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miR-135a/b modulate cisplatin resistance of human lung cancer cell line by targeting MCL1
Li Zhou1, Tianzhu Qiu, Jing Xu
1Department of Oncology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China.
Abstract:
microRNAs (miRNAs) are short non-coding RNA molecules, which post-transcriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. Here, we investigated the possible role of miRNAs in the development of drug resistance in human lung cancer cell line. We found that miR-135a/b were downregulated while MCL1 was upregulated in A549/CDDP (cisplatin) cells, compared with the parental A549 cells. In vitro drug sensitivity assay demonstrated that overexpression of miR-135a/b sensitized A549/CDDP cells to cisplatin. The luciferase activity of MCL1 3'-untranslated region-based reporter constructed in A549/CDDP cells suggested that MCL1 was the direct target gene of miR-135a/b. Enforced miR-135a/b expression reduced MCL1 protein level and sensitized A549/CDDP cells to CDDP-induced apoptosis. Taken together, our findings first suggested that hsa-miR-135a/b could play a role in the development of CDDP resistance in lung cancer cell line at least in part by modulation of apoptosis via targeting MCL1.
Insights
microRNAs (miRNAs) regulate genes and are crucial in biological processes. This study shows miR-135a/b downregulation contributes to cisplatin resistance in lung cancer by targeting MCL1 and affecting apoptosis.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- microRNAs (miRNAs) are key regulators of gene expression involved in numerous biological processes.
- Drug resistance, particularly to cisplatin (CDDP), is a major challenge in treating human lung cancer.
- Understanding the role of miRNAs in drug resistance is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of miRNAs in the development of cisplatin resistance in a human lung cancer cell line.
- To identify specific miRNAs and their target genes involved in mediating drug resistance.
- To explore the mechanism by which miRNAs influence sensitivity to cisplatin treatment.
Main Methods:
- Comparison of miRNA and gene expression profiles between parental and cisplatin-resistant lung cancer cells (A549/CDDP).
- In vitro drug sensitivity assays to evaluate the effect of miRNA modulation on cell response to cisplatin.
- Luciferase reporter assays to confirm the direct targeting of MCL1 by miR-135a/b.
- Assessment of apoptosis induction following miRNA and target gene manipulation.
Main Results:
- miR-135a/b were found to be downregulated, while MCL1 was upregulated in cisplatin-resistant A549/CDDP cells compared to parental cells.
- Overexpression of miR-135a/b resensitized A549/CDDP cells to cisplatin treatment.
- MCL1 was identified as a direct target gene of miR-135a/b.
- Enforced expression of miR-135a/b reduced MCL1 protein levels and enhanced CDDP-induced apoptosis.
Conclusions:
- The findings suggest that downregulation of hsa-miR-135a/b plays a role in the development of cisplatin resistance in lung cancer.
- This resistance mechanism involves the modulation of apoptosis through the targeting of MCL1.
- miR-135a/b represent potential therapeutic targets for overcoming cisplatin resistance in lung cancer.
