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MiR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp
Chaojing Lu1, Zhengxiang Shan2, Chunguang Li1
1Department of Thoracic Surgery, Changhai Hospital, Shanghai 200433, China.
Abstract:
Development of multiple drug resistance (MDR) to chemotherapy is the major reason for the failure of gastric cancer (GC) treatment. P-glycoprotein (P-gp), which is encoded by MDR gene 1, as one of the mechanisms responsible for MDR. Mounting evidence has demonstrated that the drug-induced dysregulation of microRNAs (miRNAs) function may mediate MDR in cancer cells. However, the underling mechanisms of miRNA-mediated MDR in GC remain unclear. Here, we found that miR-129 was downregulated in cisplatin-resistant GC tissues/cells. Our results also showed that overexpression of miR-129 decreased cisplatin-resistance in cisplatin-resistant GC cells, and miR-129 knockdown reduced chemosensitivity to cisplatin in cisplatin-sensitive GC cells. Furthermore, miR-129 activated the intrinsic apoptotic pathway via upregulating caspase-9 and caspase-3. Most importantly, we further confirmed that P-gp is the functional target of miR-129 by regulating cisplatin-resistance in GC cells. These results suggested that miR-129 reversed cisplatin-resistance through inhibiting the P-gp expression in GC cells.
Insights
MicroRNA-129 (miR-129) reverses cisplatin resistance in gastric cancer by downregulating P-glycoprotein (P-gp). This finding offers a potential therapeutic strategy to overcome drug resistance in gastric cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multiple drug resistance (MDR) is a primary cause of gastric cancer chemotherapy failure.
- P-glycoprotein (P-gp), encoded by the MDR1 gene, is a key mediator of MDR.
- MicroRNAs (miRNAs) are increasingly recognized for their role in drug resistance, but mechanisms in gastric cancer remain unclear.
Purpose of the Study:
- To investigate the role of miR-129 in cisplatin resistance in gastric cancer.
- To elucidate the underlying mechanisms of miRNA-mediated MDR in gastric cancer.
Main Methods:
- Quantitative real-time PCR to measure miR-129 levels in gastric cancer tissues and cells.
- Cell viability assays to assess chemosensitivity after miR-129 manipulation.
- Western blotting to analyze protein expression of P-gp, caspase-9, and caspase-3.
- Bioinformatic analysis and luciferase reporter assays to confirm P-gp as a direct target of miR-129.
Main Results:
- miR-129 was significantly downregulated in cisplatin-resistant gastric cancer tissues and cells.
- Overexpression of miR-129 resensitized resistant cells to cisplatin, while miR-129 inhibition increased resistance.
- miR-129 promoted apoptosis by upregulating caspase-9 and caspase-3.
- P-gp was identified as a direct functional target of miR-129, with miR-129 inhibiting P-gp expression.
Conclusions:
- miR-129 plays a crucial role in reversing cisplatin resistance in gastric cancer.
- The miR-129/P-gp axis is a key mechanism underlying chemoresistance.
- Restoring miR-129 levels may represent a novel therapeutic strategy to overcome MDR in gastric cancer.
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