Abstract
Cholangiocarcinoma (CCA) is a rare but highly fatal cancer for which the molecular mechanisms and diagnostic markers are obscure. We therefore investigated the kinetic expression of isocitrate dehydrogenase-1 (IDH1), isocitrate dehydrogenase-2 (IDH2) and homogentisate 1,2-dioxygenase (HGD) during the tumorigenesis of O. viverrini infection-associated CCA in an animal model, and confirmed down-regulation of expression in human cases of opisthorchiasis-associated CCA through real time PCR. Kinetic expression of HGD, IDH1 and IDH2 in the animal model of O. viverrini infection-induced CCA was correlated with human CCA cases. In the animal model, expression of HGD was decreased at all time points (p<0.01) and expression of both IDH1 and IDH2 was decreased in the CCA group. In human cases, expression of HGD, IDH1 and IDH2 was decreased more than 2 fold in 55 cases (70.5%), 25 cases (32.1%) and 24 cases (30.8%) respectively. The present study suggests that reduction of HGD, IDH1 and IDH2 may be involve in cholangiocarcinoma genesis and may be useful for molecular diagnosis.
Highlights
Infection of Opisthorchis viverrini can induce tumorigenesis of cholangiocarcinoma (CCA), which has been demonstrated by the epidemiological investigations and animal experiments (Thamavit et al, 1987:1983; IARC, 1994; Sithithaworn et al, 2003; Sriamporn et al, 2004; IARC, 2011)
According to above reasons isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) expressions in normal condition or uninfected normal hamster control was remained in high level in all time points whereas in abnormal conditions, O. viverrini infection, NDMA administration and O. viverrini infection plus NDMA, were decreased (Figure 2)
It may cause of the IDH1 and IDH2 mutation and electron transport abnormality in the liver including intrahepatic cholangiocarcinoma (Jiao et al, 2013) and mutated non- O. viverrini related CCA (Chan-On et al, 2013)
Summary
Infection of Opisthorchis viverrini can induce tumorigenesis of cholangiocarcinoma (CCA), which has been demonstrated by the epidemiological investigations and animal experiments (Thamavit et al, 1987:1983; IARC, 1994; Sithithaworn et al, 2003; Sriamporn et al, 2004; IARC, 2011). Many efforts have been made to reveal the mechanism of tumorigenesis of CCA induced by O. viverrini infection. It is not still unknown completely, NOS derived from inflammation caused by the infection is considered to be one of factors to cause the tumorigenesis. Our previous cDNA microarray indicated that in the animal model of O. viverrini infection-induced CCA, Asian Pacific Journal of Cancer Prevention, Vol 16, 2015 5875 the expressions of many antioxidative enzyme related genes were down-regulated, for example, IDH (isocitrate dehydrogenase), HGD (homogentisate 1,2-dioxygenase), Gsta (glutathione S-transferase), GST (glutathione synthetase) and Prdx (peroxiredoxin 6) (Wu et al, 2011).
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