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miR-185-5p May Modulate the Chemosensitivity of LUSC to Cisplatin via Targeting PCDHA11: Multi-omics Analysis and Experimental Validation

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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.

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Data Availability

The publicly available datasets were analyzed in this study. The TCGA expression profile, phenotype, methylation, and mutation data of LUSC were retrieved from the Xena database (https://xenabrowser.net/). The non-coding RNA interaction data were obtained from the RAID 3.0 database (http://www.rna-society.org/raid/). The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Author notes

  1. Yicheng Liang, Mei Liang and Tao Yan have contributed equally to this work.

Authors and Affiliations

  1. Department 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

    Yicheng Liang, Mei Liang, Xiangzhi Meng, Boxuan Zhou & Yushun Gao

  2. Department of Anesthesia, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Panjiayuan, Nanli 17, Beijing, 100021, People’s Republic of China

    Tao Yan

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  1. Yicheng Liang
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Contributions

YL: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); resources (lead); software (lead); supervision (lead); validation (lead); visualization (equal); writing—original draft (lead); writing—review and editing (lead). ML: Conceptualization (lead); data curation (lead); methodology (lead); resources (lead); validation (lead); visualization (equal); writing—original draft (lead); writing—review and editing (lead). TY: Conceptualization (lead); data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); writing—review and editing (lead). XM: Conceptualization (supporting); data curation (equal); project administration (equal); resources (supporting); software (supporting). BZ: Investigation (equal); methodology (equal); resources (supporting); validation (supporting). YG: Conceptualization (equal); data curation (equal); formal analysis (equal); funding acquisition (lead); investigation (equal); methodology (equal); project administration (equal); resources (equal); supervision (lead); validation (equal); visualization (equal); writing—review and editing (equal). YL and ML saw and verified all the raw data.

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Correspondence to Yushun Gao.

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Liang, Y., Liang, M., Yan, T. et al. miR-185-5p May Modulate the Chemosensitivity of LUSC to Cisplatin via Targeting PCDHA11: Multi-omics Analysis and Experimental Validation. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10795-5

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