Characterisation of the Urinary Metabolic Profile of Liver Fluke-Associated Cholangiocarcinoma

Alsaleh, Munirah; Sithithaworn, Paiboon; Khuntikeo, Narong; Loilome, Watcharin; Yongvanit, Puangrat; Chamadol, Nittaya; Hughes, Thomas A.; O’Connor, Thomas; Andrews, Ross H.; Holmes, Elaine; Taylor-Robinson, Simon D

doi:10.1016/j.jceh.2019.06.005

Cited by 14 publications

(24 citation statements)

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“…An association of xanthine oxidoreductase expression and oxidative stress, cancer aggressiveness, and poor clinical outcome has been reported (56). A previous study suggested that purine metabolites in the urine of patients with CCA showed increased levels of uric acid and 7-methylguanine, and reduced levels of hypoxanthine compared with a control group (11). In the present study, the higher levels of inosine in the praziquantel-treated group were negatively correlated with inflammation.…”

Section: Discussionsupporting

confidence: 68%

“…It was found that altered bile acid and phosphatidylcholine metabolism might play an important role in the carcinogenesis processes of CCA (9). Moreover, the urinary metabolic profiles in CCA compared with hepatocellular carcinoma, metastatic secondary liver cancer, pancreatic cancer and ovarian cancer revealed that the levels of acylcarnitine, bile acid, and purine were significantly elevated in CCA compared with controls (11).…”

mentioning

confidence: 99%

“…Metabolomics, one of the omics technologies in the systems biology suite, has been used to investigate the molecular mechanisms underlying the development and progression of cancer (8). The metabolic profiling of bile (9), serum (10) and urine (11) of CCA patients has been investigated. Metabolomics is defined as the quantitative and qualitative measurement of the small molecular weight metabolites of cells, tissue, or the organism (12).…”

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confidence: 99%

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Metabolic Profiling of Praziquantel-mediated Prevention ofOpisthorchis viverrini-induced Cholangiocyte Transformation in the Hamster Model of Cholangiocarcinoma

Prommajun

Phetcharaburanin

Namwat

et al. 2021

Cancer Genomics Proteomics

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Background: Opisthorchis viverrini (Ov) infectioninduced cholangiocarcinoma (CCA) is a major public health problem in northeastern Thailand. Praziquantel was shown to prevent CCA development in an Ov-infected hamster model; however, the molecular mechanism remains unknown. Materials and Methods: In this study, we used a hamster model with Ov and N-nitrosodimethylamine-induced CCA to study the mechanisms of praziquantel action. The liver tissues from the hamsters with and without praziquantel treatment were analyzed using 1 H nuclear magnetic resonance spectroscopy. Results: A total of 14 metabolites were found to be significantly different between the two groups. Furthermore, the combination of acetate, inosine and sarcosine was shown to exert an anti-inflammatory effect through interleukin-6 inhibition in a macrophage cell line, suggesting a mechanism by which praziquantel may prevent inflammation caused by Ov, cholangiocyte transformation and further CCA develpoment. Conclusion: These findings might avail the development of a preventive strategy for CCA in high-risk populations.Cholangiocarcinoma (CCA), a malignancy of bile duct epithelial cells, is a major public health problem in Northeast Thailand, which has the highest incidence in the world of this disease (1). A parasitic infection caused by Opisthorchis viverrini (Ov), a liver fluke, was identified as a cause of CCA in 1994 and is associated with CCA development (1). Upon liver fluke infection, CCA genesis is hypothesized to be initially induced via multiple mechanistic pathways, including mechanical damage caused by the fluke suckers, fluke toxic secretory products, and the host immunopathological response, leading to chronic inflammation (2). Moreover, the overproduction of reactive oxygen species and reactive nitrogen species from chronic inflammation results in tissue injury associated with CCA initiation and progression (3). In accordance with the hepatic changes first reported in 1978 in an Ov-infected hamster model, hyperplasia, adenomatous formations and periductal and portal scarring of the bile duct epithelium were also observed at 22 weeks post infection, although bile duct carcinoma was not seen at that time (4). In addition, a previous study showed that alone, Nnitrosodimethylamine (NDMA), a potential carcinogen, did not induce tumor formation in hamsters, but together with Ov infection, CCA was observed in a number of animals (5). Furthermore, histological changes, such as inflammatory reactions, bile duct proliferation, periductal fibrosis and cholangiocarcinoma lesions, were all observed in this cotreatment group (5). At the gene-expression level, we have shown a single down-regulated and 23 up-regulated give transcripts that were involved in Ov-induced CCA development (6). The up-regulated genes include signal 29 This article is freely accessible online.

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Section: Discussionsupporting

confidence: 68%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolic Profiling of Praziquantel-mediated Prevention ofOpisthorchis viverrini-induced Cholangiocyte Transformation in the Hamster Model of Cholangiocarcinoma

Prommajun

Phetcharaburanin

Namwat

et al. 2021

Cancer Genomics Proteomics

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“…In addition to the key role they play in intestinal uptake of lipids and vitamins, bile acids act as signaling molecules that regulate cell growth, as well as inflammation [36]. As such, perturbation of bile acid synthesis is known to be a factor in a variety of cancer types, such as colorectal cancer [37], hepatocellular carcinoma [38], and cholangiocarcinoma [39].…”

Section: Discussionmentioning

confidence: 99%

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

Patt

Demoret

Stets

et al. 2020

Cancers

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Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.

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“…Chronic cholestasis and cholangitis may further lead to secondary cirrhosis of the liver and are susceptible to hepatobiliary cancer. In addition, this group also identified that purine metabolism and lipid metabolism have changed in the CCA urine metabolome in Opisthorchis viverrini -induced liver fluke-associated CCA [ 98 ]. Several comprehensive analyses merged with transcriptome, proteome and metabolome profiles of CCA have been published [ 99 , 100 , 101 , 102 , 103 ].…”

Section: Metabolomics Analysis Of Oncometabolites and Metabolic Rementioning

confidence: 99%

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma

et al. 2020

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Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53mut, KRASmut) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS2 system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies.

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Characterisation of the Urinary Metabolic Profile of Liver Fluke-Associated Cholangiocarcinoma

Cited by 14 publications

References 51 publications

Metabolic Profiling of Praziquantel-mediated Prevention ofOpisthorchis viverrini-induced Cholangiocyte Transformation in the Hamster Model of Cholangiocarcinoma

Metabolic Profiling of Praziquantel-mediated Prevention ofOpisthorchis viverrini-induced Cholangiocyte Transformation in the Hamster Model of Cholangiocarcinoma

MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma

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