Advertisement

Tumor Biology

, Volume 37, Issue 3, pp 3071–3080 | Cite as

The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma

  • Elmas Kasap
  • Emre Gerceker
  • Seda Örenay Boyacıoglu
  • Hakan Yuceyar
  • Hatice Yıldırm
  • Semin Ayhan
  • Mehmet Korkmaz
Original Article

Abstract

Colorectal adenomatous polyp (CRAP) is a major risk factor for the development of sporadic colorectal cancer (CRC). Histone modifications are one of the epigenetic mechanisms that may have key roles in the carcinogenesis of CRC. The objective of the present study is to investigate the alternations in the defined histone modification gene expression profiles in patients with CRAP and CRC. Histone modification enzyme key gene expressions of the CRC, CRAP, and control groups were evaluated and compared using the reverse transcription PCR (RT-PCR) array method. Gene expression analysis was performed in the CRAP group after dividing the patients into subgroups according to the polyp diameter, pathological results, and morphological parameters which are risk factors for developing CRC in patients with CRAP. PAK1, NEK6, AURKA, AURKB, HDAC1, and HDAC7 were significantly more overexpressed in CRC subjects compared to the controls (p < 0.05). PAK1, NEK6, AURKA, AURKB, and HDAC1 were significantly more overexpressed in the CRAP group compared to the controls (p < 0.005). There were no significant differences between the CRAP and CRC groups with regards to PAK1, NEK6, AURKA, or AURKB gene overexpression. PAK1, NEK6, AURKA, and AURKB were significantly in correlation with the polyp diameter as they were more overexpressed in polyps with larger diameters. In conclusion, overexpressions of NEK6, AURKA, AURKB, and PAK1 genes can be used as predictive markers to decide the colonoscopic surveillance intervals after the polypectomy procedure especially in polyps with larger diameters.

Keywords

Colorectal adenocarcinoma Colorectal adenomatous polyp AURKA AURKB NEK6 PAK1 Epigenetic Histone modification 

Notes

Acknowledgments

This study was supported by the Celal Bayar University Coordinator of the Scientific Research Projects (2013-10) Manisa, Turkey.

