Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes.
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 DeltaNp63alpha overexpression. Our study reveals that NRP-1 helps maintain an undifferentiated phenotype in cancer cells.
Cao
Ying
Y
Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Wang
Ling
L
Nandy
Debashis
D
Zhang
Ying
Y
Basu
Ananda
A
Radisky
Derek
D
Mukhopadhyay
Debabrata
D
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D039942:Neuropilin-1 / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017931:DNA Primers; D053823:Hedgehog Proteins; C509239:SHH protein, human; D039942:Neuropilin-1; D051057:Proto-Oncogene Proteins c-akt