Overexpression of CK20, MAP3K8 and EIF5A correlates with poor prognosis in early-onset colorectal cancer patients

  • Berrin Tunca
  • Gulcin Tezcan
  • Gulsah Cecener
  • Unal Egeli
  • Abdullah Zorluoglu
  • Tuncay Yilmazlar
  • Secil Ak
  • Omer Yerci
  • Ersin Ozturk
  • Gorkem Umut
  • Turkkan Evrensel
Original Paper



Due to ethnic, genetic and environmental factors, the clinical and molecular characteristics of Turkish colorectal cancer (CRC) patients are different from those of Western populations. The aim of this study was to clarify the relevant alterations of gene expression associated with colorectal carcinogenesis in early-onset patients and to identify specific biomarkers that could provide novel therapeutic molecular targets in this population.


The expression profiles of 114 different genes were evaluated using mRNA PCR arrays in 39 tumors and 20 surgical margin tissue samples from 39 sporadic CRC patients diagnosed at less than 50 years of age.


The expression levels of IMPDH2, CK20, MAP3K8 and EIF5A were strongly up-regulated in CRC tissues compared with normal colorectal tissues (p < 0.05). The highly significant expression ratios of CK20, MAP3K8 and EIF5A observed in the colorectal tumors of patients predicted recurrence (p < 0.05). The expression of IMPDH2, CK20, MAP3K8 and EIF5A was significantly higher in the tumors of patients with short median survival (log-rank p value < 0.05). Progression-free survival was also significantly increased in patients with low expression of the EIF5A gene compared with those who exhibited high expression of this gene (log-rank p value < 0.05).


We demonstrated that high CK20, MAP3K8 and EIF5A expression levels were significant prognostic factors for poor overall survival in CRC patients. Further studies and validations are required; these genes may provide novel therapeutic molecular targets for CRC treatment, as well as new directions for the development of anticancer drugs.


Colorectal cancer CK20 MAP3K8 EIF5A Poor prognosis Turkish population 



Colorectal cancer


Formalin-fixed paraffin-embedded


Threshold cycle



This work was supported by the Science Foundation of Uludag University (Project number; T (U)-2009/6).

