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

Abstract

Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7, and KGF receptor (KGFR) play important roles in the growth of epithelial cells and are overexpressed in a variety of malignant epithelial tumors, including pancreatic ductal adenocarcinoma (PDAC). We previously reported that co-expression of KGF and KGFR in PDAC is associated with venous invasion, enhanced vascular endothelial growth 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 primary component of extracellular matrices in the vascular basement membrane. In the present study, we examined the expression and roles of KGF, KGFR and MMP-9 in human PDAC cell lines and tissues. Quantitative real-time polymerase chain reaction analysis 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 positively with venous invasion. Furthermore, expression of KGF or MMP-9 correlated positively with liver metastasis. KGF-positive cases exhibited shorter survival than KGF-negative cases, while KGFR and MMP-9 expression were unrelated to prognosis. Administration of recombinant human KGF increased MMP-9 expression in PDAC cells, while transient transfection with short hairpin RNAs targeting KGF transcripts reduced MMP-9 expression in PDAC cells. Moreover, recombinant human KGF significantly enhanced migration and invasion of PDAC cells. These findings suggest that KGF and KGFR promote venous invasion via MMP-9 in PDAC, and closely correlate with liver metastasis. The KGF/KGFR pathway may be a critical therapeutic target for PDAC metastasis.

• Authors: Kazumitsu Cho, Yoko Matsuda, Junji Ueda, Eiji Uchida, Zenya Naito, Toshiyuki Ishiwata
• Journal: International journal of oncology (Int J Oncol) Vol. 40 Issue 4 Pg. 1040-8 (Apr 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22159401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• RNA, Small Interfering
• Fibroblast Growth Factor 7
• Matrix Metalloproteinase 9

Topics

• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Pancreatic Ductal (enzymology, immunology, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (physiology)
• Female
• Fibroblast Growth Factor 7 (biosynthesis, genetics)
• Humans
• Immunohistochemistry
• Male
• Matrix Metalloproteinase 9 (biosynthesis, genetics)
• Middle Aged
• Neoplasm Invasiveness
• Pancreatic Neoplasms (enzymology, immunology, metabolism, pathology)
• RNA, Messenger (biosynthesis, genetics)
• RNA, Small Interfering (administration & dosage, genetics)
• Real-Time Polymerase Chain Reaction
• Survival Rate
• Transfection