Cao Ying, Wang Ling, Nandy Debashis, Zhang Ying, Basu Ananda, Radisky Derek, Mukhopadhyay Debabrata
Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Cancer Res. 2008 Nov 1;68(21):8667-72. doi: 10.1158/0008-5472.CAN-08-2614.
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.
在许多癌细胞中已发现神经纤毛蛋白-1（NRP-1）的表达，但其对肿瘤发生的分子作用在很大程度上尚不清楚。在本报告中，我们发现，在侵袭性肾细胞癌（RCC）中，NRP-1呈高水平表达。我们还发现，用短发夹RNA敲低NRP-1后，RCC细胞中MDM-2和p63蛋白的表达显著降低，但p53水平升高，并且迁移和侵袭能力减弱。当接种到小鼠体内时，NRP-1水平降低的RCC细胞形成肿瘤的能力在统计学上显著低于对照细胞。此外，NRP-1敲低的RCC细胞表现出更分化的表型，这可通过上皮特异性和肾特异性钙黏蛋白的表达得到证明，并且音猬因子表达的抑制参与了这一效应。DeltaNp63alpha的过表达可逆转音猬因子表达的抑制。我们的研究表明，NRP-1有助于维持癌细胞的未分化表型。
