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.
Multiple myeloma FGFR4 MMP13 ERK/MAPK PI3K JNK
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Takaishi H, Kimura T, Dalal S, Okada Y, D'Armiento J. Joint diseases and matrix metalloproteinases: a role for mmp-13. Curr Pharm Biotechnol. 2008;9:47–54.CrossRefPubMedGoogle Scholar
Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (mmp-1, mmp-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 2002;4:157–64.CrossRefPubMedGoogle Scholar
Balbin M, Pendas AM, Uria JA, Jimenez MG, Freije JP, Lopez-Otin C. Expression and regulation of collagenase-3 (mmp-13) in human malignant tumors. APMIS. 1999;107:45–53.CrossRefPubMedGoogle Scholar
Friesel R, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb Haemost. 1999;82:748–54.PubMedGoogle Scholar
Jaye M, Schlessinger J, Dionne CA. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta. 1992;1135:185–99.CrossRefPubMedGoogle Scholar
Fujimoto J, Hori M, Ichigo S, Tamaya T. Expressions of the fibroblast growth factor family (fgf-1, -2 and -4) mrna in endometrial cancers. Tumour Biol. 1996;17:226–33.CrossRefPubMedGoogle Scholar
Kuslak SL, Marker PC. Fibroblast growth factor receptor signaling through mek-erk is required for prostate bud induction. Differentiation. 2007;75:638–51.CrossRefPubMedGoogle Scholar
Williamson AJ, Dibling BC, Boyne JR, Selby P, Burchill SA. Basic fibroblast growth factor-induced cell death is effected through sustained activation of p38mapk and up-regulation of the death receptor p75ntr. J Biol Chem. 2004;279:47912–28.CrossRefPubMedGoogle Scholar
Kan M, Wu X, Wang F, McKeehan WL. Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. J Biol Chem. 1999;274:15947–52.CrossRefPubMedGoogle Scholar
Turkington RC, Longley DB, Allen WL, Stevenson L, McLaughlin K, Dunne PD, et al. Fibroblast growth factor receptor 4 (fgfr4): a targetable regulator of drug resistance in colorectal cancer. Cell Death and Disease. 2014;5:e1046.CrossRefPubMedPubMedCentralGoogle Scholar
Liu R, Li J, Xie K, Zhang T, Lei Y, Chen Y, et al. Fgfr4 promotes stroma-induced epithelial-to-mesenchymal transition in colorectal cancer. Cancer Res. 2013;73:5926–35.CrossRefPubMedGoogle Scholar
Bange J, Prechtl D, Cheburkin Y, Specht K, Harbeck N, Schmitt M, et al. Ullrich A: cancer progression and tumor cell motility are associated with the fgfr4 arg (388) allele. Cancer Res. 2002;62:840–7.PubMedGoogle Scholar