Oncogenic Functions of Secreted Frizzled-Related Protein 2 in Human Renal Cancer

Abstract

The secreted Frizzled-related proteins (sFRP) are modulators of the Wnt signaling pathway, which is involved in embryonic development and tumor progression. The functions of sFRP2 have not been studied in renal cancer. Transient transfection of sFRP2 promoted cell growth in renal carcinoma cells, whereby the largest effect was observed in A498 cells. To further study the functions of sFRP2 gene in renal carcinoma cells, we established A498 renal cancer cell lines, which stably expressed sFRP2. Stably expressed sFRP2 significantly promoted cell proliferation in vitro and in vivo tumor growth. The stably expressed sFRP2 cells were also found to have reduced UV-induced apoptosis and increased G 2 phase of the cell cycle. The phosphorylation level at Ser 33/37 /Thr 41 of β-catenin was lower in the stable sFRP2 cell lines compared with the control cell line.sFRP2 significantly activated T-cell factor/lymphoid enhancer factor transcriptional activity. In the stable sFRP2 cell line, expression of c-Fos, Bcl2, Bcl-w, cyclin B2, and cyclin E2 genes was significantly increased and p53 expression was decreased. This is the first report documenting that sFRP2 activates the canonical Wnt pathway and promotes cell growth by evoking diverse signaling cascades in renal cancer cells. This study may provide better strategies for the management of renal cancer through regulation of sFRP2 pathways. Mol Cancer Ther; 9(6); 1680-7. ©2010 AACR.

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

“…Sfrp proteins are required for Wnt diffusion, activation, canonical signaling, and proper tissue differentiation; their effects on Wnt signaling are dependent on their concentration or Wnt ligands present in tissue (23, 26, 42, 63a). For example, Sfrp-2 can enhance activation of the canonical Wnt pathway (17,64,66) while inhibiting the noncanonical pathway, resulting in abnormal cell alignment and shape (12). Sfrp-2 can inhibit BMP-4 expression and prevent programmed cell death (22).…”

The secreted Frizzled-Related Protein 2 modulates cell fate and the Wnt pathway in the murine intestinal epithelium

“…Indeed, we showed that in the intestinal progenitors in vitro, sFRP2 behaves as a positive regulator of the canonical Wnt pathway by stabilizing β-catenin through the Fzd receptors [13]. However, the effect of the sFRPs, especially that of sFRP2, on the canonical Wnt pathway remained controversial [13,15,30] and its role in intestinal homeostasis unknown. This is the first study showing that sFRP2 can activate the canonical Wnt pathway in the intestine in vivo, as demonstrated by using the TopGal reporter mice.…”

“…In light of our in vivo data and because sFRP2 can act as a modulator of the canonical Wnt pathway [15,17,[30][31][32], we felt compelled to investigate the action of sFRP2 in greater detail. Thus, we moved to an in vitro approach in the Cos7 and HCT116 cell lines using the TopFlash reporter vector.…”

Secreted frizzled related proteins: Implications in cancers

“…Functionally, knocking down SFRP1 increased apoptosis and decreased the invasive potential of the cells by decreasing matrix metalloproteinase (MMP) 10. Another molecule, SFRP2, was shown to possess oncogenic functions in renal cancer [113]. Stably expressed sFRP2 promoted in vitro cell proliferation and in vivo tumour growth.…”