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Neural epidermal growth factor‐like like ( NELL ) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of  NELL 1 and functions of  NELL 2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of  NELL 1 and  NELL 2 in renal cell carcinoma ( RCC ) using clinical specimens and cell lines. We show that, whereas  NELL 1 and  NELL 2 proteins are strongly expressed in renal tubules in non‐cancerous areas of  RCC  specimens, their expression is significantly downregulated in cancerous areas. Silencing of   NELL 1  and   NELL 2   mRNA  expression was also detected in  RCC  cell lines. Analysis of   NELL 1/2  promoter methylation status indicated that the CpG islands in the   NELL 1  and   NELL 2  genes are hypermethylated in  RCC  cell lines.  NELL 1 and  NELL 2 bind to  RCC  cells, suggesting that these cells express a receptor for  NELL 1 and  NELL 2 that can transduce signals. Furthermore, we found that both  NELL 1 and  NELL 2 inhibit  RCC  cell migration, and  NELL 1 further inhibits  RCC  cell adhesion. These results suggest that silencing of  NELL  gene expression by promoter hypermethylation plays roles in  RCC  progression by affecting cancer cell behavior.

Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma