Role of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA in intrahepatic cholangiocarcinoma

Morine, Yuji; Shimada, Mitsuo; Utsunomiya, Tohru; Imura, Satoru; Ikemoto, Tetsuya; Hanaka, Jun; Kanamoto, Mami; Kurita, Nobuhiro; Miyake, Hidenori

doi:10.1007/s00595-011-0054-z

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…Studies undertaken to determine the molecular mechanisms of intrinsic and acquired resistance to 5-FU have found various alterations of drug target(s) and metabolism (14,15), such as key enzymes of 5-FU anabolism and catabolism including thymidylate synthase (TS) (16), thymidine phosphorylase (TP) (17) and dihydropyrimidine dehydrogenase (DPD). It had been confirmed in tissue and from mRNA levels that negative DPD (not TS) expression is significantly associated with the enhanced tumor cell proliferation and poorer prognosis in patients with intrahepatic cholangiocarcinoma (18,19). In addition, altered expression of apoptosis-regulating genes also can lead to resistance to 5-FU (20).…”

Section: Nk4 Regulates 5-fluorouracil Sensitivity In Cholangiocarcinomentioning

confidence: 97%

NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway

Wang

et al. 2013

Oncology Reports

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The aim of the present study was to investigate the role of NK4, an antagonist for hepatocyte growth factor (HGF) and the Met receptor, in regulating the response of cholangiocarcinoma (CCA) cells to 5-fluorouracil (5-FU). We established the CCA cell line, HuCC-T1, to produce abundant NK4 (Hu-NK4). Cell proliferation, cell cycle distribution, apoptosis, 5-FU metabolism and intracellular signaling were examined. There were no significant differences in the mRNA levels of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase between the mock-transfected control Hu-Em cells and Hu-NK4 cells, suggesting that NK4 expression does not alter 5-FU metabolism. Moreover, cell cycle analysis showed that 5-FU treatment caused a decrease in the proportion of cells in the G2/M phase while NK4 gene expression had little effect on the cell cycle distribution. However, 5-FU-induced apoptosis was significantly increased in the Hu-NK4 cells when compared to that in the Hu-Em cells. Further investigation revealed that NK4 gene expression enhanced 5-FU-induced caspase-3 and caspase-9 activation, and that the apoptosis of cells was associated with modulation of expression of the Bcl-2 family members. Furthermore, western blot analysis revealed that both NK4 and 5-FU were inhibitors for HGF-induced phosphorylation of Met, but they may be independent factors. Collectively, these results suggest that following 5-FU treatment in CCA cell lines, NK4 was involved in apoptosis induction through the intrinsic mitochondrial pathway. This indicates that NK4 may be an important mediator of 5-FU-induced cell death. Moreover, downregulation of NK4 in response to 5-FU may represent an intrinsic mechanism of resistance to this anticancer drug.

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Section: Nk4 Regulates 5-fluorouracil Sensitivity In Cholangiocarcinomentioning

confidence: 97%

NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway

Wang

et al. 2013

Oncology Reports

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“…8). This map Morine et al (2012) Pre-mRNA splicing The genes found in the literature are characterized by pathway involvement or function depicts SNPs found in five genes known to affect homocysteine levels. Visualizing information in this manner can aid in disease-risk assessment based on constellations of SNPs and environmental and lifestyle factors that individually, or in ensemble, affect probability of developing a disease or risk factor.…”

Section: Utilizes Gene Products Frommentioning

confidence: 99%

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

et al. 2014

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Advances in the development of bioinformatic tools continue to improve investigators' ability to interrogate, organize, and derive knowledge from large amounts of heterogeneous information. These tools often require advanced technical skills not possessed by life scientists. User-friendly, low-barrier-to-entry methods of visualizing nutrigenomics information are yet to be developed. We utilized concept mapping software from the Institute for Human and Machine Cognition to create a conceptual model of diet and health-related data that provides a foundation for future nutrigenomics ontologies describing published nutrient-gene/polymorphism-phenotype data. In this model, maps containing phenotype, nutrient, gene product, and genetic polymorphism interactions are visualized as triples of two concepts linked together by a linking phrase. These triples, or ''knowledge propositions,'' contextualize aggregated data and information into easy-to-read knowledge maps. Maps of these triples enable visualization of genes spanning the One-Carbon Metabolism (OCM) pathway, their sequence variants, and multiple literature-mined associations including concepts relevant to nutrition, phenotypes, and health. The concept map development process documents the incongruity of information derived from pathway databases versus literature resources. This conceptual model highlights the importance of incorporating information about genes in upstream pathways that provide substrates, as well as downstream pathways that utilize products of the pathway under investigation, in this case OCM. Other genes and their polymorphisms, such as TCN2 and FUT2, although not directly involved in OCM, potentially alter OCM pathway functionality. These upstream gene products regulate substrates such as B12. Constellations of polymorphisms affecting the functionality of genes along OCM, together with substrate and cofactor availability, may impact resultant phenotypes. These conceptual maps provide a foundational framework for development of nutrient-gene/polymorphism-phenotype ontologies and systems visualization.

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“…The authors of a drug-response assay carried out using tumor tissue obtained from intrahepatic CCA concluded that TS mRNA levels could not predict the success of 5-FU chemotherapy [59]. This concept was further supported by in vivo studies, in which the determination of TS mRNA in tumors resected surgically from patients with intrahepatic CCA revealed no correlation between expression and prognosis [77]. In contrast, a phase II trial in patients with incurable biliary cancer treated with gemcitabine plus capecitabine reported that the longest overall survival was found in patients with the TS 5′GC polymorphism, i.e., double (2R) or triple (3R) 28-bp tandem repeats plus G>C substitution at the 12 th nucleotide in the second repeat of the 3R allele (3RG>3RC) [78]; this results in decreased RNA stability and hence a lower transcriptional activity of TS.…”

Section: Mechanisms Of Chemoresistance Type 3 Targetsmentioning

confidence: 99%

Papel del gen SLC22A1 en la refractariedad de los tumores hepáticos al sorafenib

Abdulla¹

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The multidrug resistance (MDR) phenotype accounts for the poor response of cholangiocarcinoma to available antitumor drugs. This is an important limitation to the use of pharmacological approaches, both as adjuvant therapies and for treating advanced CCA when surgical removal is not possible. MDR is the result of a complex combination of defense mechanisms against toxic compounds already present in cholangiocytes, which play a role in the physiology of these cells by protecting the biliary epithelium from the toxins reaching the biliary tree with the blood that perfuses this tissue, or that are secreted by hepatocytes into bile, to which cholangiocytes are exposed. These mechanisms of chemoresistance (MOC) are also present, usually with enhanced efficacy, in tumors derived from cholangiolar cells. The present review article is an update of the state-of-the-art regarding the MOC involved in the poor response of CCA to antitumor drugs. These MOC have been classified as: changes in the amount of drug in the cells due to decreased uptake (MOC-1a) or enhanced efflux (MOC-1b); altered proportions between prodrug, active drug and inactive metabolites (MOC-2); changes in the molecular targets of antitumor drugs (MOC-3); an enhanced ability of tumor cells to repair drug-induced DNA damage (MOC-4), and an impaired apoptosis/survival balance (MOC-5).

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Role of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA in intrahepatic cholangiocarcinoma

Abstract: Low DPD mRNA expression was related to macroscopic type and associated with poor prognosis. DPD mRNA expression in tumor cells is suggested to be an important regulator of malignant behavior in IHCC.

Cited by 3 publications

References 29 publications

NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway

NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

Papel del gen SLC22A1 en la refractariedad de los tumores hepáticos al sorafenib

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