title: Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma.
abstract: 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 β (DNA pol β). 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 β 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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Watcharin
authors.initials: W
authors.lastname: Loilome
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Sasithorn
authors.initials: S
authors.lastname: Kadsanit
authors.affiliation: Department of Forensics Science, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Kanha
authors.initials: K
authors.lastname: Muisook
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Nisana
authors.initials: N
authors.lastname: Namwat
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Medical Technology, Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Techasen
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Anucha
authors.initials: A
authors.lastname: Puapairoj
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Narong
authors.initials: N
authors.lastname: Khuntikeo
authors.affiliation: Department of Surgery, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Pichai
authors.initials: P
authors.lastname: Phonjit
keywords: DNA repairing enzymes; antioxidant enzymes; cholangiocarcinoma; imbalanced adaptive responses; microsatellite instability