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MicroRNA-155-5p Contributes to 5-Fluorouracil Resistance Through Down-Regulating TP53INP1 in Oral Squamous Cell Carcinoma.

ABSTRACT: The anticancer drug 5-fluorouracil (5-FU) resistance is a major obstacle to reducing the effectiveness of cancer treatment, and its detailed mechanism has not been fully elucidated. Here, in 5-FU-resistant human oral squamous cell carcinoma (OSCC) HSC3 cells (HSC3/5-FU), the levels of 21 miRNA candidates were detected using RT-PCR and miR-155-5p level increased strikingly in HSC3/5-FU cells compared to HSC3 cells. Compared with HSC3 cells, the CCK-8 assay showed that the HSC3/5-FU cells transfected with miR-155-5p inhibitors decreased 5-FU IC50. Ectopic expression of miR-155-5p in HSC3 and HSC4 cells increased 5-FU IC50 (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) abilities. Seven miR-155-5p target candidates were discovered by miRNA prediction algorithms (miRDB, Targetscan, and miRWalk), and the RT-PCR results showed that in HSC3/5-FU cells TP53INP1 was of the lowest mRNA expression level compared with HSC3 cells. The RT-PCR and Western blotting assays showed that ectopic expression of miR-155-5p in HSC3 and HSC4 cells decreased TP53INP1 expression level. Furthermore, the luciferase reporter and RNA pull-down assays determined the interference effect of miR-155-5p on TP53INP1 expression. The enhancement of cell viability (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) by miR-155-5p after 5-FU treatment was reversed by TP53INP1 overexpression. After treatment with 5-FU, HSC3-miR-155-5p tumor-bearing nude mice presented growing tumors, while HSC3-TP53INP1 group possessed shrinking tumors. In conclusion, these results lead to the proposal that miR-155-5p enhances 5-FU resistance by decreasing TP53INP1 expression in OSCC.

SUBMITTER: Liu B

PROVIDER: S-EPMC8770267 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHypersensitivity pneumonitis (HP) is an inflammatory disorder affecting lung parenchyma and often evolves into fibrosis (fHP). The altered regulation of genes involved in the pathogenesis of the disease is not well comprehended, while the role of microRNAs in lung fibroblasts remains unexplored.MethodsWe used integrated bulk RNA-Seq and enrichment pathway bioinformatic analyses to identify differentially expressed (DE)-miRNAs and genes (DEGs) associated with HP lungs. In vitro, we evaluated the expression and potential role of miR-155-5p in the phenotype of fHP lung fibroblasts. Loss and gain assays were used to demonstrate the impact of miR-155-5p on fibroblast functions. In addition, mir-155-5p and its target TP53INP1 were analyzed after treatment with TGF-β, IL-4, and IL-17A.ResultsWe found around 50 DEGs shared by several databases that differentiate HP from control and IPF lungs, constituting a unique HP lung transcriptional signature. Additionally, we reveal 18 DE-miRNAs that may regulate these DEGs. Among the candidates likely associated with HP pathogenesis was miR-155-5p. Our findings indicate that increased miR-155-5p in fHP fibroblasts coincides with reduced TP53INP1 expression, high proliferative capacity, and a lack of senescence markers compared to IPF fibroblasts. Induced overexpression of miR-155-5p in normal fibroblasts remarkably increases the proliferation rate and decreases TP53INP1 expression. Conversely, miR-155-5p inhibition reduces proliferation and increases senescence markers. TGF-β, IL-4, and IL-17A stimulated miR-155-5p overexpression in HP lung fibroblasts.ConclusionOur findings suggest a distinctive signature of 53 DEGs in HP, including CLDN18, EEF2, CXCL9, PLA2G2D, and ZNF683, as potential targets for future studies. Likewise, 18 miRNAs, including miR-155-5p, could be helpful to establish differences between these two pathologies. The overexpression of miR-155-5p and downregulation of TP53INP1 in fHP lung fibroblasts may be involved in his proliferative and profibrotic phenotype. These findings may help differentiate and characterize their pathogenic features and understand their role in the disease.

Project description:Long non?coding RNA (lncRNA) LINC00473 plays a carcinogenic role in a variety of different tumor types. Nevertheless, the mechanisms through which LINC00473 regulates the radiosensitivity of esophageal squamous cell carcinoma (ESCC) cells remains elusive. In the present study, reverse transcription?quantitative PCR was used to quantify the expression of LINC00473, microRNA (miRNA/miR)?497?5p and cell division cycle 25A (CDC25A) in ESCC tissues. The association between LINC00473 expression and the clinicopathological characteristics of patients with ESCC was also assessed. Furthermore, Cell Counting kit?8 and colony formation assays were carried out to monitor the proliferation of ESCC cells exposed to X?ray radiation. A dual?luciferase reporter assay was also conducted to analyze the interaction between LINC00473 and miR?497?5p, as well as the interaction between CDC25A and miR?497?5p. The findings of the present study demonstrated that in ESCC tissues and cells, the expression levels of LINC00473 and CDC25A were significantly upregulated, while the expression of miR?497?5p was downregulated. The high expression level of LINC00473 was associated with a higher T stage, lymph node metastasis stage and a lower tumor differentiation grade in patients with ESCC. Following irradiation, transfection with miR?497?5p mimics reduced the promoting effect of LINC00473 overexpression on ESCC cell proliferation, and partially impeded the resistance of ESCC cells to X?ray radiation induced by LINC00473 overexpression. Moreover, transfection with miR?497?5p inhibitors partially alleviated the inhibitory effects of LINC00473 knockdown on cellular proliferation, and partly reversed the sensitivity of cells to X?ray irradiation induced by LINC00473 knockdown. Furthermore, it was confirmed that miR?497?5p was able to bind LINC00473 and the 3'?untranslated region of CDC25A. On the whole, the findings of the present study demonstrate that LINC00473 reduces the radiosensitivity of ESCC cells by modulating the miR?497?5p/CDC25A axis.

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MicroRNA-155-5p Contributes to 5-Fluorouracil Resistance Through Down-Regulating TP53INP1 in Oral Squamous Cell Carcinoma.

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