Loss of Sef (similar expression to FGF) expression is associated with high grade and metastatic prostate cancer
- 13 February 2006
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 25 (29), 4122-4127
- https://doi.org/10.1038/sj.onc.1209428
Abstract
Fibroblast growth factors (FGF), and in particular FGF8, have been strongly implicated in prostate carcinogenesis. This study investigated the expression of Sef, a key inhibitory regulator of FGF signalling, in prostate cancer. In a panel of cell lines, hSef was detected in both androgen-dependent and independent cells but was significantly reduced in highly metastatic derivative clones. hSef expression was not influenced by androgenic stimulation. Forced downregulation of hSef by siRNA increased FGF8b induced cell migration (P=0.02) and invasion (P=0.007). Reduced hSef levels also enhanced FGF8b stimulated expression of MMP9 (P=0.005). mRNA in situ hybridization revealed hSef expression in 80% (8/10) of benign biopsies but in only 69% (23/33) of Gleason sum 4-7 and 35% (10/28) of Gleason sum 8-10 cancer biopsies (P=0.004). Quantitative PCR of microdissected glands confirmed this trend (P=0.001). hSef was expressed in 69% (27/39) of non-metastatic tumours but in only 18% (2/11) of metastatic tumours (P=0.004, n=50). hSef expression was next correlated with earlier data on FGF8b expression in a subgroup of cancers. In this cohort, 86% (19/22) of high-grade cancers expressed FGF8 but only 31% (7/22) expressed hSef. Positive FGF8 expression but a loss of hSef was observed in 88% (7/8) of metastatic tumours. In contrast, metastasis was evident in only 10% (1/10) of tumours, which co-expressed both FGF8 and hSef (P<0.001). These results suggest evidence that hSef is downregulated in advanced prostate cancer and might facilitate an enhanced tumorigenic response to FGFs. Further research into the role of hSef in cancer cell signalling and the mechanism of its downregulation may contribute to more effective targeting of growth factors in prostate cancer.Keywords
This publication has 22 references indexed in Scilit:
- Synergistic activity of Sef and Sprouty proteins in regulating the expression ofGbx2 in the mid-hindbrain regiongenesis, 2005
- The role of fibroblast growth factors and their receptors in prostate cancerEndocrine-Related Cancer, 2004
- Sef Interacts with TAK1 and Mediates JNK Activation and ApoptosisPublished by Elsevier BV ,2004
- Cancer Statistics, 2004CA: A Cancer Journal for Clinicians, 2004
- A Novel Interleukin-17 Receptor-like Protein Identified in Human Umbilical Vein Endothelial Cells Antagonizes Basic Fibroblast Growth Factor-induced SignalingJournal of Biological Chemistry, 2003
- Sef Inhibits Fibroblast Growth Factor Signaling by Inhibiting FGFR1 Tyrosine Phosphorylation and Subsequent ERK ActivationJournal of Biological Chemistry, 2003
- Regulation of FGF8 expression by the androgen receptor in human prostate cancerOncogene, 2002
- Identification of Sef, a novel modulator of FGF signallingNature, 2002
- FGF-8b increases angiogenic capacity and tumor growth of androgen-regulated S115 breast cancer cellsOncogene, 2001
- Downregulation of human FGF8 activity by antisense constructs in murine fibroblastic and human prostatic carcinoma cell systemsOncogene, 1998