Reduced hTERT protein levels are associated with DNA aneuploidy in the colonic mucosa of patients suffering from longstanding ulcerative colitis

Friis-Ottessen,Mariann; De Angelis,Paula M.; Schjølberg,Aasa R.; Andersen,Solveig N.; Clausen,Ole Petter F.

doi:10.3892/ijmm.2014.1708

Reduced hTERT protein levels are associated with DNA aneuploidy in the colonic mucosa of patients suffering from longstanding ulcerative colitis

Authors:
- Mariann Friis-Ottessen
- Paula M. De Angelis
- Aasa R. Schjølberg
- Solveig N. Andersen
- Ole Petter F. Clausen
View Affiliations

Affiliations: Division of Diagnostics and Intervention, Department of Pathology, Oslo University Hospital, Rikshospitalet, 0424 Oslo, Norway, Department of Pathology, University of Oslo, 0424 Oslo, Norway, Department of Pathology, Akershus University Hospital, Division of Medicine and Laboratory Sciences, University of Oslo, 1474 Nordbyhagen, Norway
Published online on: March 20, 2014 https://doi.org/10.3892/ijmm.2014.1708
Pages: 1477-1483
Copyright: © Friis-Ottessen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Longstanding ulcerative colitis (UC) is a disease of chronic inflammation of the colon. It is associated with the development of colorectal cancer through a multistep process including increasing degrees of dysplasia and DNA-ploidy changes. However, not all UC patients will develop these characteristics even during lifelong disease, and patients may therefore be divided into progressors who develop dysplasia or cancer, and non-progressors who do not exhibit such changes. In the present study, the amount of hTERT, the catalytic subunit of the enzyme telomerase, was estimated by using peroxidase immunohistochemistry (IHC) in a set of progressor and non-progressor UC colectomies. The protein levels in the colonic mucosa of the progressors and non‑progressors were compared, and further comparisons between different categories of dysplastic development and to DNA-ploidy status within the progressors were made. Levels of hTERT were elevated in the colonic mucosa of the progressors and non-progressors when compared to non-UC control samples, but no difference was observed between the hTERT levels in the mucosa of progressors and non-progressors. The levels of hTERT associated with levels of Ki67 to a significant degree within the non-progressors. hTERT expression in lesions with DNA-aneuploidy were decreased as compared to diploid lesions, when stratified for different classes of colonic morphology. Our results indicate an association between hTERT protein expression and aneuploidy in UC-progressor colons, and also a possible protective mechanism in the association between hTERT and Ki67, against development of malignant features within the mucosa of a UC-colon.

