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Neuropilin-1 Upholds Dedifferentiation and Propagation Phenotypes of Renal Cell Carcinoma Cells by Activating Akt and Sonic Hedgehog Axes

¹ Department of Biochemistry and Molecular Biology, ² Division of Endocrinology and Metabolism, College of Medicine, Mayo Clinic, Rochester, Minnesota; and ³ Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Jacksonville, Florida

Requests for reprints: Debabrata Mukhopadhyay, Department of Biochemistry and Molecular Biology, Mayo Clinic, Guggenheim 1401A, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-538-3581; Fax: 507-284-1767; E-mail: mukhopadhyay.debabrata{at}mayo.edu.

Key Words: Renal cell carcinoma • Neuropilin-1 • p63 • Shh

Expression of neuropilin-1 (NRP-1) has been shown in many cancer cells, but its molecular effect on tumorigenesis is largely unknown. In this report, we show that in aggressive types of renal cell carcinoma (RCC), NRP-1 is expressed at a high level. We show that after knockdown of NRP-1 by short hairpin RNA, RCC cells express significantly lower levels of MDM-2 and p63 proteins but higher levels of p53, and exhibit reduced migration and invasion. When implanted in mice, RCC cells with a reduced NRP-1 level have a statistically significant smaller tumor-forming ability than control cells. Also, NRP-1 knockdown RCC cells exhibit a more differentiated phenotype, as evidenced by the expression of epithelial-specific and kidney-specific cadherins, and the inhibition of sonic hedgehog expression participated in this effect. Inhibition of sonic hedgehog expression can be reversed by Np63 overexpression. Our study reveals that NRP-1 helps maintain an undifferentiated phenotype in cancer cells. [Cancer Res 2008;68(21):8667–72]