Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression.
Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression.
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DOI：
10.1038/sj.bjc.6605440
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发表时间：
2010-01-05
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
富含半胱氨酸的酸性分泌蛋白（Secreted protein，CYP）是一种多方面调节细胞-细胞和细胞-基质相互作用的蛋白质。在癌症中，p53不仅可以与高度侵袭性表型相关，而且还可以作为肿瘤抑制因子。本研究旨在探讨胰腺导管腺癌（PDAC）中TGF β 1的功能及其受成纤维细胞生长因子受体（FGFR）1亚型的调节。外源激素抑制生长、运动和迁移。ShRNA抑制ASPC-1和PANC-1细胞中的内源性SPARC，导致贴壁依赖性和非依赖性生长、transwell迁移和异种移植物生长增加，以及成纤维细胞生长因子（FGF）1和FGF 2的促有丝分裂功效增加。PANC-1细胞中内源性β-内酰胺酶的表达在FGFR 1-IIIb过表达的细胞中增加，但在FGFR 1-IIIc过表达的细胞中降低。p38-丝裂原活化蛋白激酶抑制剂SB 203580可抑制内源性β-内酰胺酶的上调。胰腺星状细胞（PSC）的条件培养基中可检测到β-淀粉样蛋白，而PDAC细胞则不能。PDAC细胞的条件培养基降低PSC的内源性p53表达。内源性β-淀粉样蛋白抑制PDAC细胞的恶性表型，因此可能在PDAC中起肿瘤抑制剂的作用。内源性EGFR表达可通过FGFR 1-III同种型表达调节。此外，PDAC细胞可能通过旁分泌作用抑制周围PSC中的内源性SPARC表达。
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.
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