Conflict of interest



  1. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR (1993) Clues to the pathogenesis of familial CRC. Science 260(5109):812–816PubMedCrossRefGoogle Scholar
  2. Ajao OG, Adenuga MO, Lapido JK (1988) Colorectal carcinoma in patients under the age of 30 years; a review of 11 cases. JR Coll Surg Edinb 33(5):277–279Google Scholar
  3. Aparecida Alves C, Silva ID, Villanova FE, Nicolau SM, Custódio MA, Bortoletto C, Gonçalves WJ (2006) Differential gene expression profile reveals overexpression of MAP3K8 in invasive endometrioid carcinoma. Eur J Gynaecol Oncol 27(6):589–593PubMedGoogle Scholar
  4. Atkin WS, Cuzick J, Northover JM, Whynes DK (1993) Prevention of CRC by once-only sigmoidoscopy. Lancet 341(8847):736–740PubMedCrossRefGoogle Scholar
  5. Beckman EN, Gathright JB, Ray JE (1984) A potentially brighter prognosis for colon carcinoma in the third and fourth decades. Cancer 54(7):1478–1481PubMedCrossRefGoogle Scholar
  6. Boardman LA (2009) Overexpression of MACC1 leads to downstream activation of HGF/MET and potentiates metastasis and recurrence of CRC. Genome Med 1(4):36PubMedCrossRefGoogle Scholar
  7. Brouwer C, Vermunt-de Koning DG, Trueworthy RC, Ter Riet PG, Duley JA, Trijbels FJ, Hoogerbrugge PM, Bokkerink JP, van Wering ER, De Abreu RA (2006) Monitoring of inosine monophosphate dehydrogenase activity in mononuclear cells of children with acute lymphoblastic leukemia: enzymological and clinical aspects. Pediatr Blood Cancer 46(4):434–438PubMedCrossRefGoogle Scholar
  8. Chen YJ, Yeh SH, Chen JT, Wu CC, Hsu MT, Tsai SF, Chen PJ, Lin CH (2000) Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology 119(2):431–440PubMedCrossRefGoogle Scholar
  9. Chen W, Luo JH, Hua WF, Zhou FJ, Lin MC, Kung HF, Zeng YX, Guan XY, Xie D (2009) Overexpression of EIF-5A2 is an independent predictor of outcome in patients of urothelial carcinoma of the bladder treated with radical cystectomy. Cancer Epidemiol Biomarkers Prev 18(2):400–408PubMedCrossRefGoogle Scholar
  10. Chiang JM, Chen MC, Changchien CR, Chen JS, Tang R, Wang JY, Yeh CY, Fan CW, Tsai WS (2003) Favorable influence of age on tumor characteristics of sporadic colorectal adenocarcinoma: patients 30 years of age younger may be a distinct patient group. Dis Colon Rectum 46(7):904–910PubMedCrossRefGoogle Scholar
  11. Chung YF, Eu KW, Machin D, Ho JM, Nyam DC, Leong AF, Ho YH, Seaw-Choen F (1998) Young age is not a poor prognostic marker in CRC. Br J Surg 85(9):1255–1259PubMedCrossRefGoogle Scholar
  12. Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, Tsichlis PN (2005) Tpl2/cot signals activate ERK, JNK, and NF-kappaB in a cell-type and stimulus-specific manner. J Biol Chem 280(25):23748–23757PubMedCrossRefGoogle Scholar
  13. Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN (2000) TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103(7):1071–1083PubMedCrossRefGoogle Scholar
  14. Fang Y, Guan X, Guo Y, Sham J, Deng M, Liang Q, Li H, Zhang H, Zhou H, Trent J (2001) Analysis of genetic alterations in primary nasopharyngeal carcinoma by comparative genomic hybridization. Genes Chromosomes Cancer 30(3):254–260PubMedCrossRefGoogle Scholar
  15. Fellenberg J, Bernd L, Delling G, Witte D, Zahlten-Hinguranage A (2007) Prognostic significance of drug-regulated genes in high-grade osteosarcoma. Mod Pathol 20(10):1085–1094PubMedCrossRefGoogle Scholar
  16. Forozan F, Mahlamäki EH, Monni O, Chen Y, Veldman R, Jiang Y, Gooden GC, Ethier SP, Kallioniemi A, Kallioniemi OP (2000) Comparative genomic hybridization analysis of 38 breast cancer cell lines: a basis for interpreting complementary DNA microarray data. Cancer Res 60(16):4519–4525PubMedGoogle Scholar
  17. Hall NR, Finan PJ, Ward B, Turner G, Bishop DT (1994) Genetic susceptibility to CRC in patients under 45 years of age. Br J Surg 81(10):1485–1489PubMedCrossRefGoogle Scholar
  18. Hanauske Abel HM, Park MH, Hanauske AR, Popowicz AM, Lalande M, Folk JE (1994) Inhibition of the G1-S transition of the cell cycle by inhibitors of deoxyhypusine hydroxylation. Biochim Biophys Acta 1221(2):115–124PubMedCrossRefGoogle Scholar
