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Digestive Diseases and Sciences

, Volume 60, Issue 6, pp 1663–1673 | Cite as

Oncogenic Role of BOLL in Colorectal Cancer

  • Ki Joo Kang
  • Jeung Hui Pyo
  • Kyung Ju Ryu
  • Sung Jin Kim
  • Jung Min Ha
  • Kyu Choi
  • Sung Noh Hong
  • Byung-Hoon Min
  • Dong Kyung Chang
  • Hee Jung Son
  • Poong-Lyul Rhee
  • Jae J. Kim
  • Young-Ho Kim
Original Article

Abstract

Background

Boule-like RNA-binding protein (BOLL protein) is the progenitor of the Deleted in Azoospermia (DAZ) gene family. To date, previous studies have focused on the reproductive function of BOLL. While we were identifying new DNA methylation biomarkers for colorectal cancer (CRC), we found that BOLL protein was overexpressed in CRC.

Aim

The aim of this study was to determine the role of BOLL in CRC by epigenetic and functional studies in vivo and in vitro.

Methods

BOLL promoter methylation and expression were determined by MethyLight, RT-PCR, Western blot, and immunohistochemistry. The functional role of BOLL in CRC was evaluated by cell proliferation, colony formation, migration and invasion, cell cycle status, and tumor growth in a xenograft model.

Results

BOLL promoter methylation was enhanced in CRC tissues compared with normal colorectal tissues [97/124 (78 %) vs. 2/124 (2 %)]. However, the mean immunoreactivity score of CRC tissues and paired adjacent normal tissues was 8.15 ± 0.18 (SD) and 3.35 ± 0.19 (SD), respectively (p < 0.01). No significant association was observed between immunoreactivity score and clinicopathological parameters, including age, gender, tumor size, tumor differentiation, and tumor node metastasis stage. Expression of BOLL in CRC cell lines significantly enhanced cell proliferation (p < 0.01), colony formation (p < 0.01), and migration (p < 0.01). In BOLL-expressing cells, the percentage of cells in S-phase of the cell cycle was significantly increased. Tumor volume in BOLL xenografted mice was significantly enhanced after subcutaneous implantation (p < 0.01).

Conclusions

Our study demonstrated an oncogenic role of BOLL in CRC despite tumor-specific promoter hypermethylation.

Keywords

BOLL Colorectal cancer Oncogene Hypermethylation 

Notes

Acknowledgments

This work was supported by a Samsung Biomedical Research Institute Grant (GL1-B2-091-1).

Conflict of interest

None.

References

  1. 1.
    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Stewart SL, Wike JM, Kato I, et al. A population-based study of colorectal cancer histology in the United States, 1998–2001. Cancer. 2006;107:1128–1141.CrossRefPubMedGoogle Scholar
  3. 3.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMedGoogle Scholar
  4. 4.
    Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer. 2004;101:3–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Xu EY, Moore FL, Pera RA. A gene family required for human germ cell development evolved from an ancient meiotic gene conserved in metazoans. Proc Natl Acad Sci USA. 2001;98:7414–7419.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Eberhart CG, Maines JZ, Wasserman SA. Meiotic cell cycle requirement for a fly homologue of human Deleted in Azoospermia. Nature. 1996;381:783–785.CrossRefPubMedGoogle Scholar
  7. 7.
    Karashima T, Sugimoto A, Yamamoto M. Caenorhabditis elegans homologue of the human azoospermia factor DAZ is required for oogenesis but not for spermatogenesis. Development. 2000;127:1069–1079.PubMedGoogle Scholar
  8. 8.
    Yen PH. Putative biological functions of the DAZ family. Int J Androl. 2004;27:125–129.CrossRefPubMedGoogle Scholar
  9. 9.
    Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–440.CrossRefPubMedGoogle Scholar
  10. 10.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27–36.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Kim YH, Lee HC, Kim SY, et al. Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations. Ann Surg Oncol. 2011;18:2338–2347.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Tessema M, Yu YY, Stidley CA, et al. Concomitant promoter methylation of multiple genes in lung adenocarcinomas from current, former and never smokers. Carcinogenesis. 2009;30:1132–1138.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Sinicrope FA, Ruan SB, Cleary KR, et al. bcl-2 and p53 oncoprotein expression during colorectal tumorigenesis. Cancer Res. 1995;55:237–241.PubMedGoogle Scholar
  15. 15.
    Luetjens CM, Xu EY, Rejo Pera RA, et al. Association of meiotic arrest with lack of BOULE protein expression in infertile men. J Clin Endocrinol Metab. 2004;89:1926–1933.CrossRefPubMedGoogle Scholar
  16. 16.
    Lin YM, Kuo PL, Lin YH, et al. Messenger RNA transcripts of the meiotic regulator BOULE in the testis of azoospermic men and their application in predicting the success of sperm retrieval. Hum Reprod. 2005;20:782–788.CrossRefPubMedGoogle Scholar
  17. 17.
    Kostova E, Yeung CH, Luetjens CM, et al. Association of three isoforms of the meiotic BOULE gene with spermatogenic failure in infertile men. Mol Hum Reprod. 2007;13:85–93.CrossRefPubMedGoogle Scholar
  18. 18.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–2054.CrossRefPubMedGoogle Scholar
  19. 19.
    Lin YM, Chung CL, Cheng YS. Posttranscriptional regulation of CDC25A by BOLL is a conserved fertility mechanism essential for human spermatogenesis. J Clin Endocrinol Metab. 2009;94:2650–2657.CrossRefPubMedGoogle Scholar
  20. 20.
    Tsui S, Dai T, Roettger S, et al. Identification of two novel proteins that interact with germ-cell-specific RNA-binding proteins DAZ and DAZL1. Genomics. 2000;65:266–273.CrossRefPubMedGoogle Scholar
  21. 21.
    Belinsky SA, Nikula KJ, Palmisano WA, et al. Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA. 1998;95:11891–11896.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ki Joo Kang
    • 1
  • Jeung Hui Pyo
    • 1
  • Kyung Ju Ryu
    • 2
  • Sung Jin Kim
    • 2
  • Jung Min Ha
    • 1
  • Kyu Choi
    • 1
  • Sung Noh Hong
    • 1
  • Byung-Hoon Min
    • 1
  • Dong Kyung Chang
    • 1
  • Hee Jung Son
    • 1
  • Poong-Lyul Rhee
    • 1
  • Jae J. Kim
    • 1
  • Young-Ho Kim
    • 1
  1. 1.Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  2. 2.Samsung Biomedical Research InstituteSamsung Medical CenterSeoulRepublic of Korea

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