Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma.
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.
Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Ritsuko
R
Nakamura
Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Takeru
T
Oyama
Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Ryosuke
R
Tajiri
Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Atsushi
A
Mizokami
Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Mikio
M
Namiki
Aberdeen Developmental Biology Group, School of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Masaru
M
Nakamoto
Department of Molecular and Cellular Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Akishi
A
Ooi
D000368:Aged; D001374:Azacitidine / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement; D018899:CpG Islands; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; C104145:NELL2 protein, human; D009419:Nerve Tissue Proteins; D001374:Azacitidine
Cell migration; NELL1; NELL2; methylation; renal cell carcinoma