DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide

Zhao, Mengting; Tan, Biqin; Dai, Xiaohu; Shao, Yanfei; He, Qiaojun; Yang, Bo; Wang, Jincheng; Weng, Qinjie

doi:10.1016/j.ejphar.2019.172665

Cited by 26 publications

(22 citation statements)

References 46 publications

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“…In line with these, our results from 5 representative genes in these pathways showed that they were significantly upregulated in OSCC relative to their normal counterparts and associated with unfavorable survival. Previous studies have reported that CA9, EXTL2, PGAM1, and TYMS were dysregulated across multiple human cancers and intricately associated with tumorigenesis by functioning as key enzymes underlying metabolism (33)(34)(35)(36). Moreover, high expression of CA9 and PGAM1 were associated with inferior prognosis in OSCC, which in part strengthened our data (33,35).…”

supporting

confidence: 88%

Identification of a Transcriptional Prognostic Signature From Five Metabolic Pathways in Oral Squamous Cell Carcinoma

Yao

et al. 2020

Front. Oncol.

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Dysregulated metabolic pathways have been appreciated to be intimately associated with tumorigenesis and patient prognosis. Here, we sought to develop a novel prognostic signature based on metabolic pathways in patients with primary oral squamous cell carcinoma (OSCC). The original RNA-seq data of OSCC from The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO) database were transformed into a metabolic pathway enrichment score matrix by single-sample gene set enrichment analysis (ssGSEA). A novel prognostic signature based on metabolic pathways was constructed by LASSO and stepwise Cox regression analysis in the training cohort and validated in both testing and validation cohorts. The optimal cut-off value was obtained using the Youden index by receiver operating characteristic (ROC) curve. The overall survival curves were plotted by the Kaplan-Meier method. A time-dependent ROC curve analysis with 1, 3, 5 years as the defining point was performed to evaluate the predictive value of this prognostic signature. A 5-metabolic pathways prognostic signature (5MPS) for OSCC was constructed which stratified patients into subgroups with favorable or inferior survival. It served as an independent prognostic factor for patient survival and had a satisfactory predictive performance for OSCC. Our results developed a novel prognostic signature based on dysregulated metabolic pathways in OSCC and provided support for aberrant metabolism underlying OSCC tumorigenesis.

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confidence: 88%

Identification of a Transcriptional Prognostic Signature From Five Metabolic Pathways in Oral Squamous Cell Carcinoma

Yao

et al. 2020

Front. Oncol.

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“…Violin plots show the exclusive expression of DHFR , BCL2, and TOP2A in subtype 6, as well as significantly increased BAX expression. DHFR , TOP2A , and BCL2 were unfavorable biomarkers that predict chemoresistance to temozolomide, 15 - 17 an alkylating agent, used as a chemotherapy agent in patients with pNETs. 18 , 19 Additionally, inhibition of BCL2 seemed a way to enhance the response to everolimus, 20 a mTOR inhibitor showed effect in pNETs.…”

Section: Resultsmentioning

confidence: 99%

Single-cell RNA sequencing reveals spatiotemporal heterogeneity and malignant progression in pancreatic neuroendocrine tumor

Zhou¹,

Liu²,

Liu³

et al. 2021

Int. J. Biol. Sci.

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Aims: Using Single-cell RNA sequencing (scRNA-seq), we explored the spatiotemporal heterogeneity of pancreatic neuroendocrine tumors (pNETs) and the underlying mechanism for malignant progression. Methods: scRNA-seq was conducted on three tumor tissues (two primary tissues from different sites, one liver metastatic lesion), one normal liver tissue, and peripheral blood mononuclear cells from one patient with a metastatic G2 pNET, followed by bioinformatics analysis and validation in a pNETs cohort. Results: The transcriptome data of 24.544 cells were obtained. We identified subpopulations of functional heterogeneity within malignant cells, immune cells, and fibroblasts. There were intra-and inter-heterogeneities of cell subpopulations for malignant cells, macrophages, T cells, and fibroblasts among all tumor sites. Cell trajectory analysis revealed several hallmarks of carcinogenesis, including the hypoxia pathway, metabolism reprogramming, and aggressive proliferation, which were activated at different stages of tumor progression. Evolutionary analysis based on mitochondrial mutations defined two dominant clones with metastatic capacity. Finally, we developed a gene signature (PCSK1 and SMOC1) defining the metastatic potential of the tumor and its prognostic value was validated in a cohort of thirty G1/G2 patients underwent surgical resection. Conclusions: Our scRNA-seq analysis revealed intra-and intertumor heterogeneities in cell populations, transcriptional states, and intercellular communications among primary and metastatic lesions of pNETs. The single-cell level characterization of the spatiotemporal dynamics of malignant cell progression provided new insights into the search for potential novel prognostic biomarkers of pNETs.

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“…As shown in Fig. 5B, 3 ; AdvCtrl-MTA group vs untreated AdvCtrl mice group: p<0.01, AdvCtrl-MTA group vs untreated AdvABCC5 mice group: p<0.01, AdvCtrl group vs mice treated with MTA: p<0.01). Additionally, the tumor size of AdvABCC5 group was signi cantly higher than that of AdvCtrl groups when treated with MTA (p<0.01).…”

Section: Over-expression Of Abcc5 Weaken the Cytotoxicity Of Mtamentioning

confidence: 64%

“…Read Full License Introduction Pemetrexed (MTA) is a novel multi-targeted antifolate for the treatment of non-small cell lung cancer and mesothelioma [1][2][3][4] through inhibiting thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides [5,6]. Shaughnessy et al proved that MTA had a good effect (overall response rate:8%, stable disease:36%, median survival:8 months) on metastatic breast cancer (BC) and well-tolerated in 80% patients in second-line treatment [7], and another study presented an approximately 30% response rate in advanced BC patients in rst-line, and 21% in second-line treatment, too [8].…”

mentioning

confidence: 99%

Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer

Chen

Wang

Gao

et al. 2021

Preprint

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AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette (ABC) transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell line was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell line, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.001) in breast cancer cells from 34 patients. Furthermore, we found that the expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In in vivo study, we found ABCC5 affected the sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.3 folds).ConclusionsOur results indicated ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.

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DHFR/TYMS are positive regulators of glioma cell growth and modulate chemo-sensitivity to temozolomide

Cited by 26 publications

References 46 publications

Identification of a Transcriptional Prognostic Signature From Five Metabolic Pathways in Oral Squamous Cell Carcinoma

Identification of a Transcriptional Prognostic Signature From Five Metabolic Pathways in Oral Squamous Cell Carcinoma

Single-cell RNA sequencing reveals spatiotemporal heterogeneity and malignant progression in pancreatic neuroendocrine tumor

Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer

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