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.
Highlights
Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with approximately 89,929 deaths worldwide in 2018 (Bray et al, 2018)
As our previous findings pointed out the involvement of MCL1 in epithelialmesenchymal transition (EMT) and the invasion of aggressive EC cells (Konno et al, 2014), we addressed whether Programmed death-ligand-1 (PD-L1) regulates the EMT process and the invasion of HEC-50 cells by modulating MCL-1
The role of MEG3 in suppressing cell migration was confirmed by wound-healing assays in HEC-50 and SPAC-1-L cells (Figure 6E,F). Consistent with these results, we found that knockdown of MEG3 inhibited the protein expression of PDL1 compared to control cells, while overexpression of MEG3 increased the expression of PD-L1 in EC cells (Figure 6G and Supplementary Figure 3E)
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with approximately 89,929 deaths worldwide in 2018 (Bray et al, 2018). ECs are classified into various histological subtypes: including endometrioid EC, serous EC, clear-cell EC, and mixed (usually endometrioid and serous components) EC (Gaber et al, 2016). Unlike the majority of ECs, which are usually associated with well-differentiated endometrioid histology, early stage disease, and a more favorable prognosis, poorly differentiated endometrioid ECs and serous ECs are generally seen in older patients, are more aggressive, and are characterized by a high rate of recurrence and metastasis (Gaber et al, 2016). In the early stage of tumor metastasis, an epithelialmesenchymal transition (EMT) program occurs and contributes to the acquisition of invasive properties, enabling epithelial cells to lose polarity and adhesion capacity, but acquire the features of mesenchymal cells (Valastyan and Weinberg, 2011). The functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown
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