A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus

Abstract

Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3′UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.

FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer

“…reported that miR-125a-5p expression was lower in human gastric cancer cell lines (SGC7901, HGC27 and BGC823) than in the normal gastric mucosa cell line GES1, with a similar pattern in 82 pairs of cancer tissues and matched normal tissues, as evidenced by RT-PCR analysis 22,42 , while FOXS1 was highly expressed in the above gastric cancer cell lines and gastric cancer tissues, revealing that the endogenous FOXS1 and miR-125a-5p levels were inversely correlated. miR-125a-5p can bind the 3′-UTR of FOXS1 and repress FOXS1 expression at the transcriptional level, consistent with the finding that miR-125a-5p mimics were able to inhibit FoxN1 3′UTR luciferase activity and suppress FoxN1 expression 39 . These results reveal that FOXS1 is also a target gene of miR-125a-5p and that its high expression might be due to the loss of miR-125a-5p, providing novel insight into miRNA regulation of human gene expression.…”

The Role of the Thymus in the Immune Response

“…Studies using mouse embryos have elucidated several factors intrinsic to TECs that play crucial roles in the development of thymic structure both pre-natally and post-natally 3,11 . The transcription factor FoxN1 is critical for all TEC development and maintenance (fetal and postnatal); loss of FoxN1 lead to loss of thymic structure and autoimmune disease in both humans and mice [12][13][14][15][16][17] FoxN1 is highly expressed by embryonic thymic epithelial cells and at least 50% of postnatal TECs retain FoxN1 expression, highlighting its importance 18 . The regulation of FoxN1 expression in TEC is not fully understood although signaling pathways such as the bone morphogenetic protein (BMP) and wingless/integrated (wnt) factors have been described 19,20 .…”

MicroRNA Functions in Thymic Biology: Thymic Development and Involution

“…Moreover, in a previous study from our laboratory, we compared changes in miRNA expression profiles between young and aged TECs using miRBase-V20 arrays (containing 1,892 unique probes), which clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymi ( 80 ). In addition, the application of a miR-125a-5p mimic was able to inhibit FoxN1 expression (as indicated using 3′UTR luciferase activity) in a 293T cell line and suppress FoxN1 expression in TEC Z210 cells ( 80 ).…”