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Shussman N, Wexner SD. Colorectal polyps and polyposis syndromes. Gastroenterol Rep (Oxf). 2014;2:1–15.CrossRefGoogle Scholar
  3. 3.
    Leslie A, Carey FA, Pratt NR, Steele RJ. The colorectal adenoma-carcinoma sequence. Br J Surg. 2002;89:845–60.CrossRefPubMedGoogle Scholar
  4. 4.
    Imperiale TF, Juluri R, Sherer EA, Glowinski EA, Johnson CS, Morelli MS. A risk index for advanced neoplasia on the second surveillance colonoscopy in patients with previous adenomatous polyps. Gastrointest Endosc 2014.Google Scholar
  5. 5.
    Jawad N, Direkze N, Leedham SJ. Inflammatory bowel disease and colon cancer. Recent Results Cancer Res. 2011;185:99–115.CrossRefPubMedGoogle Scholar
  6. 6.
    Kulaylat MN, Dayton MT. Ulcerative colitis and cancer. J Surg Oncol. 2010;101:706–12.CrossRefPubMedGoogle Scholar
  7. 7.
    Migheli F, Migliore L. Epigenetics of colorectal cancer. Clin Genet. 2012;81:312–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Stypula-Cyrus Y, Damania D, Kunte DP, Cruz MD, Subramanian H, Roy HK, et al. HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. PLoS ONE. 2013;8, e64600.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Higashijima J, Kurita N, Miyatani T, Yoshikawa K, Morimoto S, Nishioka M, et al. Expression of histone deacetylase 1 and metastasis-associated protein 1 as prognostic factors in colon cancer. Oncol Rep. 2011;26:343–8.PubMedGoogle Scholar
  10. 10.
    Wilson AJ, Byun DS, Popova N, Murray LB, L’Italien K, Sowa Y, et al. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J Biol Chem. 2006;281:13548–58.CrossRefPubMedGoogle Scholar
  11. 11.
    Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: what are the cancer relevant targets? Cancer Lett. 2009;277:8–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Belt EJ, Brosens RP, Delis-van Diemen PM, Bril H, Tijssen M, van Essen DF, et al. Cell cycle proteins predict recurrence in stage II and III colon cancer. Ann Surg Oncol. 2012;19 Suppl 3:S682–692.CrossRefPubMedGoogle Scholar
  13. 13.
    Glauben R, Sonnenberg E, Zeitz M, Siegmund B. HDAC inhibitors in models of inflammation-related tumorigenesis. Cancer Lett. 2009;280:154–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Khare V, Lyakhovich A, Dammann K, Lang M, Borgmann M, Tichy B, et al. Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Biochem Pharmacol. 2013;85:234–44.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    He H, Huynh N, Liu KH, Malcontenti-Wilson C, Zhu J, Christophi C, et al. P-21 activated kinase 1 knockdown inhibits beta-catenin signalling and blocks colorectal cancer growth. Cancer Lett. 2012;317:65–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Nassirpour R, Shao L, Flanagan P, Abrams T, Jallal B, Smeal T, et al. Nek6 mediates human cancer cell transformation and is a potential cancer therapeutic target. Mol Cancer Res. 2010;8:717–28.CrossRefPubMedGoogle Scholar
  17. 17.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7:21–33.CrossRefPubMedGoogle Scholar
  18. 18.
    Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011;8:686–700.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yi JM, Dhir M, Guzzetta AA, Iacobuzio-Donahue CA, Heo K, Yang KM, et al. DNA methylation biomarker candidates for early detection of colon cancer. Tumour Biol. 2012;33:363–72.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5:37–50.CrossRefPubMedGoogle Scholar
  21. 21.
    He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, et al. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45–51.CrossRefPubMedGoogle Scholar
  23. 23.
    Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Marumoto T, Zhang D, Saya H. Aurora-A—a guardian of poles. Nat Rev Cancer. 2005;5:42–50.CrossRefPubMedGoogle Scholar
  25. 25.
    Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998;17:3052–65.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Carvalho B, Postma C, Mongera S, Hopmans E, Diskin S, van de Wiel MA, et al. Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression. Gut. 2009;58:79–89.CrossRefPubMedGoogle Scholar
  27. 27.
    Jee HJ, Kim AJ, Song N, Kim HJ, Kim M, Koh H, et al. Nek6 overexpression antagonizes p53-induced senescence in human cancer cells. Cell Cycle. 2010;9:4703–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Belham C, Roig J, Caldwell JA, Aoyama Y, Kemp BE, Comb M, et al. A mitotic cascade of NIMA family kinases. Nercc1/Nek9 activates the Nek6 and Nek7 kinases. J Biol Chem. 2003;278:34897–909.CrossRefPubMedGoogle Scholar
  29. 29.
    O’Regan L, Fry AM. The Nek6 and Nek7 protein kinases are required for robust mitotic spindle formation and cytokinesis. Mol Cell Biol. 2009;29:3975–90.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cao X, Xia Y, Yang J, Jiang J, Chen L, Ni R, et al. Clinical and biological significance of never in mitosis gene A-related kinase 6 (NEK6) expression in hepatic cell cancer. Pathol Oncol Res. 2012;18:201–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Kasap E, Boyacioglu SO, Korkmaz M, Yuksel ES, Unsal B, Kahraman E, et al. Aurora kinase A (AURKA) and never in mitosis gene A-related kinase 6 (NEK6) genes are upregulated in erosive esophagitis and esophageal adenocarcinoma. Exp Ther Med. 2012;4:33–42.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Rugge M, Fassan M, Zaninotto G, Pizzi M, Giacomelli L, Battaglia G, et al. Aurora kinase A in Barrett’s carcinogenesis. Hum Pathol. 2010;41:1380–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Katsha A, Soutto M, Sehdev V, Peng D, Washington MK, Piazuelo MB, et al. Aurora kinase A promotes inflammation and tumorigenesis in mice and human gastric neoplasia. Gastroenterology. 2013;145:1312–22. e1311-1318.CrossRefPubMedGoogle Scholar
  34. 34.
    Mariadason JM. HDACs and HDAC inhibitors in colon cancer. Epigenetics. 2008;3:28–37.CrossRefPubMedGoogle Scholar
  35. 35.
    Winawer SJ, Zauber AG, Gerdes H, O’Brien MJ, Gottlieb LS, Sternberg SS, et al. Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med. 1996;334:82–7.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Elmas Kasap
    • 1
  • Emre Gerceker
    • 1
  • Seda Örenay Boyacıoglu
    • 2
  • Hakan Yuceyar
    • 1
  • Hatice Yıldırm
    • 2
  • Semin Ayhan
    • 3
  • Mehmet Korkmaz
    • 2
  1. 1.Department of Gastroenterology, Medical FacultyCelal Bayar UniversityManisaTurkey
  2. 2.Department of Medical Genetics and Medical Biology, Medical FacultyCelal Bayar UniversityManisaTurkey
  3. 3.Department of Pathology, Medical FacultyCelal Bayar UniversityManisaTurkey

Personalised recommendations