  19. Harnden P, Mahmood N, Southgate J (1999) Expression of cytokeratin 20 redefines urothelial papillomas of the bladder. Lancet 353(9157):974–977PubMedCrossRefGoogle Scholar
  20. He Y, Mou Z, Li W, Liu B, Fu T, Zhao S, Xiang D, Wu Y (2009) Identification of IMPDH2 as a tumor-associated antigen in CRC using immunoproteomics analysis. Int J Colorectal Dis 24(11):1271–1279PubMedCrossRefGoogle Scholar
  21. Isbister W (1992) CRC below age 40 in the Kingdom of Saudi Arabia. Aust NZ J Surg 62(6):468–472CrossRefGoogle Scholar
  22. Isbister WH, Fraser J (1990) Large bowel cancer in the young: a national survey study. Dis Colon Rectum 33(5):363–366PubMedCrossRefGoogle Scholar
  23. Ishitsuka K, Hideshima T, Hamasaki M, Raje N, Kumar S, Podar K, Le Gouill S, Shiraishi N, Yasui H, Roccaro AM, Tai YZ, Chauhan D, Fram R, Tamura K, Jain J, Anderson KC (2005) Novel inosine monophosphate dehydrogenase inhibitor VX-944 induces apoptosis in multiple myeloma cells primarily via caspase-independent AIF/Endo G pathway. Oncogene 24(38):5888–5896PubMedCrossRefGoogle Scholar
  24. Jeong JH, Bhatia A, Toth Z, Oh S, Inn KS, Liao CP, Roy-Burman P, Melamed J, Coetzee GA, Jung JU (2011) TPL2/COT/MAP3K8 (TPL2) activation promotes androgen depletion-independent (ADI) prostate cancer growth. PLoS ONE 6(1):e16205PubMedCrossRefGoogle Scholar
  25. Johannessen CM, Boehm JS, Kim SY et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326):968–972PubMedCrossRefGoogle Scholar
  26. Jovov B, Araujo-Perez F, Sigel CS, Stratford JK, McCoy AN, Yeh JJ, Keku T (2012) Differential gene expression between African American and European American CRC patients. PLoS ONE 7(1):e30168PubMedCrossRefGoogle Scholar
  27. Kang HA, Hershey JW (1994) Effect of initiation factor eIF-5A depletion on protein synthesis and proliferation of Saccharomyces cerevisiae. J Biol Chem 269(6):3934–3940PubMedGoogle Scholar
  28. Khanna N, Jayaram HN, Singh N (2004) Benzamide riboside induced mitochondrial mediated apoptosis in human lung cancer H520 cells. Life Sci 75(2):179–190PubMedCrossRefGoogle Scholar
  29. Knight RD, Mangum J, Lucas DL, Cooney DA, Khan EC, Wright DG (1987) Inosine monophosphate dehydrogenase and myeloid cell maturation. Blood 69(2):634–639PubMedGoogle Scholar
  30. Krcova Z, Ehrmann J, Krejci V, Eliopoulos A, Kolar Z (2008) Tpl-2/Cot and COX-2 in breast cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 152(1):21–25PubMedCrossRefGoogle Scholar
  31. Lassmann S, Bauer M, Rosenberg R, Nekarda H, Soong R, Rüger R, Höfler H, Werner M (2004) Identification of occult tumor cells in node negative lymph nodes of colorectal cancer patients by cytokeratin 20 gene and protein expression. Int J Colorectal Dis 19(2):87–94PubMedCrossRefGoogle Scholar
  32. Liang JT, Huang KC, Cheng AL, Jeng YM, Wu MS, Wang SM (2003) Clinicopathological and molecular biological features of CRC in patients less than 40 years of age. Br J Surg 90(2):205–214PubMedCrossRefGoogle Scholar
  33. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-D D C (T))method. Methods 25(4):402–408PubMedCrossRefGoogle Scholar
  34. Moll R, Löwe A, Laufer J, Franke WW (1992) Cytokeratin 20 in human carcinomas: a new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 140(2):427–447PubMedGoogle Scholar
  35. Murphy WM (1990) Current status of urinary cytology in the evaluation of bladder neoplasms. Hum Pathol 21(9):886–889PubMedCrossRefGoogle Scholar
  36. Nosho K, Yamamoto H, Adachi Y, Erdo Y, Hinoda Y, Imai K (2005) Gene expression profiling of colorectal adenomas and early invasive carcinomas by cDNA array analysis. Br J Cancer 92(7):1193–1200PubMedCrossRefGoogle Scholar
  37. Pack SD, Karkera JD, Zhuang Z, Pak ED, Balan KV, Hwu P, Park WS, Pham T, Ault DO, Glaser M, Liotta L, Detera-Wadleigh SD, Wadleigh RG (1999) Molecular cytogenetic fingerprinting of esophageal squamous cell carcinoma by comparative genomic hybridization reveals a consistent pattern of chromosomal alterations. Genes Chromosomes Cancer 25(2):160–168PubMedCrossRefGoogle Scholar
  38. Park MH, Wolff EC, Folk JE (1993) Is hypusine essential for eukaryotic cell proliferation? Trends Biochem Sci 18(12):475–479PubMedCrossRefGoogle Scholar
