Keratinocyte growth factor induces matrix metalloproteinase-9 expression and correlates with venous invasion in pancreatic cancer

Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7,and KGF receptor (KGFR) play important roles in the growth of epithelial cellsand are overexpressed in a variety of malignant epithelial tumors, including pancreaticductal adenocarcinoma (PDAC). We previously reported that co-expression of KGFand KGFR in PDAC is associated with venous invasion, enhanced vascular endothelialgrowth factor A expression and poor prognosis. Matrix metalloproteinase-9 (MMP-9)is known to participate in the degradation of type IV collagen, which is a primarycomponent of extracellular matrices in the vascular basement membrane. In thepresent study, we examined the expression and roles of KGF, KGFR and MMP-9 inhuman PDAC cell lines and tissues. Quantitative real-time polymerase chain reactionanalysis demonstrated the expression of MMP-9 mRNA in all eight PDAC cell lines.KGF, KGFR and MMP-9 were, respectively, expressed in 27 (43%), 23 (37%) and 35(56%) of 63 patients. Each expression of KGF, KGFR or MMP-9 correlated positivelywith venous invasion. Furthermore, expression of KGF or MMP-9 correlated positivelywith liver metastasis. KGF-positive cases exhibited shorter survival than KGF-negativecases, while KGFR and MMP-9 expression were unrelated to prognosis. Administrationof recombinant human KGF increased MMP-9 expression in PDAC cells, while transienttransfection with short hairpin RNAs targeting KGF transcripts reduced MMP-9 expressionin PDAC cells. Moreover, recombinant human KGF significantly enhanced migrationand invasion of PDAC cells. These findings suggest that KGF and KGFR promote venousinvasion via MMP-9 in PDAC, and closely correlate with liver metastasis. The KGF/KGFRpathway may be a critical therapeutic target for PDAC metastasis.