p53/MicroRNA-34 axis in cancer and beyond

Pan, Wei; Chai, Binshu; Li, Langping; Lu, Zhijun

doi:10.1016/j.heliyon.2023.e15155

Cited by 13 publications

(11 citation statements)

References 113 publications

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“…This result is attributed to the inactive Jurkat T cells not producing enough IFN-γ factors or molecules directly affecting SLC7A11/Xct expression or activity, but when they were stimulated well by anti-CD3/CD28, sufficiently releasing IFN-γ enhances the suppression effect in SLC7A11/Xct expression. MiRNA34a can upregulate p53 activity by directly targeting inhibitors of p53 such as SIRT1 (silent mating type information regulation 2 homologue 1) . The expression of SLC7A11/Xct can also be downregulated at the transcriptional level by p53.…”

Section: Resultsmentioning

confidence: 99%

“…MiRNA34a can upregulate p53 activity by directly targeting inhibitors of p53 such as SIRT1 (silent mating type information regulation 2 homologue 1). 64 The expression of SLC7A11/Xct can also be downregulated at the transcriptional level by p53. The repressed expression reduces the cystine uptake, and it is unavailability can limit glutathione synthesis and sensitize cells to ferroptosis.…”

Section: Resultsmentioning

confidence: 99%

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Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

Pandey,

Chiu,

Wang

2024

Mol. Pharmaceutics

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Immunotherapy has emerged as a promising approach for cancer treatment, and the use of microRNAs (miRNAs) as therapeutic agents has gained significant attention. In this study, we investigated the effectiveness of immunotherapy utilizing miRNA34a and Jurkat T cells in inducing cell death in non-small-cell lung cancer cells, specifically A549 cells. Moreover, we explored the impact of Jurkat T cell activation and miRNA34a delivery using iron oxide nanorods (IONRs) on the killing of cancer cells. A549 cells were cocultured with both activated and inactivated Jurkat T cells, both before and after the delivery of miRNA34a. Surprisingly, our results revealed that even inactive Jurkat T cells were capable of inducing cell death in cancer cells. This unexpected observation suggested the presence of alternative mechanisms by which Jurkat T cells can exert cytotoxic effects on cancer cells. We stimulated Jurkat T cells using anti-CD3/CD28 and analyzed their efficacy in killing A549 compared to that of the inactive Jurkat T cells in conjunction with miRNA34a. Our findings indicated that the activation of Jurkat T cells significantly enhanced their cytotoxic potential against cancer cells compared to their inactive counterparts. The combined treatment of A549 cells with activated Jurkat T cells and miRNA34a demonstrated the highest level of cancer cell death, suggesting a synergistic effect between Jurkat T cell activation and miRNA therapy. Besides the apoptosis mechanism for the Jurkat T cells' cytotoxic effects on A549 cells, we furthermore investigated the ferroptosis pathway, which was found to have an impact on the cancer cell killing due to the presence of miRNA34a and IONRs as the delivery agent inside the cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

Pandey,

Chiu,

Wang

2024

Mol. Pharmaceutics

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“…In our study, the level of PD-L1 in the TP53 -mutant group was significantly lower than that in the TP53 wild-type group, and the result was consistent across multiple databases (RNA-sequencing and RPPA). Previous studies have reported that p53 can enhance PD-L1 expression by regulating the loss of function of miR-34 ( 24 , 25 ). However, we did not find a positive correlation between miR-34 and TP53 status in our study.…”

Section: Discussionmentioning

confidence: 99%

Predicting therapeutic responses in head and neck squamous cell carcinoma from TP53 mutation detected by cell-free DNA