View Figures

View References

1	Macdougall IP: The Cancer risk in ulcerative colitis. Lancet. 2:655–658. 1964. View Article : Google Scholar : PubMed/NCBI
2	Eaden JA, Abrams KR and Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 48:526–535. 2001. View Article : Google Scholar : PubMed/NCBI
3	Mathy C, Schneider K, Chen YY, Varma M, Terdiman JP and Mahadevan U: Gross versus microscopic pancolitis and the occurrence of neoplasia in ulcerative colitis. Inflamm Bowel Dis. 9:351–355. 2003. View Article : Google Scholar : PubMed/NCBI
4	Gorfine SR, Bauer JJ, Harris MT and Kreel I: Dysplasia complicating chronic ulcerative colitis: is immediate colectomy warranted? Dis Colon Rectum. 43:1575–1581. 2000. View Article : Google Scholar : PubMed/NCBI
5	Stenoien DL, Sen S, Mancini MA and Brinkley BR: Dynamic association of a tumor amplified kinase, Aurora-A, with the centrosome and mitotic spindle. Cell Motil Cytoskeleton. 55:134–146. 2003. View Article : Google Scholar : PubMed/NCBI
6	Hammarberg C, Slezak P and Tribukait B: Early detection of malignancy in ulcerative colitis. A flow-cytometric DNA study. Cancer. 53:291–295. 1984. View Article : Google Scholar : PubMed/NCBI
7	Meyer KF, Nause SL, Freitag-Wolf S, et al: Aneuploidy characterizes adjacent non-malignant mucosa of ulcerative colitis-associated but not sporadic colorectal carcinomas: a matched-pair analysis. Scand J Gastroenterol. 48:679–687. 2013. View Article : Google Scholar
8	Fozard JB, Quirke P, Dixon MF, Giles GR and Bird CC: DNA aneuploidy in ulcerative colitis. Gut. 27:1414–1418. 1986. View Article : Google Scholar : PubMed/NCBI
9	Meling GI, Clausen OP, Bergan A, Schjølberg A and Rognum TO: Flow cytometric DNA ploidy pattern in dysplastic mucosa, and in primary and metastatic carcinomas in patients with longstanding ulcerative colitis. Br J Cancer. 64:339–344. 1991. View Article : Google Scholar : PubMed/NCBI
10	Gerling M, Nousiainen K, Hautaniemi S, et al: Aneuploidy-associated gene expression signatures characterize malignant transformation in ulcerative colitis. Inflamm Bowel Dis. 19:691–703. 2013. View Article : Google Scholar : PubMed/NCBI
11	Gerling M, Meyer KF, Fuchs K, et al: High frequency of aneuploidy defines ulcerative colitis-associated carcinomas: a comparative prognostic study to sporadic colorectal carcinomas. Ann Surg. Jun:42010.(Epub ahead of print).
12	Sauerwald A, Sandin S, Cristofari G, Scheres SH, Lingner J and Rhodes D: Structure of active dimeric human telomerase. Nat Struct Mol Biol. 20:454–460. 2013. View Article : Google Scholar : PubMed/NCBI
13	Mukherjee S, Firpo EJ, Wang Y and Roberts JM: Separation of telomerase functions by reverse genetics. Proc Natl Acad Sci USA. 108:E1363–E1371. 2011. View Article : Google Scholar : PubMed/NCBI
14	Kim NW, Piatyszek MA, Prowse KR, et al: Specific association of human telomerase activity with immortal cells and cancer. Science. 266:2011–2015. 1994. View Article : Google Scholar : PubMed/NCBI
15	Chadeneau C, Hay K, Hirte HW, Gallinger S and Bacchetti S: Telomerase activity associated with acquisition of malignancy in human colorectal cancer. Cancer Res. 55:2533–2536. 1995.PubMed/NCBI
16	Shay JW and Bacchetti S: A survey of telomerase activity in human cancer. Eur J Cancer. 33:787–791. 1997. View Article : Google Scholar : PubMed/NCBI
17	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
18	Baykal A, Rosen D, Zhou C, Liu J and Sahin AA: Telomerase in breast cancer: a critical evaluation. Adv Anat Pathol. 11:262–268. 2004. View Article : Google Scholar : PubMed/NCBI
19	Usselmann B, Newbold M, Morris AG and Nwokolo CU: Deficiency of colonic telomerase in ulcerative colitis. Am J Gastroenterol. 96:1106–1112. 2001. View Article : Google Scholar : PubMed/NCBI
20	Engelhardt M, Drullinsky P, Guillem J and Moore MA: Telomerase and telomere length in the development and progression of premalignant lesions to colorectal cancer. Clin Cancer Res. 3:1931–1941. 1997.PubMed/NCBI
21	Kleideiter E, Friedrich U, Möhring A, et al: Telomerase activity in chronic inflammatory bowel disease. Dig Dis Sci. 48:2328–2332. 2003. View Article : Google Scholar : PubMed/NCBI
