LncRNA LPAL2/miR-1287-5p/EGFR Axis Modulates TED-Derived Orbital Fibroblast Activation Through Cell Adhesion Factors

Abstract

Background and aims The activation of orbital fibroblasts, the prime targets in thyroid eye disease, is central to its underlying pathogenesis. We aimed to investigate the mechanism of thyroid eye disease orbital fibroblast activation from the perspective of non-coding RNA regulation. Methods Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation were evaluated by EDU and colony formation assays. Collagen I concentration was determined by ELISA assay. Human microarray analysis was performed on three thyroid eye disease and 3 healthy control orbital tissue samples. Results Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in thyroid eye disease tissues, including I-CAM-1, I-CAM-4, V-CAM, and CD44, which were all upregulated in diseased orbital tissues. LncRNA LPAL2 level was also upregulated in orbital tissues and positively correlated with I-CAM-1 and I-CAM-4 expression. Stimulation of the thyroid eye disease orbital fibroblasts by TGF-β1 significantly increased the expression of I-CAM-1, I-CAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1-induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on thyroid eye disease and normal orbital tissues to identify differentially expressed miRNAs and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to EGFR 3’UTR and LPAL2 and LPAL2 modulated EGFR/AKT signaling through targeting miR-1287-5p. Conclusions The LPAL2/miR-1287-5p axis modulated TGF-β1-induced increases in cell adhesion factor levels and thyroid eye disease orbital fibroblast activation through EGFR/AKT signaling.

Upregulation of hsa_circ_0004812 promotes COVID‐19 cytokine storm via hsa‐miR‐1287‐5p/IL6R, RIG‐I axis

“…In a study, N Wang et al 31 introduced the lncRNA LPAL2 in thyroid eye disease (TED) by sponging the hsa‐miR‐1287‐5p. In contrast to our study, W. Hao argues that increased miR‐1287‐5p levels may inhibit LPS‐induced human nasal epithelial cells (HNECs) from releasing pro‐inflammatory cytokines 32 .…”

Comprehensive Analysis of lncRNA Expression Profile and the Potential Role of ENST00000604491 in Graves’ Disease

“…A previous study revealed that lncRNA RUX1-IT1 contributed to the differentiation of Th1 cells by regulating neural cell adhesion molecule (NrCAM) expression in GD [ 31 ]. A lncRNA named LPAL2 was found to modulate epidermal growth factor receptor (EGFR) signalling by targeting miR-1287-5p in orbital tissues from thyroid eye disease [ 32 ]. Gene expression is regulated by lncRNAs at multiple levels, and lncRNAs may broadly serve to fine-tune the expression of neighbouring genes [ 33 ].…”

Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes

“…For example, co-expression interactions of lncRNA with COL12A1 and negative coexpression of lnc-PTP4A2-3:7 with TNXB may be associated with altered ECM in GO orbital adipose/connective tissue (89). Wang et al shown that the combination of upregulated lncRNA LPAL2 and downregulated miR-1287-5p in orbital tissues of GO patients induced increased levels of cell adhesion factors and activation of GO OFs by TGF-b1 through EGFR/AKT signaling (90). Meanwhile, EGFR has been reported to increase the proliferation of OFs, which may contribute to the fibrosis of extraocular muscles (91).…”

“…Wang et al. shown that the combination of upregulated lncRNA LPAL2 and downregulated miR-1287-5p in orbital tissues of GO patients induced increased levels of cell adhesion factors and activation of GO OFs by TGF-β1 through EGFR/AKT signaling ( 90 ). Meanwhile, EGFR has been reported to increase the proliferation of OFs, which may contribute to the fibrosis of extraocular muscles ( 91 ).…”