Cellular prion protein accelerates colorectal cancer metastasis via the Fyn-SP1-SATB1 axis

Wang,Qianwei; Qian,Jianming; Wang,Fangrui; Ma,Zhenyu

doi:10.3892/or.2012.2025

Cellular prion protein accelerates colorectal cancer metastasis via the Fyn-SP1-SATB1 axis

Authors:
- Qianwei Wang
- Jianming Qian
- Fangrui Wang
- Zhenyu Ma
View Affiliations

Affiliations: Department of Surgery, Huashan Hospital, Fudan University, Shanghai 200032, P.R. China
Published online on: September 12, 2012 https://doi.org/10.3892/or.2012.2025
Pages: 2029-2034

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The cellular prion protein (PrPc) is a glycoprotein anchored by glycosylphosphatidylinositol to the cell surface and is abundantly expressed in various tissues. The putative roles of PrPc are thought to be related to cell signaling, survival, and differentiation and cancer progression. In this study, we demonstrated that the expression of PrPc correlates with a more aggressive and histologically unfavorable disease in colorectal carcinomas. Moreover, we found that PrPc mediates the process of epithelial-mesenchymal transition and, thereby, promotes CRC metastasis. Transcriptome profiling of PrPc-depleted cells revealed downregulation of the special AT-rich sequence-binding protein-1 (SATB1). PrPc is demonstrated to be involved in regulating SATB1 expression via the Fyn-SP1 pathway. Since SATB1 has been previously proposed as a key protein that controls tumor development and progression, knockdown of PrPc resulted in a reduced metastatic capacity in CRC cells, as well as a reduction in distant metastases in vivo. In conclusion, our data characterize a novel molecular mechanism that links PrPc expression to the regulation of CRC metastasis. Targeting PrPc will, therefore, be a promising strategy to overcome the metastatic advantage in colorectal tumors.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics. CA Cancer J Clin. 58:71–96. 2008.
2	Boyle P and Ferlay J: Cancer incidence and mortality in Europe, 2004. Ann Oncol. 16:481–488. 2005. View Article : Google Scholar : PubMed/NCBI
3	Bardelli A, Parsons DW, Silliman N, et al: Mutational analysis of the tyrosine kinome in colorectal cancers. Science. 300:949–950. 2003. View Article : Google Scholar : PubMed/NCBI
4	Stahl N, Borchelt DR, Hsiao K and Prusiner SB: Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell. 51:229–249. 1987. View Article : Google Scholar : PubMed/NCBI
5	Brown DR, Qin K, Herms JW, et al: The cellular prion protein binds copper in vivo. Nature. 390:684–687. 1997. View Article : Google Scholar : PubMed/NCBI
6	Brown DR, Nicholas RS and Canevari L: Lack of prion protein expression results in a neuronal phenotype sensitive to stress. J Neurosci Res. 67:211–224. 2002. View Article : Google Scholar : PubMed/NCBI
7	Chen S, Mangé A, Dong L, Lehmann S and Schachner M: Prion protein as trans-interacting partner for neurons is involved in neurite outgrowth and neuronal survival. Mol Cell Neurosci. 22:227–233. 2003. View Article : Google Scholar : PubMed/NCBI
8	Kikuchi Y, Kakeya T, Yamazaki T, et al: G1-dependent prion protein expression in human glioblastoma cell line T98G. Biol Pharm Bull. 25:728–733. 2002. View Article : Google Scholar : PubMed/NCBI
9	Meslin F, Conforti R, Mazouni C, et al: Efficacy of adjuvant chemotherapy according to Prion protein expression in patients with estrogen receptor-negative breast cancer. Ann Oncol. 18:1793–1798. 2007. View Article : Google Scholar : PubMed/NCBI
10	Ochel HJ, Gademann G, Trepel J and Neckers L: Modulation of prion protein structural integrity by geldanamycin. Glycobiology. 13:655–660. 2003. View Article : Google Scholar : PubMed/NCBI
11	Pan Y, Zhao L, Liang J, et al: Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J. 20:1886–1888. 2006. View Article : Google Scholar : PubMed/NCBI
12	Zhuang D, Liu Y, Mao Y, et al: TMZ-induced PrPc/par-4 interaction promotes the survival of human glioma cells. Int J Cancer. 130:309–318. 2012. View Article : Google Scholar : PubMed/NCBI
13	Liang J, Pan Y, Zhang D, et al: Cellular prion protein promotes proliferation and G1/S transition of human gastric cancer cells SGC7901 and AGS. FASEB J. 21:2247–2256. 2007. View Article : Google Scholar : PubMed/NCBI
14	Li QQ, Chen ZQ, Cao XX, et al: Involvement of NF-κB/miR-448 regulatory feedback loop in chemotherapy-induced epithelial-mesenchymal transition of breast cancer cells. Cell Death Differ. 18:16–25. 2011.
15	Boussiotis VA, Barber DL, Lee BJ, Gribben JG, Freeman GJ and Nadler LM: Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation. J Exp Med. 184:365–376. 1996. View Article : Google Scholar
16	Natalwala A, Spychal R and Tselepis C: Epithelial-mesenchymal transition mediated tumourigenesis in the gastrointestinal tract. World J Gastroenterol. 14:3792–3797. 2008. View Article : Google Scholar : PubMed/NCBI
17	Du J, Pan Y, Shi Y, et al: Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR. Int J Cancer. 113:213–220. 2005. View Article : Google Scholar : PubMed/NCBI
18	Han HJ, Russo J, Kohwi Y and Kohwi-Shigematsu T: SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 452:187–193. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kumar PP, Purbey PK, Sinha CK, Notani D, Limaye A, Jayani RS and Galande S: Phosphorylation of SATB1, a global gene regulator, acts as a molecular switch regulating its transcriptional activity in vivo. Mol Cell. 22:231–243. 2006. View Article : Google Scholar : PubMed/NCBI
20	Graner E, Mercadante AF, Zanata SM, et al: Cellular prion protein binds laminin and mediates neuritogenesis. Mol Brain Res. 76:85–92. 2000. View Article : Google Scholar : PubMed/NCBI
21	Graner E, Mercadante AF, Zanata SM, Martins VR, Jay DG and Brentani RR: Laminin-induced PC-12 cell differentiation is inhibited following laser inactivation of cellular prion protein. FEBS Lett. 482:257–260. 2000. View Article : Google Scholar : PubMed/NCBI
22	Hajj GN, Lopes MH, Mercadante AF, et al: Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins. J Cell Sci. 120:1915–1926. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zanata SM, Lopes MH, Mercadante AF, et al: Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J. 21:3307–3316. 2002. View Article : Google Scholar : PubMed/NCBI