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Published on: March 30, 2019
MicroRNA-326 negatively regulates CD155 expression in lung adenocarcinoma
Takayuki Nakanishi1, Yasuto Yoneshima1, Koji Okamura1
1Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract:
Treatment with immune checkpoint inhibitors induces a durable response in some patients with non-small-cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual-luciferase reporter assay identified miR-346, miR-328-3p, miR-326, and miR-330-5p as miRNAs that bind to the 3'-UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR-326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level (p < 0.005). Our results thus suggest that miR-326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD-1/PD-L1 inhibitors.
Insights
MicroRNAs regulate CD155 expression, a mechanism of resistance to PD-1/PD-L1 inhibitors in non-small-cell lung cancer. miR-326 was identified as a key regulator, offering potential therapeutic targets for overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 inhibitors show durable responses in non-small-cell lung cancer (NSCLC).
- Drug resistance to ICIs is a significant clinical challenge in NSCLC treatment.
- Upregulation of CD155 expression is a known mechanism contributing to ICI resistance.
Purpose of the Study:
- To identify microRNAs (miRNAs) that posttranscriptionally regulate CD155 expression in lung cancer.
- To investigate the role of specific miRNAs in controlling CD155 levels in tumor cells.
- To explore potential therapeutic strategies targeting miRNA-mediated regulation of CD155 to overcome ICI resistance.
Main Methods:
- Comprehensive miRNA screening and target prediction programs were employed.
- Dual-luciferase reporter assays were used to validate miRNA binding to CD155 mRNA.
- Immunohistochemical staining assessed CD155 expression in patient tumor specimens.
Main Results:
- Four miRNAs (miR-346, miR-328-3p, miR-326, miR-330-5p) were identified as binding to the 3'-UTR of CD155 mRNA.
- Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines.
- A significant inverse correlation was observed between miR-326 abundance and CD155 expression levels in lung adenocarcinoma tissues.
Conclusions:
- miR-326 negatively regulates CD155 expression in lung adenocarcinoma.
- This miRNA-mediated regulation suggests a role for miR-326 in modulating resistance to PD-1/PD-L1 inhibitors.
- Targeting miR-326 may represent a novel therapeutic approach to enhance ICI efficacy in NSCLC.
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