RESUMEN
The adaptive response of the genome protection mechanism occurs in cells when exposed to genotoxic stress due to the overproduction of free radicals via inflammation and infection. In such circumstances, cells attempt to maintain health via several genome protection mechanisms. However, evidence is increasing that this adaptive response may have deleterious effect; a reduction of antioxidant enzymes and/or imbalance in the DNA repair system generates microsatellite instability (MSI), which has procarcinogenic implications. Therefore, the present study hypothesized that MSI caused by imbalanced responses of antioxidant enzymes and/or DNA repair enzymes as a result of oxidative/nitrative stress arising from the inflammatory response is involved in liver fluke-associated cholangiocarcinogenesis. The present study investigated this hypothesis by identifying the expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), and DNA repair enzymes, including alkyladenine DNA glycosylase (AAG), apurinic endonuclease (APE) and DNA polymerase ß (DNA pol ß). In addition, the activities of the antioxidant enzymes, SOD2 and CAT, were examined in human cholangiocarcinoma (CCA) tissues using immunohistochemical staining. MSI was also analyzed in human CCA tissues. The resulting data demonstrated that the expression levels of the SOD2 and CAT enzymes decreased. The activities of SOD2 and CAT decreased significantly in the CCA tissues, compared with the hepatic tissue of cadaveric donors. In the DNA repairing enzymes, it was found that the expression levels of AAG and DNA pol ß enzymes increased, whereas the expression of APE decreased. In addition, it was found that MSI-high was present in 69% of patients, whereas MSI-low was present in 31% of patients, with no patients classified as having microsatellite stability. In the patients, a MSI-high was correlated with poor prognosis, indicated by a shorter survival rate. These results indicated that the reduction of antioxidant enzymes and adaptive imbalance of base excision repair enzymes in human CCA caused MSI, and may be associated with the progression of cancer.
RESUMEN
A possible mechanism of liver fluke (Opisthorchis viverrini; Ov) -associated cholangiocarcinoma (CCA) genesis may be imbalance in responses of antioxidant enzymes and/or DNA repair enzymes which are the consequence of oxidative/nitrative stress, arising from inflammatory processes. This study aimed to investigate changes in the expression patterns of antioxidant enzymes, including superoxide dismutase 2 (SOD2) and catalase (CAT), as well as their activities in Ov-associated hamster CCA tissues. Expression of DNA repair enzymes including apurinic endonuclease (APE) and DNA polymerase beta (DNA pol ß) was also investigated. Our results showed that SOD2 and CAT levels were increased in CCA-induced liver hamster tissues at every time point during cholangiocarcinogenesis. However, once tumors were well established, activities of both enzymes were significantly decreased. Expression of APE and DNA pol ß was increased in the acute phase of Ov infection and this persisted until tumors developed. These findings suggest that a reduction in antioxidant enzymes and an increase in DNA repair enzymes may contribute to DNA translesion-mediated CCA in liver fluke-associated cholangiocarcinogenesis in the hamster model.