ImpairedNFKBIEgene function decreases cellular uptake of methotrexate by down-regulatingSLC19A1expression in a human rheumatoid arthritis cell line

Imamura, Hitoshi; Yoshina, Sawako; Ikari, Katsunori; Miyazawa, Keiji; Momohara, Shigeki; Mitani, Shohei

doi:10.3109/14397595.2015.1112481

Cited by 10 publications

(6 citation statements)

References 44 publications

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“…Importantly, Imamura et al (65) provided further support for the role of rs2233424 in RA. They analyzed both knockdown and overexpression of NFKBIE in human RA synovial cells with and without the Val194Ala genetic variant (rs2233434).…”

Section: Candidate Pathogenic Variantsmentioning

confidence: 95%

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Laufer

Tiwari

Reynolds

et al. 2018

Human Molecular Genetics

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Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls. We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (P AA < 5 × 10 −9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes. We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs. We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

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Section: Candidate Pathogenic Variantsmentioning

confidence: 95%

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Laufer

Tiwari

Reynolds

et al. 2018

Human Molecular Genetics

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“…As an important inhibitor of the NFKB pathway, NFKBIE were strongly associated with chronic lymphocytic leukaemia (CLL) and melanoma, where NFKBIE mutations occur in 7% of CLL patients with a poor prognosis (29) and 14.5% of melanoma patients with a poor prognosis (30). Additionally, NFKBIE regions in granulocytes and macrophages participate in the regulation of the autoimmune response, which was an important immune signature in the rheumatoid arthritis microenvironment (31). These studies show that NFKBIE can limit tumour trans-differentiation from immune infiltration by the NFKB pathway.…”

Section: Taking Into Account the Importance Of Immune Infiltrationmentioning

confidence: 99%

Exploration of the immune-related signature and immune infiltration analysis for breast ductal and lobular carcinoma

Zhang

Wang

et al. 2019

Ann Transl Med

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Background: In this study, we aimed to explore the tumour associated immune signature of breast cancer (BC) and conduct integrative analyses with immune infiltrates in BC.Methods: We downloaded the transcriptome profiling and clinical data of BC from The Cancer Genome Atlas (TCGA) database. The list of immune-related signatures was from the Innate database. The limma package was utilized to conduct the normalization, and we screened the differential immune signatures in BC.A univariate Cox regression model and the LASSO method were used to find the hub prognostic immune genes. The TAIG risk model was calculated based on the multivariate Cox regression results, and a receiver operating characteristic (ROC) curve was generated to assess the predictive power of TAIG. Moreover, we also conducted a correlation analysis between TAIG and the clinical characteristics. Additionally, we utilized the METABRIC cohort as the validation data set. The TIMER database is a comprehensive resource for performing systematic analyses of immune infiltrates across various malignancies. We evaluated the associations of immune signatures with several immune cells based on TIMER. Furthermore, we used the CIBERSORT algorithm to determine the fractions of immune cells in each sample and compared the differential distributions of immune infiltrates between two TAIG groups using the Wilcoxon rank-sum test.Results: A total of 1,178 samples were obtained from the TCGA-BRCA database, but only 1,045 breast tumour samples were matched with complete transcriptome expression data. Meanwhile, we collected a total of 1,094 BC patients from the METABRIC cohort. We found a list of 1,399 differential immune signatures associated with survival, and functional analysis revealed that these genes participated in cytokine-cytokine receptor interactions, Th1 and Th2 cell differentiation and the JAK-STAT signalling pathway. The TAIG risk model was established from the multivariate Cox analysis, and we observed that high TAIG levels correlated with poor survival outcomes based on Kaplan-Meier analysis. The Kruskal-Wallis test suggested that high TAIG levels correlated with high AJCC-TNM stages and advanced pathological stages (P<0.01). We validated the well robustness of TAIG in METABRIC cohort and 5-year AUC reached up to 0.829. Moreover, we further uncovered the associations of hub immune signatures with immune cells and calculated the immune cell fractions in specific tumour samples based on gene signature expression. Last, we used the Wilcoxon ranksum test to compare the differential immune density in the two groups and found that several immune cells had a significantly lower infiltrating density in the high TAIG groups, including CD8 + T cells (P=0.031), memory resting CD4 + T cells (P=0.026), M0 macrophages (P=0.023), and M2 macrophages (P=0.048). Conclusions:In summary, we explored the immune signature of BC and constructed a TAIG risk model to predict prognosis. Moreover, we integrated the identified immune signature with tumour-infiltrating immune cell...

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“…Since MTX cannot pass through the plasma membrane because of its anionic nature, SLC19A1 ‐mediated cellular uptake has been regarded as the first step in the mode of action of MTX. Previous studies have shown that MTX‐resistance is associated with reduced expression and inactivation of SLC19A1 . DHFR catalyses the reduction of folic acid to dihydrofolic acid and further to tetrahydrofolic acid, an essential cofactor in the biosynthesis of thymidylate, purines and glycine .…”

Section: Introductionmentioning

confidence: 99%

SKA1 induces de novo MTX‐resistance in osteosarcoma through inhibiting FPGS transcription

Min²,

Lin

et al. 2019

The FEBS Journal

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De novo methotrexate (MTX)‐resistance, whose underlying mechanism remains largely unknown, usually leads to very poor prognosis in patients with osteosarcoma (OS). In this study, we established the de novo MTX‐resistant OS cell line SF‐86 and identified the candidate gene spindle and kinetochore associated complex subunit 1 (SKA1) as potentially related to de novo MTX‐resistance. Analysis of a cohort of 95 OS patients demonstrated that SKA1 overexpression significantly correlated with de novo MTX‐resistance and poor 5‐year survival. Mechanistically, SKA1 overexpression lead to a downregulation of folylpoly‐γ‐glutamate synthetase (FPGS), a key enzyme that converts MTX into its active form, MTX‐PG. We further demonstrated that SKA1 interacts with DNA‐directed RNA polymerase II subunit RPB3. ChIP analysis revealed that RPB3 binds the promoter region of the FPGS gene and triggers FPGS transcription upon MTX treatment in SW1353, a MTX‐sensitive OS cell line lacking endogenous SKA1 expression. On the contrary, this process is blocked in SF‐86 cells due to the formation of an inhibitory SKA1‐RPB3 complex. Furthermore, downregulation of SKA1 levels restores MTX sensitivity in SF‐86. Collectively, our study has established the de novo MTX‐resistant cell line SF‐86 and identified SKA1 as a novel regulator of FPGS, playing a key role in the development of de novo MTX‐resistance in OS.

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ImpairedNFKBIEgene function decreases cellular uptake of methotrexate by down-regulatingSLC19A1expression in a human rheumatoid arthritis cell line

Cited by 10 publications

References 44 publications

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Exploration of the immune-related signature and immune infiltration analysis for breast ductal and lobular carcinoma

SKA1 induces de novo MTX‐resistance in osteosarcoma through inhibiting FPGS transcription

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