Open Access

CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer

  • Authors:
    • Kazuki Toki
    • Hideki Enokida
    • Kazumori Kawakami
    • Takeshi Chiyomaru
    • Shuichi Tatarano
    • Hirofumi Yoshino
    • Yousuke Uchida
    • Kazuya Kawahara
    • Kenryu Nishiyama
    • Naohiko Seki
    • Masayuki Nakagawa
  • View Affiliations

  • Published online on: December 1, 2010     https://doi.org/10.3892/ijo_00000789
  • Pages: 1379-1388
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Abstract

We have previously reported a simple technique that combines microarray data from clinical bladder cancer (BC) specimens with those from a BC cell line (BOY) treated with a pharmacological demethylating agent [5-aza-2'-deoxycytidine (5-aza-dC)] to find candidate genes that have tumor suppressive functions. We focused on the cellular retinol-binding protein 1 (CRBP1) gene that was selected by using the microarray data. As CRBP1 regulates intracellular retinoic acid (vitamin A) homeostasis, which is involved in morphogenesis, and cellular proliferation and differentiation, the loss of CRBP1 could cause tumorigenesis in BC. We hypothesized that the inactivation of the CRBP1 gene through CpG methylation contributes to cell viability, including the migration and invasion activity of human BC cells. After the 5-aza-dC treatment, the mRNA and protein expression levels of CRBP1 markedly increased in all BOY and T24 BC cell lines. Combined bisulfite-restriction analysis and bisulfite DNA sequencing revealed that promoter CpG hypermethylation existed in 28 out of the 65 BCs (43%) and in none of the 16 normal bladder epithelia (NBEs). Conversely, CRBP1 mRNA expression in the BCs was significantly lower than that in the NBEs (0.63±0.11 vs. 4.92±0.80, p<0.0001). We found significant inhibition of cell growth (p<0.0001) and migration (p<0.0001) in the CRBP1 stable transfectants compared to the control cell line, in a cell proliferation and wound-healing assay, respectively. In conclusion, the aberrant CpG hypermethylation of the CRBP1 gene promoter could be involved in the development of BC. We demonstrate here for the first time that the CRBP1 gene could have a tumor suppressive function in BC.

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December 2010
Volume 37 Issue 6

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Toki K, Enokida H, Kawakami K, Chiyomaru T, Tatarano S, Yoshino H, Uchida Y, Kawahara K, Nishiyama K, Seki N, Seki N, et al: CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer. Int J Oncol 37: 1379-1388, 2010
APA
Toki, K., Enokida, H., Kawakami, K., Chiyomaru, T., Tatarano, S., Yoshino, H. ... Nakagawa, M. (2010). CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer. International Journal of Oncology, 37, 1379-1388. https://doi.org/10.3892/ijo_00000789
MLA
Toki, K., Enokida, H., Kawakami, K., Chiyomaru, T., Tatarano, S., Yoshino, H., Uchida, Y., Kawahara, K., Nishiyama, K., Seki, N., Nakagawa, M."CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer". International Journal of Oncology 37.6 (2010): 1379-1388.
Chicago
Toki, K., Enokida, H., Kawakami, K., Chiyomaru, T., Tatarano, S., Yoshino, H., Uchida, Y., Kawahara, K., Nishiyama, K., Seki, N., Nakagawa, M."CpG hypermethylation of cellular retinol-binding protein 1 contributes to cell proliferation and migration in bladder cancer". International Journal of Oncology 37, no. 6 (2010): 1379-1388. https://doi.org/10.3892/ijo_00000789