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The miR-193a-3p-regulated ING5 gene activates the DNA damage response pathway and inhibits multi-chemoresistance in
1Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui, China.
Abstract:
As the major barrier to curative cancer chemotherapy, chemoresistance presents a formidable challenge to both cancer researchers and clinicians. We have previously shown that the bladder cancer (BCa) cell line 5637 is significantly more sensitive to the cytoxicity of five chemotherapeutic agents than H-bc cells. Using an RNA-seq-based omic analysis and validation at both the mRNA and protein levels, we found that the inhibitor of growth 5 (ING5) gene was upregulated in 5637 cells compared with H-bc cells, indicating that it has an inhibitory role in BCa chemoresistance. siRNA-mediated inhibition of ING5 increased the chemoresistance and inhibited the DNA damage response pathway in 5637 cells. Conversely, forced expression of EGFP-ING5 decreased the chemoresistance of and activated the DNA damage response pathway in H-bc cells. We also showed that ING5 gene expression is inhibited by miR-193a-3p and is instrumental in miR-193a-3p's role in activating BCa chemoresistance. Our results demonstrate both the role and mechanism of inhibition of BCa chemoresistance by ING5.
Insights
The inhibitor of growth 5 (ING5) gene suppresses bladder cancer chemoresistance by activating DNA damage response pathways. Its downregulation by miR-193a-3p promotes chemoresistance, highlighting ING5 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chemoresistance is a major obstacle in achieving curative cancer chemotherapy.
- Bladder cancer (BCa) exhibits varying sensitivity to chemotherapeutic agents.
- Understanding the molecular mechanisms of chemoresistance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the role of the inhibitor of growth 5 (ING5) gene in bladder cancer chemoresistance.
- To elucidate the molecular mechanisms by which ING5 influences chemoresistance and DNA damage response.
- To identify potential regulatory pathways involving ING5 in bladder cancer.
Main Methods:
- RNA-sequencing (RNA-seq) based omic analysis to compare gene expression between chemo-sensitive and chemoresistant bladder cancer cell lines.
- Validation of gene and protein expression levels.
- siRNA-mediated gene silencing to inhibit ING5 expression.
- Forced expression of EGFP-ING5 to study its effects.
- Investigation of the interaction between ING5 and miR-193a-3p.
Main Results:
- ING5 was found to be upregulated in chemo-sensitive 5637 bladder cancer cells compared to chemoresistant H-bc cells.
- Inhibition of ING5 in 5637 cells increased chemoresistance and impaired the DNA damage response pathway.
- Forced expression of ING5 in H-bc cells decreased chemoresistance and activated the DNA damage response pathway.
- ING5 gene expression is negatively regulated by miR-193a-3p, which plays a role in promoting chemoresistance.
Conclusions:
- ING5 acts as a suppressor of chemoresistance in bladder cancer.
- ING5 promotes chemoresistance by regulating the DNA damage response pathway.
- miR-193a-3p contributes to bladder cancer chemoresistance by inhibiting ING5 expression.
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