Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes.
Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes.
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DOI：
10.1158/0008-5472.can-08-2614
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Mukhopadhyay D
中科院分区：
文献类型：
--
作者：
Cao Y;Wang L;Nandy D;Zhang Y;Basu A;Radisky D;Mukhopadhyay D
神经纤毛蛋白-1（NRP-1）的表达已被证明在许多癌细胞中，但其在肿瘤发生中的分子作用在很大程度上是未知的。在这份报告中，我们表明，在侵袭性类型的肾细胞癌（RCC），NRP-1是在一个高水平表达。我们发现，通过短发夹RNA敲低NRP-1后，RCC细胞表达的MDM-2和p63蛋白水平显著降低，但p53水平升高，并表现出迁移和侵袭能力降低。当植入小鼠体内时，NRP-1水平降低的RCC细胞与对照细胞相比具有统计学显著更小的肿瘤形成能力。此外，NRP-1敲低RCC细胞表现出更分化的表型，如通过上皮特异性和肾特异性钙粘蛋白的表达所证明的，并且音刺猬表达的抑制参与了这种效果。Sonic hedgehog表达的抑制可以通过Δ Np 63 α过表达逆转。我们的研究表明，NRP-1有助于维持癌细胞中的未分化表型。
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 ΔNp63α overexpression. Our study reveals that NRP-1 helps maintain an undifferentiated phenotype in cancer cells.