Oxidative DNA Damage in the Mucosa of Ulcerative Colitis Increases With Disease Duration and Dysplasia

Abstract

Oxidative DNA damage accumulates with the duration of the disease in ulcerative colitis reaching maximal increase if dysplastic lesions are found with possible implications for mutagenic and carcinogenic progression.

Avaliação do dano oxidativo ao DNA de células normais e neoplásicas da mucosa cólica de doentes com câncer colorretal

“…A relação entre estresse oxidativo e inflamação já foi anteriormente descrita, quando se verificou aumento na intensidade de dano oxidativo ao DNA quanto mais duradouro e intenso fosse o processo inflamatório, determinando o aparecimento de lesões displásicas possivelmente relacionadas ao surgimento do câncer. 31 Estudos experimentais demonstraram que em camundongos silenciados para o gene Il-10, aproximadamente 60% deles desenvolveram tumores no cólon proximal após um período inicial de intenso processo inflamatório na mucosa cólica. 32 Da mesma forma, 30% dos camundongos silenciados simultaneamente para os genes Il-2 e b2 microglobulina desenvolveram adenocarcinoma no cólon, após longo período de exuberante processo inflamatório, com ín-dices de mutações nos genes APC e p53 de 100 % e 60% respectivamente.…”

Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2‐deficient mice upon dextran sulfate treatment

“…4,5 Ulcerative colitis provides an example of chronic inflammation resulting in an accumulation of oxidative DNA damage. D'Inca et al reported that longer duration of ulcerative colitis resulted in increased levels of 8-hydroxyguanosine , an oxidative DNA adduct, 6 possibly explaining why the risk of developing colorectal cancer from colitis increases by 0.5-1.0% every year after 7 years of disease. 7 Additionally, excess ROS because of chronic inflammation may result in oxidative modification of proteins leading to inappropriate activity of regulatory pathways important in the progression of carcinogenesis.…”

Current overview of colitis-associated colorectal cancer

“…This condition leads to an increased risk of carcinogenesis. In line with this hypothesis, D'Inca recently showed that the maximum level of the oxidative DNA damage can be found in lesions with carcinogenic progression [3,24]. Concurrently, it was shown by Martinez et al [25] that RNS may also induce colon carcinogenesis.…”

“…Oxidative stress-related pathways are a possible cause of IBD and they also play a major role in the transformation of IBD into CACRC [24]. The amount of phagocytic leukocytes is increased in IBD patients, mainly in UC patients, what results in an enhanced production of pro-oxidant molecules.…”