GSR Mediates Cisplatin Resistance in Oral Cancer by Protecting Mitochondria

Abstract

Background The existing cisplatin chemotherapy treatment for recurrent or metastatic oral squamous cell carcinoma (R/M OSCC) has been the conventional treatment, and it is also a relatively effective treatment method to improve the survival rate of patients. However, due to the resistance of tumor cells to chemotherapy, the treatment effect is poor. So far, the causes of chemotherapy resistance of tumor cells and the potential targets to overcome chemotherapy resistance remain unclear. Methods Based on CRISPR/Cas9 library high-throughput screening technology, small guide RNA (sgRNA) targeting candidate genes (coding and non-coding genes) were enriched to find target candidate genes. The complete process includes the following main steps: lentivirus library construction, library virus infected cells, cell experimental screening, genomic DNA extraction and amplification of sgRNA fragments, high-throughput sequencing and bioinformatics analysis. Subsequently, a series of phenotypic verification of candidate genes and the molecular mechanism behind the phenotype were explored, so as to find molecular targets that can effectively overcome cisplatin resistance in R/M OSCC. Results We found that GSR gene can cause cisplatin resistance in OSCC cells. The database showed no difference in the expression of GSR in head and neck cancer patients and normal people, but there was a difference between patients who were sensitive to cisplatin chemotherapy and those who were resistant to cisplatin, with higher expression in patients who were resistant to chemotherapy. Compared with tumor cells with GSR gene knocked out, under the same concentration of cisplatin, tumor cells without GSR gene knocked out can activate endoplasmic reticulum stress to relieve the pressure brought by cisplatin, thereby protecting intracellular mitochondria from damage and leading to cisplatin resistance. Conclusion These results suggest that GSR gene is a key gene that regulates and drives cisplatin chemotherapy resistance in oral squamous cell carcinoma, and at the same time provides a screening and analysis strategy for studying OSCC cisplatin chemotherapy resistance.