Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1

Okano, Yusuke; Kuramochi, Hidekazu; Nakajima, Go; Katagiri, Seiji; Yamamoto, Masakazu

doi:10.3892/ol.2017.6241

Cited by 5 publications

(6 citation statements)

References 17 publications

(21 reference statements)

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“…However, little is known about TYMS in HCC. Although a previous study suggested that high expression of TYMS may be an independent prognostic factor for HCC, their results are not statistically significant [ 35 ]. In this study, we found that high expression of TYMS was significantly associated with poor OS and PFS using the data extracted from the TCGA-LIHC dataset.…”

Section: Discussionmentioning

confidence: 93%

FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma

Wang

Shi

et al. 2022

Cancer Cell Int

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Background Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the major causes of cancer-related death. Thymidylate synthase (TYMS) catalyzes the methylation of deoxy guanosine to deoxy thymidylate, which is a crucial gene for DNA repair and replication. Thus, TYMS was reported to be closely associated with developing a variety of tumors, but it has been poorly studied in HCC. Materials and methods We used the cell counting kit-8 (CCK-8), BrdU, and CFSE assay to measure cell proliferation. The flow cytometry assay and the TUNEL assay were used for assessing cell apoptosis. The flow cytometry assay was used to analyze the cell cycle. The Transwell invasion assay and the wound healing assay were conducted to determine the invasive ability of the cells. RT-qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression levels of specific genes, respectively. Results TYMS was found to be upregulated in both HCC cells and patient samples. High expression of TYMS was associated with an unfavorable prognosis in HCC patients based on the TCGA-LIHC dataset. Cell proliferation, apoptosis, and invasion assays revealed that TYMS promoted the proliferation and invasion of HCC cells as well as inhibited apoptosis. In addition, TYMS is a downstream target of FOXM1. TYMS knockdown reversed the 5-FU resistance caused by FOXM1 overexpression and re-sensitized HCC cells to 5-FU treatment. Conclusion This study suggested that TYMS serves as an oncogene in HCC, and targeting the FOXM1-TYMS axis may help improve the survival of HCC patients as well as provide new insights for treating advanced HCC patients.

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Section: Discussionmentioning

confidence: 93%

FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma

Wang

Shi

et al. 2022

Cancer Cell Int

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“…This is an orally administered preparation that combines tegafur (a prodrug of 5-FU), 5-chloro-2,4-dihydropyridine (a reversible DPD inhibitor), and oteracil potassium (an inhibitor of orotate phosphoribosyltransferase) used to inhibit 5-FU activity within normal gastrointestinal mucosa and hence reduce its toxic side effect on this tissue. Surprisingly, individuals with high expression of DPD showed improved OS after S-1-based chemotherapy [ 26 ]. DPD has been proposed as a therapeutic target for interferon-α (IFN-α) treatment, which is effective in some HCC patients in reducing metastasis by inhibition of epithelial-mesenchymal transition (EMT) through DPD down-regulation.…”

Section: Drug Metabolism (Moc-2)mentioning

confidence: 99%

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Marin

Macı́as

Monte

et al. 2020

Cancers

133

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The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.

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“…17 The response rate of tumors to fluoropyrimidine drugs depends on thymidylate synthase and dihydropyrimidine dehydrogenase (DPD) activity. 18 DPD is a main enzyme in the biochemical functions of the antimetabolite 5-FU as well as capecitabine. 19-21…”

Section: Introductionmentioning

confidence: 99%

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine

et al. 2019

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Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolism of fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatin chemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newly developed chemotherapeutic agent, 17-allyloamino-17-demethoxy-geldanamycin (17-AAG) can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer (CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabine-based chemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17-AAG in combination with oxaliplatin and capecitabine in HT-29 and HCT-116 cell lines. Methods: Drug sensitivity was determined by the water-soluble tetrazolium-1 assay in a previous survey. Then, we evaluated the expression levels of DPD and its relationship with the chemotherapy response in capecitabine, oxaliplatin, and 17-AAG treated cases in single and combination cases in two panels of CRC cell lines. DPD gene and protein expression levels were determined by real-time polymerase chain reaction and western blotting assay, respectively. Results: DPD gene expression levels insignificantly increased in single-treated cases versus untreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatin were added in double combinations, where DPD gene and protein expression increased in combination cases compared to pre-chemotherapy and single drug treatments. Conclusion: The elevated levels of cytotoxicity in more effective combinations could be related to a different mechanism apart from DPD mediating effects or high DPD level in the remaining resistance cells (drug-insensitive cells), which should be investigated in subsequent studies.

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Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1

Cited by 5 publications

References 17 publications

FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma

FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine

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