ABSTRACT
BACKGROUND: Doxorubicin (DOX) resistance remains a major challenge for adriamycin-based treatment of breast cancer (BC). Transforming growth factor ß (TGF-ß) has been reported to contribute to drug resistance. Although the role of long noncoding RNAs (LncRNAs) in cancer progression has been widely studied, its effect on TGF-ß-induced resistance remains limited. This study aimed to investigate the role of LncRNA on the regulation of TGF-ß-induced drug resistance. METHODS: Cell counting kit-8 (CCK-8) and an EdU assay were used to evaluate cell viability and proliferation. The level of LncRNA mRNA expression in BC tissues and cells was examined by quantitative real-time PCR. Changes in epithelial-mesenchymal transition (EMT) and cell apoptosis were quantified by Western blot and immunofluorescence. RESULTS: TGF-ß induced EMT and promoted DOX resistance. LncRNA urothelial carcinoma-associated 1(lncRNA UCA1) associated with TGF-ß was upregulated in BC cells and tissues. LncRNA UCA1 silencing enhanced sensitivity to DOX decreased cellular proliferation and increased apoptosis in BC cells. The effect of TGF-ß on EMT and DOX resistance disappeared following a lncRNA UCA1 knockdown. CONCLUSIONS: These findings suggest that lncRNA-UCA1, a mediator of TGF-ß signaling, could predispose BC patients to EMT and DOX resistance.
Subject(s)
Breast Neoplasms , Doxorubicin , Drug Resistance, Neoplasm , RNA, Long Noncoding , Apoptosis , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation , Doxorubicin/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , RNA, Long Noncoding/genetics , Transforming Growth Factor beta/metabolism , Up-RegulationABSTRACT
Modified nucleosides on tRNA are critical for decoding processes and protein translation. tRNAs can be modified through 1-methylguanosine (m1G) on position 37; a function mediated by Trm5 homologs. We show that AtTRM5a (At3g56120) is a Trm5 ortholog in Arabidopsis thaliana. AtTrm5a is localized to the nucleus and its function for m1G and m1I methylation was confirmed by mutant analysis, yeast complementation, m1G nucleoside level on single tRNA, and tRNA in vitro methylation. Arabidopsis attrm5a mutants were dwarfed and had short filaments, which led to reduced seed setting. Proteomics data indicated differences in the abundance of proteins involved in photosynthesis, ribosome biogenesis, oxidative phosphorylation and calcium signalling. Levels of phytohormone auxin and jasmonate were reduced in attrm5a mutant, as well as expression levels of genes involved in flowering, shoot apex cell fate determination, and hormone synthesis and signalling. Taken together, loss-of-function of AtTrm5a impaired m1G and m1I methylation and led to aberrant protein translation, disturbed hormone homeostasis and developmental defects in Arabidopsis plants.
Subject(s)
Arabidopsis Proteins/metabolism , Arabidopsis/enzymology , Guanosine/analogs & derivatives , Inosine/analogs & derivatives , RNA, Transfer/metabolism , tRNA Methyltransferases/metabolism , Arabidopsis/growth & development , Arabidopsis Proteins/genetics , Arabidopsis Proteins/physiology , Biocatalysis , Calcium Signaling , Cell Nucleus/enzymology , Guanosine/metabolism , Indoleacetic Acids/metabolism , Inosine/metabolism , Mutation , Photosynthesis , RNA, Transfer/chemistry , Ribosomes/metabolism , tRNA Methyltransferases/genetics , tRNA Methyltransferases/physiologyABSTRACT
CORRECTION: Following publication of the original article [1], the authors reported that there was a mistake in the presentation of their funding information. The sentence "This study was supported by the National Natural Science Foundation of China (31,100,268 to Peng Chen, 31,270,658 to Bo Zheng);" should instead read "This study was supported by the National Natural Science Foundation of China (31100268 to Peng Chen, 31370604 to Bo Zheng);".
ABSTRACT
BACKGROUND: Modification of nucleosides on transfer RNA (tRNA) is important either for correct mRNA decoding process or for tRNA structural stabilization. Nucleoside methylations catalyzed by MTase (methyltransferase) are the most common type among all tRNA nucleoside modifications. Although tRNA modified nucleosides and modification enzymes have been extensively studied in prokaryotic systems, similar research remains preliminary in higher plants, especially in crop species, such as rice (Oryza sativa). Rice is a monocot model plant as well as an important cereal crop, and stress tolerance and yield are of great importance for rice breeding. RESULTS: In this study, we investigated how the composition and abundance of tRNA modified nucleosides could change in response to drought, salt and cold stress, as well as in different tissues during the whole growth season in two model plants-O. sativa and Arabidopsis thaliana. Twenty two and 20 MTase candidate genes were identified in rice and Arabidopsis, respectively, by protein sequence homology and conserved domain analysis. Four methylated nucleosides, Am, Cm, m1A and m7G, were found to be very important in stress response both in rice and Arabidopsis. Additionally, three nucleosides,Gm, m5U and m5C, were involved in plant development. Hierarchical clustering analysis revealed consistency on Am, Cm, m1A and m7G MTase candidate genes, and the abundance of the corresponding nucleoside under stress conditions. The same is true for Gm, m5U and m5C modifications and corresponding methylation genes in different tissues during different developmental stages. CONCLUSIONS: We identified candidate genes for various tRNA modified nucleosides in rice and Arabidopsis, especially on MTases for methylated nucleosides. Based on bioinformatics analysis, nucleoside abundance assessments and gene expression profiling, we propose four methylated nucleosides (Am, Cm, m1A and m7G) that are critical for stress response in rice and Arabidopsis, and three methylated nucleosides (Gm, m5U and m5C) that might be important during development.
