MicroRNA-375 reverses the expression of PD-L1 by inactivating the JAK2/STAT3 signaling pathways in gastric cancer

Background: The mechanism of PD-L1 expression in gastric cancer patients remains unclear. microRNAs (miRs) have been reported to be crucial components of the crosstalk between tumor-immune cells and emerging evidence suggests that microRNA-375 (miR-375) is signifi-cantly downregulated in digestive system tumors, but its association with PD-L1 expression in gastric cancer remains to be determined. Methods: The expression level of miR-375 was first investigated in human gastric cancer tissues and cell lines. Its effect on gastric cancer cell proliferation, migration, invasion, and apoptosis were evaluated in vitro via CCK8, colony formation assays, wound healing assays, transwell assays, and flow cytometry. In vivo experiments using immunodeficient BALB/c nude female mice were also performed. Luciferase reporter assays were employed to identify interactions between miR-375 and its target genes. Results: Quantitative real-time PCR showed that the expression of miR-375 was negatively correlated with PD-L1 in gastric cancer tissues. The overexpression of miR-375 inhibited gastric cancer cell proliferation, migration, invasion, and the knockdown of miR-375 demonstrated opposite effects, both in vitro and in vivo. Luciferase reporter assays showed that miR-375 could bind to the 3'-UTR regions of JAK2 and an inverse association between miR-375 and JAK2/STAT3/PD-L1 expression in gastric cancer cell lines was also observed. In vivo experiments showed that miR-375-overexpression decreased the growth of xenograft tumors in immunode-ficient BALB/c mice. Conclusions: miR-375 negatively regulates PD-L1 expression in gastric cancer via the JAK2/STAT3 signaling pathway and could be a promising novel therapeutic target in gastric cancer. (c) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

miR-375 negatively regulates PD-L1 expression in gastric cancer via the JAK2/STAT3 signaling pathway, showing potential as a promising new therapeutic target in the future treatment of gastric cancer.