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MiR-34a-5p/PD-L1 axis regulates cisplatin chemoresistance of ovarian cancer cells
1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
Abstract:
Ovarian cancer is the most lethal gynecologic malignancy in women with an increasing number of cases worldwide. Chemoresistance is the main obstacle for ovarian cancer treatment during clinical therapy. Previous studies found that programmed cell death 1 ligand 1 (PD-L1) was associated with chemoresistance of cancer. However, there were little reports about the function of PD-L1 involved in chemoresistance of ovarian cancer. In our study, cisplatin (DDP)-resistant SKOV3 and A2780 ovarian cancer cell lines (SKOV3/DDP and A2780/DDP) were established. We found that the expression of PD-L1 was increased and miR-34a-5p was decreased in DDP-resistant cells. PD-L1 silencing inhibited chemoresistance of DDP-resistant ovarian cancer cells to DDP, as evidenced by decreased proliferation, G1-phase cell cycle arrest and increased apoptosis. Western blot assay showed that in the presence of DDP, PD-L1 silencing decreased multidrug resistance protein 1 and Cyclin D1 protein levels, whereas increased cleaved-caspase-3 and cleaved-PARP protein levels in these cells. Moreover, we demonstrated that miR-34a-5p negatively regulated the expression of PD-L1 by targeting its 3'-untranslated region. The effects of miR-34a-5p mimic on DDP-treated SKOV3/DDP cells were reversed by the overexpression of PD-L1. Moreover, the tumorigenicity of DDP-resistant ovarian cancer cells in nude mice treated with DDP was attenuated by miR-34a-5p in vivo. The combined data indicate that miR-34a-5p/PD-L1 axis regulates DDP chemoresistance of ovarian cancer cells, providing a deeper insight into the treatment for ovarian cancer.
Insights
This study reveals that the miR-34a-5p/PD-L1 axis impacts cisplatin chemoresistance in ovarian cancer. Targeting programmed cell death 1 ligand 1 (PD-L1) can overcome chemoresistance, offering new therapeutic strategies for ovarian cancer.
Area of Science:
- Gynecology
- Oncology
- Molecular Biology
Background:
- Ovarian cancer is a lethal gynecologic malignancy with increasing global incidence.
- Chemoresistance presents a major challenge in ovarian cancer treatment.
- Programmed cell death 1 ligand 1 (PD-L1) is implicated in cancer chemoresistance, but its role in ovarian cancer requires further investigation.
Purpose of the Study:
- To investigate the role of PD-L1 in cisplatin (DDP) chemoresistance in ovarian cancer.
- To elucidate the regulatory relationship between miR-34a-5p and PD-L1 in DDP-resistant ovarian cancer cells.
- To evaluate the therapeutic potential of targeting the miR-34a-5p/PD-L1 axis for overcoming DDP chemoresistance.
Main Methods:
- Establishment of cisplatin-resistant ovarian cancer cell lines (SKOV3/DDP and A2780/DDP).
- Assessment of PD-L1 and miR-34a-5p expression levels in resistant cells.
- Silencing of PD-L1 and overexpression of miR-34a-5p to evaluate effects on chemoresistance, cell proliferation, cell cycle, and apoptosis.
- Western blot analysis to determine protein levels of key molecules involved in chemoresistance.
- In vivo studies using nude mice to assess the impact of miR-34a-5p on tumor growth.
Main Results:
- PD-L1 expression was upregulated, and miR-34a-5p was downregulated in DDP-resistant ovarian cancer cells.
- PD-L1 silencing significantly reduced chemoresistance, inhibited proliferation, induced G1-phase arrest, and promoted apoptosis in DDP-resistant cells.
- PD-L1 silencing decreased multidrug resistance protein 1 and Cyclin D1, while increasing cleaved-caspase-3 and cleaved-PARP.
- miR-34a-5p directly targeted and negatively regulated PD-L1 expression.
- Overexpression of PD-L1 reversed the effects of miR-34a-5p mimic on DDP-treated cells.
- miR-34a-5p attenuated the tumorigenicity of DDP-resistant cells in vivo.
Conclusions:
- The miR-34a-5p/PD-L1 axis plays a critical role in regulating cisplatin chemoresistance in ovarian cancer.
- miR-34a-5p acts as a tumor suppressor by downregulating PD-L1.
- Targeting the miR-34a-5p/PD-L1 pathway presents a promising therapeutic strategy for overcoming chemoresistance in ovarian cancer.