  39. Park MH, Lee YB, Joe YA (1997) Hypusine is essential for eukaryotic cell proliferation. Biol Signals 6(3):115–123PubMedCrossRefGoogle Scholar
  40. Parramore JB, Wei JP, Yeh KA (1998) CRC in patients under forty: presentation and outcome. Am Surg 64(6):563–568PubMedGoogle Scholar
  41. Penuelas S, Noe V, Ciudad CJ (2005) Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells. FEBS J 272(3):696–710PubMedCrossRefGoogle Scholar
  42. Petersen I, Bujard M, Petersen S, Wolf G, Goeze A, Schwendel A, Langreck H, Gellert K, Reichel M, Just K, du Manoir S, Cremer T, Dietel M, Ried T (1997) Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res 57(12):2331–2335PubMedGoogle Scholar
  43. Sattler HP, Rohde V, Bonkhoff H, Zwergel T, Wullich B (1999) Comparative genomic hybridization reveals DNA copy number gains to frequently occur in human prostate cancer. Prostate 39(2):79–86PubMedCrossRefGoogle Scholar
  44. Sham JS, Tang TC, Fang Y, Sun L, Qin LX, Wu QL, Xie D, Guan XY (2003) Recurrent chromosome alterations in primary ovarian carcinoma in Chinese women. Cancer Genet Cytogenet 133(1):39–44CrossRefGoogle Scholar
  45. Shi XP, Yin KC, Ahern J, Davis LJ, Stern AM, Waxman L (1996) Effects of N1-guanyl–1,7-diaminoheptane, an inhibitor of deoxyhypusine synthase, on the growth of tumorigenic cell lines in culture. Biochim Biophys Act 1310(1):119–126CrossRefGoogle Scholar
  46. Soliman AS, Bondy ML, Levin B, Hamza MR, Ismail K, Ismail S, Hammam HM, El-Hattab OH, Kamal SM, Soliman AGA, Dorgham LA, McPherson S, Beasley P (1997) CRC in Egyptian patients under 40 years of age. Int J Cancer 71(1):26–30PubMedCrossRefGoogle Scholar
  47. Tatsumi N, Mukaisho K, Mitsufuji S, Tatsumi Y, Sugihara H, Okanoue T, Hattori T (2005) Expression of cytokeratins 7 and 20 in serrated adenoma and related diseases. Dig Dis Sci 50(9):1741–1746PubMedCrossRefGoogle Scholar
  48. Turkish Ministry of Health, (1999)
  49. Wildi S, Kleeff J, Maruyama H, Maurer CA, Friess H, Büchler MW, Lander AD, Korc M (1999) Characterization of cytokeratin 20 expression in pancreatic and CRC. Clin Cancer Res 5(10):2840–2847PubMedGoogle Scholar
  50. Xie D, Ma NF, Pan ZZ, Wu HX, Liu YD, Wu GQ, Kung HF, Guan XY (2008) Overexpression of EIF-5A2 is associated with metastasis of human colorectal carcinoma. Hum Pathol 39(1):80–86PubMedCrossRefGoogle Scholar
  51. Yalowitz JA, Jayaram HN (2000) Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis. Anticancer Res 20(4):2329–2338PubMedGoogle Scholar
  52. Yang GF, Xie D, Liu JH, Luo JH, Li LJ, Hua WF, Wu HM, Kung HF, Zeng YX, Guan XY (2009) Expression and amplification of eIF-5A2 in human epithelial ovarian tumors and overexpression of EIF-5A2 is a new independent predictor of outcome in patients with ovarian carcinoma. Gynecol Oncol 112(2):314–318PubMedCrossRefGoogle Scholar
  53. Yilmazlar T, Zorluoglu A, Ozguc H, Korun N, Duman H, Kaya E, Kızıl A (1995) CRCs in young adults. Tumori 81(4):230–233PubMedGoogle Scholar
  54. Zimmermann A, Gu JJ, Spychala J, Mitchell BS (1996) Inosine monophosphate dehydrogenase expression: transcriptional regulation of the type I and type II genes. Adv Enzyme Regul 36:75–84PubMedCrossRefGoogle Scholar
  55. Zorluoglu A, Yilmazlar T, Ozguc H, Bagcivan E, Guner O (2004) CRCs under 45 years of age. Hepatogastroenterology 51(55):118–120PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Berrin Tunca
    • 1
  • Gulcin Tezcan
    • 1
  • Gulsah Cecener
    • 1
  • Unal Egeli
    • 1
  • Abdullah Zorluoglu
    • 2
  • Tuncay Yilmazlar
    • 3
  • Secil Ak
    • 1
  • Omer Yerci
    • 4
  • Ersin Ozturk
    • 3
  • Gorkem Umut
    • 1
  • Turkkan Evrensel
    • 5
  1. 1.Department of Medical Biology, Medical FacultyUludag UniversityBursaTurkey
  2. 2.Department of General SurgeryAcıbadem HospitalBursaTurkey
  3. 3.Department of General Surgery, Medical FacultyUludag UniversityBursaTurkey
  4. 4.Department of Pathology, Medical FacultyUludag UniversityBursaTurkey
  5. 5.Department of Medical Oncology, Medical FacultyUludag UniversityBursaTurkey

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