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.

Prediction of mismatch repair deficient biliary tract cancer: Role of morphological features and host immune response detected by routine hematoxylin‐eosin staining

“…The variability in the incidence of dMMR might be explained by two reasons. First, in iCCA, reports based on analysis in Southeast Asia, particularly Thailand, appear to be strongly associated with liver fluke 19,20 . In these reports, the incidence of MSI‐H were high with 20%‐69%.…”

Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital‑based population

“…However, it was hypothesized that methylation and somatic alterations may have been associated with loss of MLH1 or MSH2 expression in the cases with dMMR/MSH-H, since these patients did not have any past history or family history of cancer. A study from Thailand ( 45 ) reported that CCA derived from liver fluke infection had a high incidence of MSI-H (9/13 cases, 69%). Although the pathogenesis of BTC in Japan is expected to be different from that in Thailand, the study will contribute to identify the mechanisms of alteration to MSI-H, leading to an increased understanding of the development of BTC.…”

Proteomic analysis identifies deregulated metabolic and oxidative-associated proteins in Italian intrahepatic cholangiocarcinoma patients

“…Loilome and collaborators demonstrated, in an O. viverrini hamster cholangiocarcinoma model, that both enzymes are highly expressed during cholangiocarcinogenesis, while there is a decreased expression when tumors are well established [ 30 ]. The same group demonstrated that both proteins are expressed at different levels in CCA tissues, but they are also expressed in normal bile ducts and hepatocytes [ 31 ]. Interestingly, its activity is dramatically reduced in CCA compared to normal bile ducts.…”