Targeting FBXO22 enhances radiosensitivity of non-small cell lung cancer by inhibiting FOXM1/Rad51 axis
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ABSTRACT:
PROVIDER: PRJNA985761 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24971913_1.fastq.gz | Fastqsanger.gz | |||
| SRR24971913_2.fastq.gz | Fastqsanger.gz | |||
| SRR24971914_1.fastq.gz | Fastqsanger.gz | |||
| SRR24971914_2.fastq.gz | Fastqsanger.gz | |||
| SRR24971915_1.fastq.gz | Fastqsanger.gz |
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Project description:FBXO22 is the substrate recognition subunit of SCF E3 ubiquitin ligase, which plays an important role in the occurrence, development and therapeutic response of solid tumors.At present, the relationship between FBXO22 and radiosensitivity of lung cancer has not been fully elucidated.Here we present evidence to prove that abnormally expressed FBXO22 in lung cancer promotes transcriptional activation of homologous recombination enzyme Rad51 by up-regulating transcription factor FOXM1, which in turn induces radioresistance in lung cancer.By comparing with the reference data set of cMap database, Deguelin was identified as a small molecular inhibitor of FBXO22.Deguelin increases the radiosensitivity of lung cancer cells in vitro and in vivo in a FBXO22-dependent manner and is safely tolerated.This study revealed the identity of a novel radioresistance biomarker of FBXO22 and provided preclinical evidence for the clinical transformation of this target by screening small molecular inhibitors.
2024-02-07 | GSE235374 | GEO
Project description:Radioresistance is a predominant obstacle of effective treatments in non-small cell lung cancer (NSCLC), while the underlying mechanism remains incompletely elucidated. Spindlin 1(SPIN1) has been reported to participate in tumor initiation and progression, while its role in NSCLC tumorigenesis and radioresistance remains largely unknown. In this study, bioinformatics analysis, immunohistochemistry (IHC) and western blotting assays were performed to test SPIN1 expression in NSCLC samples and cell lines. The carcinogenic role of SPIN1 was evaluated by cell growth and proliferation, EdU staining, transwell and colony formation assays. Besides, the radiosensitivity of NSCLC cells was determined by clonogenic cell survival, neutral comet and γ-H2AX and Rad51 foci formation assays. Xenograft tumor model was constructed to access the effects of SPIN1 on tumorigenesis and radiosensitivity. Furthermore, RNA sequencing, quantitative real-time PCR, CHX and ubiquitination assays were applied to elucidate the correlation between SPIN1 and FOXO3a-FOXM1 axis. Therefore, our results suggest that the SPIN1-MDM2-FOXO3a/FOXM1 signaling axis is essential for NSCLC progression and radioresistance, and it could serve as therapeutic targets in irradiation-resistance NSCLC.
2024-11-20 | GSE276500 | GEO
Project description:Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines, generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression OSCC cell lines, including CRR cell lines, and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell types. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific siRNA treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.
2022-10-01 | GSE210922 | GEO
Project description:Twenty-five miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation. MiR-449a might be a novel radiosensitizer for clinical applications. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5) with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips.
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Project description:KDM4C, a histone lysine demethylase, has been proposed to participate in malignant transformation and progression in several types of cancer. However, its roles in hepatocellular carcinoma (HCC) remain poorly understood. In this study, we report that KDM4C protein level is upregulated and KDM4C silencing inhibits cell growth, proliferation and migration in HCC. Furthermore, we provide evidence that depletion of KDM4C leads to defective G2/M checkpoint, increases radiation-induced DNA damage and impairs DNA repair, and enhances radiosensitivity in HCC cells. Using RNA sequencing, we uncover that chemokine CXCL2 is a downstream effector of KDM4C. KDM4C knockdown upregulates the expression of CXCL2 and promotes the secretion of CXCL2 in HCC cells. Importantly, the observed effects caused by KDM4C depletion in HCC cells can be partially rescued by CXCL2 silencing. Thus, our findings demonstrate that KDM4C is involved in the cell migration and radiosensitivity via modulating CXCL2, indicating that KDM4C may be a potential therapeutic target in HCC.
2023-05-03 | GSE189941 | GEO
Project description:Glioblastoma is among the most common malignant brain tumors and has a dismal prognosis due to the poor response to therapeutic regimens such as ionizing radiation and DNA-alkylating agents. In our study, we investigated the radiosensitizing activity of the N6-isopentenyladenosine (iPA), an naturally modified adenosine harboring an isopenenyl moiety, which shows antiproliferative effects on glioblastoma cell lines. We observed that co-treatment with ionizing radiation and iPA at micromolar concentration inhibited colony formation and viability of glioblastoma cell lines but not of non-malignant human cells. The combined treatment significantly attenuated the repair of radiation-induced DNA damage by inhibiting both the expression and irradiation-induced foci formation of RAD51, a key player in the homologous recombination repair process, leading to persistent DNA damage, as reflected by an increase of ?-H2AX foci. The radiosensitizing effect relied also on the inhibition of STAT5a/b activation, which is crucial for RAD51 expression, suggesting that iPA modulates the STAT5a/b-RAD51 axis following exposure to ionizing radiation. Overall, these data suggest that iPA, by acting through RAD51 inhibition at the mechanistic level, could function as a promising radiosensitizing agent and warrants further evaluation in prospective clinical trials.
