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miR-185-5p May Modulate the Chemosensitivity of LUSC to Cisplatin via Targeting PCDHA11: Multi-omics Analysis and
Yicheng Liang1, Mei Liang1, Tao Yan2
1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Drug resistance is the major difficulty in treatment of lung squamous cell carcinoma (LUSC). This study aims to explore drug response-related miRNAs (DRmiRNAs) based on multi-omics research. We identified DRmiRNAs of LUSC with a multi-omics integrated system that combines expression data of microRNA, lncRNA, mRNA, methylation levels, somatic mutations. After identifying DRmiRNAs, we screened and validated of the target mRNAs of DRmiRNAs through Targetscan and the miRDB database. Then, Real-time PCR and Western blot assays were used to estimate the expression of DRmiRNAs and target protein, and the dual-luciferase assays were used to confirm the interaction of DRmiRNAs and target mRNA. Furthermore, CCK-8 (Cell Counting Kit-8) assays were used to evaluate cell proliferation and drug sensitivity. After integrated analysis, hsa-miR-185-5p was identified as DRmiRNA based on multi-omics data. Through Targetscan and miRDB database, the possible target mRNAs were obtained and PCDHA11 was validated as a target mRNA of miR-185-5p by real-time PCR, Western blot assays and dual-luciferase assays. CCK-8 assays and clone formation assays showed that the proliferation of miR-185-5p mimics was significantly slower than that of miR-185-5p inhibitors, which means overexpression of miR-185-5p enhanced the anticancer effects of cisplatin, whereas the downregulation of miR-185-5p reduced the effects. Furthermore, the proliferation of silencing PCDHA11 was significantly slower than that of overexpression of PCDHA11, which means PCDHA11 overexpression weakened the anticancer effects of cisplatin, and silencing PCDHA11 enhanced the effects. This study demonstrated that miR-185-5p was involved in chemoresistance of LUSC cells to cisplatin partly via down-regulating PCDHA11, which may promote understanding the underlying molecular mechanisms of drug response.
Insights
Drug resistance in lung squamous cell carcinoma (LUSC) is a challenge. This study identifies hsa-miR-185-5p as a key microRNA influencing cisplatin response by regulating PCDHA11, offering new insights into LUSC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Drug resistance significantly hinders effective treatment of lung squamous cell carcinoma (LUSC).
- Identifying molecular mechanisms underlying chemoresistance is crucial for improving patient outcomes.
Purpose of the Study:
- To explore drug response-related microRNAs (DRmiRNAs) in LUSC using a multi-omics approach.
- To elucidate the role of identified DRmiRNAs and their targets in chemoresistance to cisplatin.
Main Methods:
- Integrated analysis of multi-omics data (microRNA, lncRNA, mRNA, methylation, mutations).
- Bioinformatic screening and experimental validation (RT-PCR, Western blot, dual-luciferase assays) of miRNA-target interactions.
- Cell Counting Kit-8 (CCK-8) and clone formation assays to assess cell proliferation and drug sensitivity.
Main Results:
- hsa-miR-185-5p was identified as a DRmiRNA in LUSC.
- PCDHA11 was validated as a direct target of hsa-miR-185-5p.
- Overexpression of hsa-miR-185-5p enhanced cisplatin's anticancer effects, while PCDHA11 downregulation improved sensitivity.
Conclusions:
- hsa-miR-185-5p plays a role in LUSC chemoresistance to cisplatin by downregulating PCDHA11.
- This finding provides a potential therapeutic target and deepens the understanding of drug resistance mechanisms in LUSC.
