The miR-199a-5p/PD-L1 axis regulates cell proliferation, migration and invasion in follicular thyroid carcinoma

Abstract

Background Follicular thyroid carcinoma (FTC) is the second most common cancer of the thyroid and easily develops into distant metastasis. PD-L1 is known to be associated with the carcinogenesis and progression of thyroid carcinoma. Our study aimed to investigate the biological functions of PD-L1 and to identify miRNAs that were responsible for modulating the activity of PD-L1. Methods A total of 72 patients with FTC at The Second Affiliated Hospital of Fujian Medical University were enrolled in this retrospective study. Immunohistochemical (IHC) assay was used to measure PD-L1 expression in FTC. The association between PD-L1 expression and clinicopathologic characteristics was evaluated. Bioinformatics analysis, RT–qPCR and western blotting were used to examine the relationships between miR-199a-5p, PD-L1 and Claudin-1. Cell proliferation, migration and invasion were evaluated by using CCK8 and Transwell migration and invasion assays. Target prediction and luciferase reporter assays were performed to verify the binding between miR-199a-5p and PD-L1. Rescue assay was performed to confirm whether PD-L1 downregulation abolished the inhibitory effect of miR-199a-5p. Results Among 72 pairs of tumor and normal specimens, the proportion of PD-L1 positive samples was higher in FTC tissues than in normal tissues. The results of ESTIMATE and CIBERSORT illustrated that there was a positive correlation between PD-L1 expression and immune infiltration, especially regulatory T cells and M1 macrophages. Prediction of immunotherapy revealed that patients with high PD-L1 expression might benefit from immune checkpoint inhibitors. Transwell migration and invasion assays showed that PD-L1 downregulation in FTC cells could significantly inhibit cell migration and invasion. The bioinformatics analysis and luciferase activity results indicated that PD-L1 was a potential target of miR-199a-5p. Knockdown of PD-L1 reversed the miR-199a-5p inhibitor mediated promotion effect. In addition, we found that PD-L1 expression was positively correlated with Claudin-1 expression and that miR-199a-5p affected the progression of FTC cells through the negative regulation of PD-L1 and Claudin-1. Conclusions Our study revealed that PD-L1 expression was elevated in FTC and was closely associated with tumor aggressiveness and progression. MiR-199a-5p has a functional role in the progression and metastasis of FTC by regulating PD-L1 and Claudin-1 expression.

Downstream Target Analysis for miR-365 among Oral Squamous Cell Carcinomas Reveals Differential Associations with Chemoresistance

“…Similar studies of other cancers have revealed an array of microRNAs that modulate these phenotypes through specific downstream targets, such as miR-331 and the downstream target BID, as well as miR-199 and the downstream target PD-L1, that have been demonstrated to mediate both proliferation and migration among thyroid cancers [ 26 , 27 ]. Similarly, miR-106 has been identified as mediating progression and invasion through HPGD and Smad7, while miR-296 may function through modulation of STAT3 among esophageal squamous cell carcinomas [ 28 , 29 , 30 ].…”

MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: targeting PD-1/PD-L1 and CTLA-4 pathways

“…Additionally, PD-L1 expression is positively correlated with Claudin-1 expression. Eventually, MiR-199a-5p plays a functional role in the progression and metastasis of FTC by regulating the expression of PD-L1 and Claudin-1 (p values < 0.05) [ 157 ].…”

Multi-Omics and Management of Follicular Carcinoma of the Thyroid

“…The level of certain proteins and their metabolites is either increased or decreased, and their expression profile may be used for the diagnosis or risk stratification of cancers. There is a difference in the profile of proteins that are increased in the serum of patients who have thyroid nodules that may be used to assist in differentiating FTC from FA or PTC [ 201 ]. Immunohistochemistry on the FNAC specimen may be used in the diagnostic evaluation of indeterminate thyroid nodules [ 183 ].…”

“…Adipocytes in the TME can promote tumor growth, progression, and metastasis through the secretion of adipokines). The differentiated profile of metabolites in the tumor itself, TME, and fluid in a patient with a thyroid nodule whose FNAC result is inconclusive may be used to differentiate FTC from FA or other follicular-patterned lesions [ 201 ]. The study of the change in levels of these molecules (metabolomics) is assessed using nuclear magnetic resonance spectrometry or mass spectrometry.…”