Wei,

Zhi,

et al. 2023

Transl Cancer Res

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Background Head and neck squamous cell carcinoma (HNSCC) is an epithelial malignant tumor originating from the oral cavity, oropharynx, nasal cavity, sinuses, nasopharynx, hypopharynx, or larynx. Mutations in TP53 are the most common of all somatic genomic changes in HNSCC, and TP53 mutations are associated with the response to immunotherapy and chemotherapy. Tumor-derived circulating cell-free DNA (cfDNA) is a minimally invasive method to determining genetic alterations in cancer. This study aimed to explore the therapeutic responses of patients with HNSCC with TP53 mutation and the accuracy of cfDNA for detecting TP53 mutation. Methods Information on TP53 mutations, patient survival time, and clinical data in HNSCC were downloaded from The Cancer Genome Atlas database. The difference in immune infiltration between the TP53- mutant group and the wild-type group was compared. We applied the single-sample gene set enrichment analysis method on the transcriptome of HNSCC samples to assess the distribution of immune cell types between the two groups. The chemotherapy response was constructed using the R software package, “pRRophetic”. Gene set enrichment analysis was performed based on the TP53 mutation. The next-generation sequencing was executed on cfDNA from nine patients with HNSCC to detect genetic alterations. Tumor biopsy (n=9) was sequenced using the same technique. Results TP53 was the most frequently mutated gene in HNSCC. The TP53 mutation was related to immune cells and the expression of immune-associated genes. The TP53 mutation group showed lower response to immunotherapy but high sensitivity to some chemotherapies compared with the wild-type group. TP53 was the most frequently mutated gene (6/9; 66.67%) in cfDNA. Only 27.27% of TP53 mutations in tumor tissue were detected outside of cfDNA. Conclusions TP53 mutation could be used as a specific predictor of treatment response in patients with HNSCC. Using cfDNA to detect the TP53 mutations in patients with HSNCC is a feasible method. The results suggested that the therapeutic response in patients could be predicted by detecting TP53 mutations in cfDNA, and large-scale and prospective studies are needed to validate this hypothesis.

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“…MiRNA-34a, the master regulator of tumor suppression, was discovered to be downregulated in a variety of malignancies, including BC [ 6 , 32 ]. Furthermore, miRNA-34a-5p, derived from miRNA-34a, has been perceived to inhibit cell migration, invasion, and tumor development [ 14 ] and suggested a correlated mechanism between miRNA-34a and anti-apoptotic proteins [ 39 ]. The strategy of miRNA-34a replacement has been explored in clinical trials as the first challenge of miRNA application in cancer treatment [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Because of its critical role in several oncogenic pathways of cancer types, including apoptosis and cell proliferation, miRNA-34a has recently motivated the interest of numerous researchers. Moreover, miRNA-34a has been established to be associated with drug resistance in BC [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Restoring microRNA-34a overcomes acquired drug resistance and disease progression in human breast cancer cell lines via suppressing the ABCC1 gene

Yahya,

Nabih,

Elsayed

et al. 2023

Breast Cancer Res Treat

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Purpose Breast cancer is one of the leading types of cancer diagnosed in women. Despite the improvements in chemotherapeutic cure strategies, drug resistance is still an obstacle leading to disease aggressiveness. The small non-coding RNA molecules, miRNAs, have been implicated recently to be involved as regulators of gene expression through the silencing of mRNA targets that contributed to several cellular processes related to cancer metastasis. Hence, the present study aimed to investigate the beneficial role and mechanism of miRNA-34a-based gene therapy as a novel approach for conquering drug resistance mediated by ATP-binding cassette (ABC) transporters in breast cancer cells, besides exploring the associated invasive behaviors. Material and Methods Bioinformatics tools were used to predict miRNA ABC transporter targets by tracking the ABC transporter pathway. After the establishment of drug-resistant breast cancer MCF-7 and MDA-MB-231 sublines, cells were transfected with the mimic or inhibitor of miRNA-34a-5p. The quantitative expression of genes involved in drug resistance was performed by QRT-PCR, and the exact ABC transporter target specification interaction was confirmed by dual-luciferase reporter assay. Furthermore, flow cytometric analysis was utilized to determine the ability of miRNA-34a-treated cells against doxorubicin uptake and accumulation in cell cycle phases. The spreading capability was examined by colony formation, migration, and wound healing assays. The apoptotic activity was estimated as well. Results Our findings firstly discovered the mechanism of miRNA-34a-5p restoration as an anti-drug-resistant molecule that highly significantly attenuates the expression of ABCC1 via the direct targeting of its 3′- untranslated regions in resistant breast cancer cell lines, with a significant increase of doxorubicin influx by MDA-MB-231/Dox-resistant cells. Additionally, the current data validated a significant reduction of metastatic potentials upon miRNA-34a-5p upregulation in both types of breast cancer-resistant cells. Conclusion The ectopic expression of miRNA-34a ameliorates the acquired drug resistance and the migration properties that may eventually lead to improved clinical strategies and outcomes for breast cancer patients. Additionally, miRNA-34a could be monitored as a diagnostic/prognostic biomarker for resistant conditions.

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p53/MicroRNA-34 axis in cancer and beyond

Cited by 13 publications

References 113 publications

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

Immunotherapy Study on Non-small-Cell Lung Cancer (NSCLC) Combined with Cytotoxic T Cells and miRNA34a

Predicting therapeutic responses in head and neck squamous cell carcinoma from TP53 mutation detected by cell-free DNA

Restoring microRNA-34a overcomes acquired drug resistance and disease progression in human breast cancer cell lines via suppressing the ABCC1 gene

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