Dataset Information

CD44 occurring alternative splicing promotes cisplatin resistance and evokes tumor immune response in oral squamous cell carcinoma cells.

ABSTRACT:

Background

Oral squamous cell carcinoma (OSCC) is the most prevalent malignant tumor in head and neck region. Platinum drug resistance limits the clinical application of chemotherapy regardless of medical development. The aim of our study is to identify cisplatin-resistant genes which can be used as new therapeutic targets and investigate the functional mechanism of OSCC chemoresistance.

Methods

The OSCC Cal27 and HSC4 cisplatin-resistant cell lines were constructed to screen the differential genes/transcripts expression. GO, KEGG and GSEA were performed to reveal the relevant signaling pathways. Alternative splicing (AS) software rMATs was applied to explore AS events in chemoresistance. R package and TIMER tools were used to evaluate the linear correlation between CD44 and immune cell subpopulations. The co-culture model of dendritic cells (DCs) and OSCC cells was applied to explore the effect of CD44 on immune microenvironment and cisplatin resistance.

Results

Our results showed that CD44 was differentially expressed in cisplatin-resistant OSCC cells. Through bioinformatics prediction and experimental verification, we confirmed that CD44 occurring AS was involved in tumor progression and cisplatin resistance. Moreover, CD44 could further enhance the cisplatin resistance of OSCC by activating DCs, making CD44 to be a potential intervention target. We also identified DC as a new target for platinum drugs to stimulate the growth of OSCC.

Conclusion

Our findings not only make it possible to explore new therapeutic methods, such as CD44 inhibitors or antisense oligonucleotides, but also provide insights into the new mechanisms of cisplatin resistance to chemotherapy.

SUBMITTER: Qiao X

PROVIDER: S-EPMC9982036 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

CD44 occurring alternative splicing promotes cisplatin resistance and evokes tumor immune response in oral squamous cell carcinoma cells.

Qiao Xue X Zhu Li L Song Rongbo R Shang Chao C Guo Yan Y

Translational oncology 20230222

<h4>Background</h4>Oral squamous cell carcinoma (OSCC) is the most prevalent malignant tumor in head and neck region. Platinum drug resistance limits the clinical application of chemotherapy regardless of medical development. The aim of our study is to identify cisplatin-resistant genes which can be used as new therapeutic targets and investigate the functional mechanism of OSCC chemoresistance.<h4>Methods</h4>The OSCC Cal27 and HSC4 cisplatin-resistant cell lines were constructed to screen the ...[more]

PMID: 36827716

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Project description:BackgroundRadiotherapy is the primary treatment for patients with nasopharyngeal carcinoma (NPC); however, almost 20% of patients experience treatment failure due to radioresistance. Therefore, understanding the mechanisms of radioresistance is imperative. HOTAIRM1 is deregulated in various human cancers, yet its role in NPC radioresistance are largely unclear.MethodsThis study investigated the association between HOTAIRM1 and radioresistance using CCK8, flow cytometry, and comet assays. Additionally, xenograft mice and patient-derived xenografts (PDX) models were employed to elucidate the biological functions of HOTAIRM1, and transcriptomic RNA sequencing was utilized to identify its target genes.ResultsOur study revealed an upregulation of HOTAIRM1 levels in radioresistant NPC cell lines and tissues. Furthermore, a positive correlation was noted between high HOTAIRM1 expression and increased NPC cell proliferation, reduced apoptosis, G2/M cell cycle arrest, and diminished cellular DNA damage following radiotherapy. HOTAIRM1 modulates the acetylation and stability of the FTO protein, and inhibiting FTO elevates the m6A methylation level of CD44 precursor transcripts in NPC cells. Additionally, silencing the m6A reading protein YTHDC1 was found to increase the expression of CD44V. HOTAIRM1 enhances NPC cell resistance to ferroptosis and irradiation through the HOTAIRM1-FTO-YTHDC1-CD44 axis. Mechanistically, HOTAIRM1 interacts with the FTO protein and induces m6A demethylation of the CD44 transcript. The absence of m6A modification in the CD44 transcript prevents its recognition by YTHDC1, resulting in the transition from CD44S to CD44V. An abundance of CD44V suppresses ferroptosis induced by irradiation and contributes to NPC radioresistance.ConclusionsIn conclusion, the results in this study support the idea that HOTAIRM1 stimulates CD44 alternative splicing via FTO-mediated demethylation, thereby attenuating ferroptosis induced by irradiation and promoting NPC radioresistance.

Dataset Information

CD44 occurring alternative splicing promotes cisplatin resistance and evokes tumor immune response in oral squamous cell carcinoma cells.

Background

Methods

Results

Conclusion

Publications

CD44 occurring alternative splicing promotes cisplatin resistance and evokes tumor immune response in oral squamous cell carcinoma cells.

Similar Datasets

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