22	Risques RA, Lai LA, Himmetoglu C, et al: Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. Cancer Res. 71:1669–1679. 2011. View Article : Google Scholar : PubMed/NCBI
23	Holzmann K, Klump B, Weis-Klemm M, et al: Telomerase activity in long-standing ulcerative colitis. Anticancer Res. 20:3951–3955. 2000.PubMed/NCBI
24	Myung SJ, Yang SK, Chang HS, et al: Clinical usefulness of telomerase for the detection of colon cancer in ulcerative colitis patients. J Gastroenterol Hepatol. 20:1578–1583. 2005. View Article : Google Scholar : PubMed/NCBI
25	Burum-Auensen E, De Angelis PM, Schjølberg AR, Røislien J, Andersen SN and Clausen OP: Spindle proteins Aurora A and BUB1B, but not Mad2, are aberrantly expressed in dysplastic mucosa of patients with longstanding ulcerative colitis. J Clin Pathol. 60:1403–1408. 2007. View Article : Google Scholar : PubMed/NCBI
26	Salk JJ, Bansal A, Lai LA, et al: Clonal expansions and short telomeres are associated with neoplasia in early-onset, but not late-onset, ulcerative colitis. Inflamm Bowel Dis. 19:2593–2602. 2013. View Article : Google Scholar : PubMed/NCBI
27	Risques RA, Lai LA, Brentnall TA, et al: Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. Gastroenterology. 135:410–418. 2008. View Article : Google Scholar : PubMed/NCBI
28	Greco V, Lauro G, Fabbrini A and Torsoli A: Histochemistry of the colonic epithelial mucins in normal subjects and in patients with ulcerative colitis. A qualitative and histophotometric investigation. Gut. 8:491–496. 1967. View Article : Google Scholar : PubMed/NCBI
29	Sipos F, Galamb O, Herszényi L, et al: Elevated insulin-like growth factor 1 receptor, hepatocyte growth factor receptor and telomerase protein expression in mild ulcerative colitis. Scand J Gastroenterol. 43:289–298. 2008. View Article : Google Scholar : PubMed/NCBI
30	Roessner A, Kuester D, Malfertheiner P and Schneider-Stock R: Oxidative stress in ulcerative colitis-associated carcinogenesis. Pathol Res Pract. 204:511–524. 2008. View Article : Google Scholar : PubMed/NCBI
31	O’Sullivan JN, Bronner MP, Brentnall TA, et al: Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet. 32:280–284. 2002.PubMed/NCBI
32	Lo AW, Sabatier L, Fouladi B, Pottier L, Ricoul M and Murnane JP: DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia. 4:531–538. 2002. View Article : Google Scholar : PubMed/NCBI
33	Hackett JA and Greider CW: Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene. 21:619–626. 2002. View Article : Google Scholar : PubMed/NCBI
34	Narducci ML, Grasselli A, Biasucci LM, et al: High telomerase activity in neutrophils from unstable coronary plaques. J Am Coll Cardiol. 50:2369–2374. 2007. View Article : Google Scholar : PubMed/NCBI
35	Wu YL, Dudognon C, Nguyen E, et al: Immunodetection of human telomerase reverse-transcriptase (hTERT) re-appraised: nucleolin and telomerase cross paths. J Cell Sci. 119:2797–2806. 2006. View Article : Google Scholar : PubMed/NCBI
36	Duarte MC, Babeto E, Leite KRM, et al: Expression of TERT in precancerous gastric lesions compared to gastric cancer. Braz J Med Biol Res. 44:100–104. 2011. View Article : Google Scholar : PubMed/NCBI
37	Simsek BC, Pehlivan S and Karaoglu A: Human telomerase reverse transcriptase expression in colorectal tumors: correlations with immunohistochemical expression and clinicopathologic features. Ann Diagn Pathol. 14:413–417. 2010. View Article : Google Scholar
38	Hiyama E, Hiyama K, Yokoyama T and Shay JW: Immunohistochemical detection of telomerase (hTERT) protein in human cancer tissues and a subset of cells in normal tissues. Neoplasia. 3:17–26. 2001. View Article : Google Scholar : PubMed/NCBI
39	Friis-Ottessen M, Bendix L, Kølvraa S, Norheim-Andersen S, De Angelis PM and Clausen OP: Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis. BMC Gastroenterol. 14:82014. View Article : Google Scholar : PubMed/NCBI
40	Andersen SN, Rognum TO, Bakka A and Clausen OP: Ki-67: a useful marker for the evaluation of dysplasia in ulcerative colitis. Mol Pathol. 51:327–332. 1998. View Article : Google Scholar : PubMed/NCBI