PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3

Abstract

BackgroundPoorly 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.MethodsPD-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.ResultsPositive 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.ConclusionThese 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.

Critical Roles of PIWIL1 in Human Tumors: Expression, Functions, Mechanisms, and Potential Clinical Implications

“…Genome projects have shown that functional products encoded by the genome are not limited to proteins, but include a large number of biologically meaningful non-coding RNAs, such as miRNAs, circular RNAs (circRNAs) and lncRNAs (Anastasiadou et al, 2018;Yamamura et al, 2018). MiRNAs are known to target 3 -UTRs in mRNAs, thereby silencing gene expression at the post-transcriptional level (Anastasiadou et al, 2018;Yamamura et al, 2018;Xu et al, 2020). MiRNAs also interact with circRNAs and lncRNAs to regulate their stability (Anastasiadou et al, 2018;Yamamura et al, 2018).…”

“…MiRNAs also interact with circRNAs and lncRNAs to regulate their stability (Anastasiadou et al, 2018;Yamamura et al, 2018). Owing to their functions in the regulation of gene expression, noncoding RNAs regulate multiple biological processes, such as cancer (Anastasiadou et al, 2018;Yamamura et al, 2018;Xu et al, 2020). The expression of PIWIL1 could be regulated by different miRNAs at the post-transcriptional level.…”

Prognostic Significance of PD-L1 Expression In Patients With Primary Oropharyngeal Squamous Cell Carcinoma: A Meta-Analysis

“…The results of this meta-analysis confirmed that, in patients diagnosed with OPSCC, PD-L1 expression was associated with a better OS and PSF, but not with LRC. Notably, higher PD-L1 expression was correlated with improved OS rates in other tumor types, including melanoma ( 45 ), colorectal cancer ( 46 ), Merkel-cell carcinoma ( 47 ), and endometrial cancer ( 48 , 49 ).…”

The Role of Long Non-Coding RNAs (lncRNAs) in Female Oriented Cancers

“…Furthermore, Xu et al evaluated a total of 65 human EC tissues and 18 normal samples and showed that MEG3 downregulates the miR-216a expression, leading to increased expression of tumor suppressor PD-L1. Thus, it inhibits the EC cell migration and invasion [ 234 ].…”