Comprehensive Assessment of Host Responses to 5-Fluorouracil-Induced Oral Mucositis through Transcriptomic Analysis
Chung-Ta Chang1, Chien-Yun Hsiang2, Tin-Yun Ho3
1Department of Emergency Medicine, Far Eastern Memorial Hospital, Taipei, 22056, Taiwan; School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
Background:
Chemotherapy plays an important role in current cancer therapy; however, several problems remain unsolved on the issue of host-therapeutics interaction. The purpose of this study was to investigate the host responses after 5-flurouracil (5-FU) administration and to find the target genes and their relationship with other cytokines in the 5-FU-induced oral mucositis (OM) mouse model through transcriptomic analysis.
Materials And Methods:
Thirty-six 6 to 8 week-old male BALB/c mice were randomly divided into the control group and 5-FU-treated group. In the 5-FU group, mice received 5-FU (100 mg/kg, intraperitoneally) on day 1, day 8, day 15, day 22, and day 29, respectively. We evaluated the oral mucosal change under macroanalysis and histological examination at indicated periods, and then applied transcriptomic analysis of gene expression profile and Immunohistochemical stain to identify the target molecules related to 5-FU-induced OM.
Results:
The most prominent histological change in this model was observed in the fifth week. The gene expression of Bone gamma-carboxyglutamate protein, related sequence 1 (Bglap-rs1) (-12.69-fold) and Chitinase 3-like 4 (Chi3l4) (-6.35-fold) were significantly down-regulated in this phase. The quantitative real-time PCR results also revealed the expression levels were 0.62-fold in Bglap-rs1 and 0.13-fold in Chi3l4 compared with the control group. Immunohistochemical stain showed significant expression of cluster of differentiation 11b (p<0.01), interleukin-1β (p<0.001) and tumor necrosis factor-α (p<0.05), and down-regulation of Bglap-rs1 (p<0.01) compared with the control group. By Kyoto Encyclopedia of Genes and Genomes pathway analysis, there were twenty-three pathways significantly participated in this study (p<0.05).
Conclusions:
Through comprehensively transcriptomic analysis and IHC stain, we discovered several valuable pathways, verified the main pro-inflammatory cytokines, and revealed two significantly down-regulated genes in the 5-FU-induced OM model. These findings highlighted the way of seeking effective therapeutic agents for chemotherapy-induced OM in future.
Insights
This study investigated host responses to 5-fluorouracil (5-FU) chemotherapy, identifying two key down-regulated genes, Bglap-rs1 and Chi3l4, in a mouse model of 5-FU-induced oral mucositis (OM). These findings offer insights for developing novel therapeutic agents for chemotherapy-induced OM.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Chemotherapy is vital in cancer treatment but poses challenges in host-therapeutics interactions.
- Understanding host responses to chemotherapy is crucial for managing side effects.
- 5-fluorouracil (5-FU) is a widely used chemotherapeutic agent with known toxicities.
Purpose of the Study:
- To investigate host responses following 5-fluorouracil (5-FU) administration.
- To identify target genes and their relationship with cytokines in a 5-FU-induced oral mucositis (OM) mouse model.
- To utilize transcriptomic analysis for comprehensive gene expression profiling.
Main Methods:
- Utilized a 5-FU-induced oral mucositis (OM) mouse model with BALB/c mice.
- Administered 5-FU intraperitoneally over a 5-week period.
- Conducted macro and histological examinations, transcriptomic analysis, and immunohistochemical staining to identify molecular changes.
Main Results:
- Significant histological changes were observed by the fifth week.
- Bone gamma-carboxyglutamate protein, related sequence 1 (Bglap-rs1) and Chitinase 3-like 4 (Chi3l4) genes were significantly down-regulated (-12.69-fold and -6.35-fold, respectively).
- Immunohistochemistry revealed significant expression of cluster of differentiation 11b, interleukin-1β, and tumor necrosis factor-α, alongside Bglap-rs1 down-regulation.
Conclusions:
- Transcriptomic analysis and IHC identified key pathways and pro-inflammatory cytokines in 5-FU-induced OM.
- Two significantly down-regulated genes, Bglap-rs1 and Chi3l4, were identified in the 5-FU-induced OM model.
- Findings provide a foundation for developing targeted therapies for chemotherapy-induced OM.
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