Comprehensive analysis of microRNA-messenger RNA regulatory network in gemcitabine-resistant bladder cancer cells
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Published on: February 21, 2014
Su Zhang1, Yong-Yan Chang1, Yu-Wen Gong1
1Institute of Gansu Nephro-Urological Clinical Center, Department of Urology, Institute of Urology, Key Laboratory of Urological Disease of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China.
Abstract:
Chemotherapy is still a standard treatment of unresectable bladder cancer or distant metastases. The chemotherapy resistance always occurs after a period of treatment indicating poor prognosis. The current study aimed to explore the molecular mechanism of chemoresistance in bladder cancer cells. The gene expression profiles of GSE77883, including three untreated T24 cells samples and three gemcitabine-resistant T24 cells samples, was downloaded from Gene Expression Omnibus database. The screening of differentially expressed genes (DEGs), gene function analysis, and interaction prediction between microRNAs (miRNAs) and DEGs were performed by R software. The protein-protein interaction (PPI) and miRNA-DEGs networks were constructed and visualized by Cytoscape software. Then, the small molecules, with potential synergistic or antagonistic effects to gemcitabine resistance, were identified using the Connectivity Map database. Finally, gemcitabine-resistant T24 cell line was established and key genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR). In total, 536 upregulated and 513 downregulated genes were screened and mainly enriched in oxidative stress response and signaling pathways related to extracellular matrix-receptor interaction and focal adhesion. PPI network showed interleukin 6, tumor necrosis factor, kinesin family member 11, and BUB1 mitotic checkpoint serine/threonine kinase B were key genes. The miRNA-DEGs regulatory networks included 18 miRNAs and 185 DEGs, including miR-182-5p, miR-590-3p, miR-320a and serum- and glucocorticoid-regulated kinase 1 (SGK1). Then, the related key genes and miRNAs were confirmed by qRT-PCR. Furthermore, 81 small molecules with antagonistic or synergistic effect to GEM were screened. We have investigated the molecular mechanisms driving GEM-resistance in bladder cancer cells that would contribute to the development of chemotherapy for advanced bladder cancer.
Insights
Chemotherapy resistance in bladder cancer is a major challenge. This study identified key genes and microRNAs involved in gemcitabine resistance, offering potential targets for overcoming treatment failure in advanced bladder cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Chemotherapy resistance is a significant clinical challenge in unresectable or metastatic bladder cancer, leading to poor patient prognosis.
- Understanding the molecular mechanisms underlying chemotherapy resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of gemcitabine resistance in bladder cancer cells.
- To identify key genes, microRNAs, and potential therapeutic targets involved in chemoresistance.
Main Methods:
- Gene expression profiles of gemcitabine-resistant T24 cells were analyzed using the Gene Expression Omnibus database.
- Bioinformatic analyses, including screening differentially expressed genes (DEGs), functional enrichment, and network construction (PPI and miRNA-DEGs), were performed.
- Quantitative real-time polymerase chain reaction (qRT-PCR) was used for validation of key genes and microRNAs.
Main Results:
- 536 upregulated and 513 downregulated genes were identified, enriched in pathways like oxidative stress response and extracellular matrix-receptor interaction.
- Key genes in the protein-protein interaction network included interleukin 6 and tumor necrosis factor.
- MicroRNA-DEG regulatory networks implicated miR-182-5p and serum- and glucocorticoid-regulated kinase 1 (SGK1) in gemcitabine resistance.
Conclusions:
- This study elucidates molecular mechanisms driving gemcitabine resistance in bladder cancer.
- Identified key genes and microRNAs provide potential targets for novel therapeutic strategies to overcome chemotherapy resistance in advanced bladder cancer.
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