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PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3
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| Title: | PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3 |
| Authors: | Xu, Daozhi Browse this author | | Dong, Peixin Browse this author →KAKEN DB | | Xiong, Ying Browse this author | | Chen, Rui Browse this author | | Konno, Yosuke Browse this author →KAKEN DB | | Ihira, Kei Browse this author →KAKEN DB | | Yue, Junming Browse this author | | Watari, Hidemichi Browse this author →KAKEN DB |
| Keywords: | PD-L1 | | MEG3 | | miR-216a | | long non-coding RNA | | EMT | | endometrial cancer |
| Issue Date: | 2020 |
| Publisher: | Frontiers Media |
| Journal Title: | Frontiers in Cell and Developmental Biology |
| Volume: | 8 |
| Start Page: | 598205 |
| Publisher DOI: | 10.3389/fcell.2020.598205 |
| Abstract: | Background: Poorly differentiated endometrioid adenocarcinoma and serous adenocarcinoma represent an aggressive subtype of endometrial cancer (EC). Programmed death-ligand-1 (PD-L1) was known to exhibit a tumor cell-intrinsic function in mediating immune-independent tumor progression. However, the functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown. Methods: PD-L1 expression in 65 EC tissues and 18 normal endometrium samples was analyzed using immunohistochemical staining. The effects of PD-L1 on aggressive EC cell growth, migration and invasion were investigated by cell functional assays. Luciferase reporter assays were used to reveal the microRNA-216a (miR-216a)-dependent mechanism modulating the expression of PD-L1. Results: Positive PD-L1 expression was identified in 84% of benign cases but only in 12% of the EC samples, and the staining levels of PD-L1 in EC tissues were significantly lower than those in the normal tissues. Higher PD-L1 expression predicts favorable survival in EC. Ectopic expression of PD-L1 in aggressive EC cells results in decreased cell proliferation and the loss of mesenchymal phenotypes. Mechanistically, PD-L1 exerts the anti-tumor effects by downregulating MCL-1 expression. We found that PD-L1 levels in aggressive EC cells are regulated by miR-216a, which directly targets PD-L1. We further identified a mechanism whereby the long non-coding RNA MEG3 represses the expression of miR-216a, thereby leading to increased PD-L1 expression and significant inhibition of cell migration and invasion. Conclusion: These results reveal an unappreciated tumor cell-intrinsic role for PD-L1 as a tumor suppressor in aggressive EC cells, and identify MEG3 and miR-216a as upstream regulators of PD-L1. |
| Rights: | http://creativecommons.org/licenses/by/4.0/ |
| Type: | article |
| URI: | http://hdl.handle.net/2115/79934 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 董 培新
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