Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression
Open Access
- 17 November 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 102 (1), 188-195
- https://doi.org/10.1038/sj.bjc.6605440
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell–cell and cell–matrix interactions. In cancer, SPARC can be not only associated with a highly aggressive phenotype, but also acts as a tumour suppressor. The aim of this study was to characterise the function of SPARC and its modulation by fibroblast growth factor receptor (FGFR) 1 isoforms in pancreatic ductal adenocarcinoma (PDAC). Exogenous SPARC inhibited growth, movement, and migration. ShRNA inhibition of endogenous SPARC in ASPC-1 and PANC-1 cells resulted in increased anchorage-dependent and -independent growth, transwell migration, and xenograft growth as well as increased mitogenic efficacy of fibroblast growth factor (FGF) 1 and FGF2. Endogenous SPARC expression in PANC-1 cells was increased in FGFR1-IIIb over-expressing cells, but decreased in FGFR1-IIIc over-expressing cells. The up-regulation of endogenous SPARC was abrogated by the p38-mitogen-activated protein kinase inhibitor SB203580. SPARC was detectable in conditioned medium of pancreatic stellate cells (PSCs), but not PDAC cells. Conditioned medium of PDAC cells reduced endogenous SPARC expression of PSCs. Endogenous SPARC inhibits the malignant phenotype of PDAC cells and may, therefore, act as a tumour suppressor in PDAC. Endogenous SPARC expression can be modulated by FGFR1-III isoform expression. In addition, PDAC cells may inhibit endogenous SPARC expression in surrounding PSCs by paracrine actions.Keywords
This publication has 22 references indexed in Scilit:
- Exon III Splicing of Fibroblast Growth Factor Receptor 1 Is Modulated by Growth Factors and Cyclin D1Pancreas, 2008
- SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2′deoxycytidine to increase SPARC expression and improve therapy responseBritish Journal of Cancer, 2008
- A prototypic matricellular protein in the tumor microenvironment—Where there's SPARC, there's fireJournal of Cellular Biochemistry, 2008
- Peritumoral Fibroblast SPARC Expression and Patient Outcome With Resectable Pancreatic AdenocarcinomaJournal of Clinical Oncology, 2007
- Osteonectin Influences Growth and Invasion of Pancreatic Cancer CellsAnnals of Surgery, 2005
- Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cellsGastroenterology, 2005
- SPARC regulates cell cycle progression in mesangial cells via its inhibition of IGF‐dependent signalingJournal of Cellular Biochemistry, 2002
- IIIc isoform of fibroblast growth factor receptor 1 is overexpressed in human pancreatic cancer and enhances tumorigenicity of hamster ductal cellsGastroenterology, 2002
- SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injuryJCI Insight, 2001
- Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: evidence for autocrine and paracrine actionsOncogene, 1997