| S-EPMC6971108 | biostudies-literature
Project description:Fork-head box protein M1 (FoxM1) is a transcription factor which plays critical roles in development and progression of multiple cancers, including human hepatocellular carcinoma (HCC). However, the regulatory mechanism of FoxM1 itself remains largely unclear. Here, we discovered a novel role of abnormal spindle-like microcephaly associated (ASPM) in HCC, which binds to FoxM1 protein and enhances its stability by preventing proteasome-mediated degradation. ChIP-sequencing data showed that ASPM and FoxM1 co-occupies on the promoter region of multiple genes to promote their transcriptions, leading to the enhancement of a FoxM1-driven oncogenic progression. Intriguingly, FoxM1 binds to the promoter region of ASPM and transcriptionally activates the ASPM expression. Furthermore, data from clinical samples showed that a higher co-expression of ASPM and FoxM1 significantly correlates with poor prognosis in HCC, indicating that a positive feedforward loop between ASPM and FoxM1 coordinately promotes the aggressive progression in HCC. Collectively, our study reveals that reciprocal regulation of ASPM and FoxM1 amplifies the oncogenic progression and emphasizes an ASPM-FoxM1 feedforward loop could be a potential biomarker and therapeutic target in HCC.
2024-11-01 | GSE218100 | GEO
Project description:NAA enhances cell yields by inhibiting apoptosis pathway
| PRJNA1027747 | ENA
Project description:The Forkhead Box m1 (Foxm1 or Foxm1b) protein (previously called HFH-11B, Trident, Win, or MPP2) is abundantly expressed in human non-small cell lung cancers where it transcriptionally induces expression of genes essential for proliferation of tumor cells. In this study, we used Rosa26-Foxm1 transgenic mice, in which the Rosa26 promoter drives ubiquitous expression of Foxm1 transgene, to identify new signaling pathways regulated by Foxm1. Lung tumors in Rosa26-Foxm1 mice were induced using the 3-methylcholanthrene (MCA)/ butylated hydroxytoluene (BHT) lung tumor initiation/ promotion protocol. MCA/BHT-treated Rosa26-Foxm1 mice displayed a significant increase in the proliferation of lung tumor cells as well as in the number and size of lung adenomas. Elevated tumor formation in Rosa26-Foxm1 transgenic lungs was associated with persistent pulmonary inflammation, macrophage infiltration and increased expression of Cdc25C phosphatase, cyclin E2, chemokine ligands Cxcl5, Cxcl1 and Ccl3, cathepsins, and Matrix metalloprotease 12, all of which stimulate signaling pathways essential for cellular proliferation, pulmonary inflammation and remodeling. Lung tumors from Rosa26-Foxm1 mice displayed increased expression of Cyclooxygenase-2 (Cox-2), whereas diminished Cox-2 levels were observed in Foxm1-deficient lung tumors from Mx-Cre Foxm1 fl/fl mice. Cell culture experiments with A549 human lung adenocarcinoma cells demonstrated that depletion of Foxm1 by either siRNA transfection or treatment with Foxm1-inhibiting ARF 26-44 peptide significantly reduced Cox-2 expression. Foxm1 protein bound to the –3479/–3461 and –7826/–7795 bp regions of the human Cox-2 promoter, indicating that the human Cox-2 gene is a direct transcriptional target of Foxm1 in lung tumor cells. Keywords: Influence of genetic modification to the tumor development
2007-09-28 | GSE6641 | GEO
Project description:Background:Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line. Methods:Cell proliferation was measured with cell counting kit-8 (CCK-8) assay. Flow cytometry analysis was performed to examine cell cycle distribution and apoptosis. The phosphorylation of EGFR and its downstream signaling molecules were measured by Western blot analysis. ?-H2AX foci and RAD51 foci in the cellular nucleus were visualized using immunofluoresence staining. Expression levels of RAD51 in the whole cells and subceullar fractions were detected to demonstrate the impact of IH on DNA repair. Results:IH can significantly inhibit cell proliferation, redistribute cell cycle, enhance apoptosis and impair DNA damage response of Hela S3 cells following radiation or cisplatin treatment through suppressing the activation of the EGFR signaling pathway and attenuating the expression and function of homologous recombination (HR) protein RAD51. Conclusion:This study suggests that IH is a potential sensitizer in radiotherapy and cisplatin-based chemotherapy for CC and RAD51 may serve as a prognosis biomarker for this combination treatment.
| S-EPMC5843137 | biostudies-literature