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

Abstract

Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 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.

NELL-1 expression in tumors of cartilage

“…For example, NELL-1 has been found to be epigenetically silenced via methylation in several carcinomas, including colon adenocarcinoma, 26 esophageal adenocarcinoma, 27 as well as renal cell carcinoma. 28 Our study, in combination with our previous observations, 25 suggests that the opposite is true in skeletal sarcomas, including consistent NELL-1 overexpression in both osteosarcoma and chondrosarcoma. The bioactive effects of NELL-1 in skeletal sarcomas remain a matter of speculation; however, recent understanding of NELL-1 as an integrin b1 ligand may reveal new insights.…”

Nell‐1‐ΔE, a novel transcript of Nell‐1, inhibits cell migration by interacting with enolase‐1

“…Moreover, in another study focusing on the effect of Nell-1 on cell migration, researchers found that Nell-1 could inhibit migration in two cancer cell lines (OS-RC-2 and VMRC-RCW). 29 Furthermore, we observed that the subcellular locations of full-length Nell-1 and Nell-1-ΔE were similar ( Figure 3A). We also analyzed the protein expression patterns of full-length Nell-1 and Nell-1-ΔE and found that full-length Nell-1 and Nell-1-ΔE exhibited similar expression patterns at the protein level in both the cell lysates and extracellular space ( Figures 3B and 3C), which was consistent with our previous report.…”

Identification of key molecular targets that correlate with breast cancer through bioinformatic methods

“…NELL2 was first identified as a mammalian homolog of the chicken NEL protein, and was a novel target gene of E2F1 , which was a key regulator of cell proliferation . NELL1 and NELL2 were strongly expressed in renal tubules in non‐cancerous areas of renal cell carcinoma specimens . In addition, NELL2 was trans‐activated by E2 and contributed to mediating the survival promoting effects of E2 via the intracellular signaling pathway of ERK .…”

“…22 NELL1 and NELL2 were strongly expressed in renal tubules in non-cancerous areas of renal cell carcinoma specimens. 23 In addition, NELL2 was trans-activated by E2 and contributed to mediating the survival promoting effects of E2 via the intracellular signaling pathway of ERK. 24 AGTR1 played a critical role in several diseases and was considered as a therapeutic target in ER-positive and ERBB-negative breast cancer cases.…”