論文 - 詳細
| RRC ID | 65474 |
|---|---|
| 著者 | Ashizawa M, Okayama H, Ishigame T, Thar Min AK, Saito K, Ujiie D, Murakami Y, Kikuchi T, Nakayama Y, Noda M, Tada T, Endo H, Fujita S, Sakamoto W, Saito M, Saze Z, Momma T, Ohki S, Mimura K, Kono K. |
| タイトル | miRNA-148a-3p Regulates Immunosuppression in DNA Mismatch Repair-Deficient Colorectal Cancer by Targeting PD-L1. |
| ジャーナル | Mol Cancer Res |
| Abstract |
Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). The study aimed to identify miRNAs that posttranscriptionally control PD-L1 expression on tumor cells and also regulate immune evasion. A comprehensive miRNA screening using The Cancer Genome Atlas (TCGA) dataset (n = 260) combined with eight different miRNA target prediction programs resulted in the identification of a tumor suppressive miRNA, miR-148a-3p, as a potential negative regulator of PD-L1 expression, particularly in dMMR/MSI-H colorectal cancer. Using multiple cohorts of colorectal cancer, including TCGA data, a microarray dataset (n = 148), and formalin-fixed, paraffin-embedded samples (n = 395), we found that the expression of miR-148a-3p was decreased in dMMR/MSI-H tumors, correlating inversely with PD-L1 levels. We demonstrate that miR-148a-3p directly binds to the 3'-untranslated region of PD-L1, thereby reducing whole-cell and cell surface PD-L1 levels in HCT116 and SW837 cell lines. Overexpression of miR-148a-3p repressed IFNγ-induced PD-L1 expression on tumor cells and consequently diminished T-cell apoptosis in a coculture model of IL2-activated T cells and IFNγ-treated tumor cells. In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer. IMPLICATIONS: This study provides novel evidence that miR-148a-3p negatively regulates tumor cell PD-L1 expression and decreased levels of miR-148a-3p contributes to the immunosuppressive tumor microenvironment. |
| 巻・号 | 17(6) |
| ページ | 1403-1413 |
| 公開日 | 2019-6-1 |
| DOI | 10.1158/1541-7786.MCR-18-0831 |
| PII | 1541-7786.MCR-18-0831 |
| PMID | 30872332 |
| MeSH | 3' Untranslated Regions / genetics Apoptosis / genetics B7-H1 Antigen / genetics* Cell Line, Tumor Colorectal Neoplasms / genetics* DNA Mismatch Repair / genetics* Gene Expression Regulation, Neoplastic / genetics HCT116 Cells Humans MicroRNAs / genetics* Microsatellite Instability |
| IF | 4.63 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HCT116(RCB2979) |