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Identification of genes associated with cisplatin resistance in human oral squamous cell carcinoma cell line
Ping Zhang1, Zhiyuan Zhang, Xiaojian Zhou
1Department of Oral & Maxillofacial Surgery, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China. pingzhang73@hotmail.com
Background:
Cisplatin is widely used for chemotherapy of head and neck squamous cell carcinoma. However, details of the molecular mechanism responsible for cisplatin resistance are still unclear. The aim of this study was to identify the expression of genes related to cisplatin resistance in oral squamous cell carcinoma cells.
Methods:
A cisplatin-resistant cell line, Tca/cisplatin, was established from a cisplatin-sensitive cell line, Tca8113, which was derived from moderately-differentiated tongue squamous cell carcinoma. Global gene expression in this resistant cell line and its sensitive parent cell line was analyzed using Affymetrix HG-U95Av2 microarrays. Candidate genes involved in DNA repair, the MAP pathway and cell cycle regulation were chosen to validate the microarray analysis results. Cell cycle distribution and apoptosis following cisplatin exposure were also investigated.
Results:
Cisplatin resistance in Tca/cisplatin cells was stable for two years in cisplatin-free culture medium. The IC50 for cisplatin in Tca/cisplatin was 6.5-fold higher than that in Tca8113. Microarray analysis identified 38 genes that were up-regulated and 25 that were down-regulated in this cell line. Some were novel candidates, while others are involved in well-characterized mechanisms that could be relevant to cisplatin resistance, such as RECQL for DNA repair and MAP2K6 in the MAP pathway; all the genes were further validated by Real-time PCR. The cell cycle-regulated genes CCND1 and CCND3 were involved in cisplatin resistance; 24-hour exposure to 10 microM cisplatin induced a marked S phase block in Tca/cisplatin cells but not in Tca8113 cells.
Conclusion:
The Tca8113 cell line and its stable drug-resistant variant Tca/cisplatin provided a useful model for identifying candidate genes responsible for the mechanism of cisplatin resistance in oral squamous cell carcinoma. Our data provide a useful basis for screening candidate targets for early diagnosis and further intervention in cisplatin resistance.
Insights
Researchers identified genes linked to cisplatin resistance in oral squamous cell carcinoma using a resistant cell line model. This study enhances understanding of drug resistance mechanisms for potential diagnostic and therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cisplatin is a key chemotherapy for head and neck squamous cell carcinoma.
- Mechanisms of cisplatin resistance in oral squamous cell carcinoma remain incompletely understood.
- Identifying genes involved in resistance is crucial for improving treatment outcomes.
Purpose of the Study:
- To identify gene expression profiles associated with cisplatin resistance in oral squamous cell carcinoma (OSCC).
- To establish and characterize a cisplatin-resistant OSCC cell line model for resistance mechanism studies.
Main Methods:
- Established a cisplatin-resistant Tca/cisplatin cell line from the sensitive Tca8113 OSCC cell line.
- Utilized Affymetrix HG-U95Av2 microarrays for global gene expression analysis.
- Validated candidate genes (e.g., RECQL, MAP2K6, CCND1, CCND3) using Real-time PCR and assessed cell cycle effects.
Main Results:
- The Tca/cisplatin cell line exhibited stable, significantly increased cisplatin resistance (6.5-fold higher IC50).
- Microarray analysis revealed differential expression of 38 up-regulated and 25 down-regulated genes.
- Key genes involved in DNA repair (RECQL) and cell cycle regulation (CCND1, CCND3) were implicated in cisplatin resistance, with observed S-phase arrest in resistant cells.
Conclusions:
- The Tca8113 and Tca/cisplatin cell lines serve as a valuable model for investigating cisplatin resistance mechanisms in OSCC.
- The identified genes provide a foundation for developing diagnostic markers and therapeutic strategies to overcome cisplatin resistance.
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