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

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.

TP53/p53 alterations and Aurora A expression in progressor and non-progressor colectomies from patients with longstanding ulcerative colitis

“…We have previously presented findings of similar levels of human telomerase reverse transcriptase (hTERT) protein expression and equal shortening of mean telomere length in the colonic mucosa of progressors compared to non-progressors from the same UC patient material ( 36 , 37 ). These results are in accordance with UC being a disease that accelerates the ageing of the colonic mucosa ( 51 ); however, these parameters are unable to differentiate a progressor from a non-progressor UC colon.…”

“…The colectomy specimens have been previously described ( 35 – 37 ). We divided the colectomies into progressors and non-progressors, revealing 10 non-progressors that did not present any dysplastic lesions or DNA aneuploidy, and 20 progressors that all presented at least one area of dysplasia/cancer, where the majority of cases also presented lesions with DNA aneuploidy.…”

“…By definition, all non-progressor lesions were diploid and non-dysplastic. Detailed distributions of dysplasia and aneuploid lesions within the progressors have been previously described ( 35 , 37 ).…”

“…We also re-evaluated previously published data on Aurora A expression assessed by immunohistochemical staining in the same colectomies ( 35 ). The colectomies were stratified as progressors and non-progressors, as previously presented ( 36 , 37 ). Within the progressors, we assessed the results from Aurora A in association with DNA ploidy status and advancing degrees of dysplasia, as well as with the protein levels of p53 and the TP53 mutation status.…”

Telomerase: a target for colorectal cancer treatment?

“…Telomerase enables cancerous cells to achieve replicative immortality, which is one of the hallmarks of cancer. 4 While hTR is constitutively present in normal and tumor cells, hTERT is the rate-limiting component of the telomerase complex, and its expression correlates with telomerase activity. This has made hTERT a focus of oncology research and an attractive target for anticancer drug development.…”