Candidate genes involving in tumorigenesis of cholangiocarcinoma induced by Opisthorchis viverrini infection

Wu, Zhiliang; Boonmars, Thidarut; Boonjaraspinyo, Sirintip; Nagano, Isao; Pinlaor, Somchai; Puapairoj, Anucha; Yongvanit, Puangrat; Takahashi, Yūzō

doi:10.1007/s00436-011-2298-3

Cited by 21 publications

(22 citation statements)

References 64 publications

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“…Several antioxidant genes including CAT showed downregulation in animal model of (Wu et al 2011). In agreement with other liver fluke, Fasciola hepatica, antioxidant potential was decreased in rat livers after post-infection (Kolodziejczyk et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen

et al. 2011

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Re-infection with liver fluke, Opisthorchis viverrini, increases proinflammatory molecules involved in inflammation-mediated disease and carcinogenesis in an animal model. To clarify whether these genes respond to parasite antigen in peripheral blood leukocytes (PBL) of opisthorchiasis patients, we examined the transcriptional level of oxidant-generating (toll-like receptor 2 (TLR-2), nuclear factor-kappa B (NF-KB), and cyclooxygenase 2 (COX-2)), anti-oxidant-generating (manganese superoxide dismutase 2 (SOD-2) and catalase (CAT)), proinflammatory cytokine (interleukin (IL)-1β), and anti-inflammatory cytokine (IL-10), in PBL exposed to parasite antigen in O. viverrini-infected patients compared with healthy individuals in an in vitro experiment. After O. viverrini antigen-treated PBL, quantitative RT-PCR analysis revealed that increased expression of cytokines and oxidant-generating genes in PBL was similar between O. viverrini-infected and healthy groups. Interestingly, compared with healthy subjects, increase of TLR-2, COX-2, and SOD-2 and decreased CAT mRNA expression levels were observed in O. viverrini-infected group. The results indicate that O. viverrini antigen induces upregulation of TLR-2, COX-2, and SOD-2 and downregulation of CAT genes in opisthorchiasis patients, suggesting that imbalance of oxidant/anti-oxidant transcripts during re-infection may be involved in the inflammatory-driven carcinogenesis. These molecules may be used as the chemopreventive target for intervention of opisthorchiasis patients in an endemic area.

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Section: Discussionmentioning

confidence: 99%

Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen

et al. 2011

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“…Our previous cDNA microarray analysis showed that some of S100 proteins were up‐regulated in the early stage of tumorigenesis in the animal model of O. viverrini infection‐induced CCA . S100 family is a super family of Ca2+‐binding proteins, consisting of >20 low molecular weight proteins which possess the EF‐hands to bind Ca2+.…”

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Significance of S100P as a biomarker in diagnosis, prognosis and therapy of opisthorchiasis‐associated cholangiocarcinoma

Boonmars

Nagano

et al. 2015

Intl Journal of Cancer

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Cholangiocarcinoma (CCA) is a malignancy of bile duct with the difficulty in early diagnosis, poor prognosis and less alternation in therapy. S100P is a member of S100 family proteins and plays important roles in cancers. We investigated the S100P expression and its correlation with clinicopathology in 78 cases of opisthorchiasis-associated CCA, and the effects of S100P knockdown with shRNA interference on the proliferation, cell cycle, migration, apoptosis and sensitivity to anti-cancer drug. Extremely high expression of S100P mRNA was detected in the CCA tumor tissues. The increased S100P protein expression was immunohistochemically confirmed and localized in the CCA cytoplasm and/or nuclei as well as in the hyperneoplasia and dysplasia bile ducts, but not in normal bile ducts. The intensity of immunostaining was correlated with survival, tumor stage and metastasis, and the high expression could be an independent prognostic factor. High levels of S100P were detected in the serum and bile fluid of CCA patients. The shRNA-mediated knockdown of S100P expression inhibited the proliferation in vitro and in vivo, and migration of CCA cells, arrested cell cycle with the up-regulated expression of cell cycle arrest related factors, p21, p27, GADD45A, and 14-3-3 zeta. S100P knockdown also promoted CCA cell apoptosis by up-regulating expression of apoptosis related factors, DR5, TRADD, caspase 3 and BAX, and increased the sensitivity of CCA cells to the chemotherapeutic agents sunitinib and apigenin. Taken together, this study indicates that S100P might be a promising biomarker for the diagnosis, prognosis and therapy of CCA.Cholangiocarcinoma (CCA) is a malignancy arising from bile ducts. Although it is rare, the incidence and mortality of the cancer have been increasing worldwide over the past decades, while the prognosis is remained dismal and substantially unchanged.1 Because of the lack of the method of early diagnosis, most of patients, when diagnosed, are incurable advanced and metastatic; their 5-year survival rate is extremely low. Chronic inflammation is one of important risks of CCA tumorigenesis, including Opisthorchis viverrini infection. Clear relationship between O. viverrini infection and CCA incidence has been demonstrated.2,3 The epidemiological investigations have indicated the astonished high incidence of CCA in opisthorchiasis endemic areas, especially in northeast of Thailand where both opisthorchiasis prevalence and CCA incidence are the highest in the world. 4,5 Serious O. viverrini infection, the lack of early diagnostic methods and poor prognosis of CCA put the millions of people at the risk of CCA in endemic areas. Although many efforts have been made, the biomarkers for diagnosis, prognosis and therapy of CCA are still quite limited. Therefore, it is urgent to delve into the tumorigenesis mechanism and develop novel biomarkers for the early diagnosis, prognosis, and therapy of the opisthorchiasis-associated CCA.Our previous cDNA microarray analysis showed that some of S100 proteins were up-re...

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“…Furthermore, the results of our previous study showed that the decreased gene expression of CAT in the peripheral blood leukocytes of patients with opisthorchiasis is induced by Ov antigen (27). Additionally CAT was found to be downregulated in an animal model of opisthorchaiasis-associated CCA, detected via kinetic analysis using the cDNA microarray technique (28). …”

Section: Discussionmentioning

confidence: 99%

Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma

et al. 2016

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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.

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Candidate genes involving in tumorigenesis of cholangiocarcinoma induced by Opisthorchis viverrini infection

Cited by 21 publications

References 64 publications

Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen

Increased expression of TLR-2, COX-2, and SOD-2 genes in the peripheral blood leukocytes of opisthorchiasis patients induced by Opisthorchis viverrini antigen

Significance of S100P as a biomarker in diagnosis, prognosis and therapy of opisthorchiasis‐associated cholangiocarcinoma

Imbalanced adaptive responses associated with microsatellite instability in cholangiocarcinoma

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