the signaling cascades downstream of FGFR4 activation for MMP13 activation, we applied specific inhibitors for PI3K, Jun N-terminal kinase (JNK), and ERK/MAPK, respectively, to the FGF1-stimulated 8,226 cells. We found that only inhibition of ERK1/2 significantly decreased the activation of MMP13 in response to FGF stimulation, suggesting that activation of FGFR signaling may activate ERK/MAPK, rather than JNK or PI3K pathway to activate MMP13 expression in 8,226 cells. Our study thus highlights FGFR4 signaling pathway and MMP13 as novel therapeutic targets for MM.
authors.affiliation: Department of Pediatrics, Provincial Hospital affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong, 250021, China, xiaoru_wang14@163.com.
authors.forename: Xiaoru
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaocang
authors.initials: X
authors.lastname: Cao
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D034622:RNA Interference; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016220:Fibroblast Growth Factor 1; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D048049:Extracellular Signal-Regulated MAP Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13