Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-04-2013 | Original Paper

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

Authors: Berrin Tunca, Gulcin Tezcan, Gulsah Cecener, Unal Egeli, Abdullah Zorluoglu, Tuncay Yilmazlar, Secil Ak, Omer Yerci, Ersin Ozturk, Gorkem Umut, Turkkan Evrensel

Published in: Journal of Cancer Research and Clinical Oncology | Issue 4/2013

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.

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):812–816PubMedCrossRef

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):277–279

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):589–593PubMed

Atkin WS, Cuzick J, Northover JM, Whynes DK (1993) Prevention of CRC by once-only sigmoidoscopy. Lancet 341(8847):736–740PubMedCrossRef

Beckman EN, Gathright JB, Ray JE (1984) A potentially brighter prognosis for colon carcinoma in the third and fourth decades. Cancer 54(7):1478–1481PubMedCrossRef

Boardman LA (2009) Overexpression of MACC1 leads to downstream activation of HGF/MET and potentiates metastasis and recurrence of CRC. Genome Med 1(4):36PubMedCrossRef

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):434–438PubMedCrossRef

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):431–440PubMedCrossRef

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):400–408PubMedCrossRef

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):904–910PubMedCrossRef

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):1255–1259PubMedCrossRef

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):23748–23757PubMedCrossRef

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):1071–1083PubMedCrossRef

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):254–260PubMedCrossRef

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):1085–1094PubMedCrossRef

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):4519–4525PubMed

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):1485–1489PubMedCrossRef

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):115–124PubMedCrossRef

Harnden P, Mahmood N, Southgate J (1999) Expression of cytokeratin 20 redefines urothelial papillomas of the bladder. Lancet 353(9157):974–977PubMedCrossRef

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):1271–1279PubMedCrossRef

Isbister W (1992) CRC below age 40 in the Kingdom of Saudi Arabia. Aust NZ J Surg 62(6):468–472CrossRef

Isbister WH, Fraser J (1990) Large bowel cancer in the young: a national survey study. Dis Colon Rectum 33(5):363–366PubMedCrossRef

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):5888–5896PubMedCrossRef

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):e16205PubMedCrossRef

Johannessen CM, Boehm JS, Kim SY et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468(7326):968–972PubMedCrossRef

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):e30168PubMedCrossRef

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):3934–3940PubMed

Khanna N, Jayaram HN, Singh N (2004) Benzamide riboside induced mitochondrial mediated apoptosis in human lung cancer H520 cells. Life Sci 75(2):179–190PubMedCrossRef

Knight RD, Mangum J, Lucas DL, Cooney DA, Khan EC, Wright DG (1987) Inosine monophosphate dehydrogenase and myeloid cell maturation. Blood 69(2):634–639PubMed

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):21–25PubMedCrossRef

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):87–94PubMedCrossRef

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):205–214PubMedCrossRef

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):402–408PubMedCrossRef

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):427–447PubMed

Murphy WM (1990) Current status of urinary cytology in the evaluation of bladder neoplasms. Hum Pathol 21(9):886–889PubMedCrossRef

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):1193–1200PubMedCrossRef

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):160–168PubMedCrossRef

Park MH, Wolff EC, Folk JE (1993) Is hypusine essential for eukaryotic cell proliferation? Trends Biochem Sci 18(12):475–479PubMedCrossRef

Park MH, Lee YB, Joe YA (1997) Hypusine is essential for eukaryotic cell proliferation. Biol Signals 6(3):115–123PubMedCrossRef

Parramore JB, Wei JP, Yeh KA (1998) CRC in patients under forty: presentation and outcome. Am Surg 64(6):563–568PubMed

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):696–710PubMedCrossRef

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):2331–2335PubMed

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):79–86PubMedCrossRef

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):39–44CrossRef

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):119–126CrossRef

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):26–30PubMedCrossRef

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):1741–1746PubMedCrossRef

Turkish Ministry of Health, (1999) http://www.saglik.gov.tr

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):2840–2847PubMed

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):80–86PubMedCrossRef

Yalowitz JA, Jayaram HN (2000) Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis. Anticancer Res 20(4):2329–2338PubMed

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):314–318PubMedCrossRef

Yilmazlar T, Zorluoglu A, Ozguc H, Korun N, Duman H, Kaya E, Kızıl A (1995) CRCs in young adults. Tumori 81(4):230–233PubMed

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 36:75–84PubMedCrossRef

Zorluoglu A, Yilmazlar T, Ozguc H, Bagcivan E, Guner O (2004) CRCs under 45 years of age. Hepatogastroenterology 51(55):118–120PubMed

Title: Overexpression of CK20, MAP3K8 and EIF5A correlates with poor prognosis in early-onset colorectal cancer patients
Authors: Berrin Tunca
Gulcin Tezcan
Gulsah Cecener
Unal Egeli
Abdullah Zorluoglu
Tuncay Yilmazlar
Secil Ak
Omer Yerci
Ersin Ozturk
Gorkem Umut
Turkkan Evrensel
Publication date: 01-04-2013
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 4/2013
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-013-1372-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2013

CNS metastases of breast cancer show discordant immunohistochemical phenotype compared to primary

Survival of infiltrative hepatocellular carcinoma patients with preserved hepatic function after treatment with transarterial chemoembolization

Cilengitide affects tumor compartment, vascularization and microenvironment in experimental bone metastases as shown by longitudinal 18F-FDG PET and gene expression analysis

A randomized controlled study of single-agent cisplatin and radiotherapy versus docetaxel/cisplatin and radiotherapy in high-risk early-stage cervical cancer after radical surgery

Predictors of early distant metastasis in women with breast cancer

Invasive breast cancer: a significant correlation between histological types and molecular subgroups

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page