Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis

Abstract

The level of microRNA (miR)‐431 was found to be markedly up‐regulated in intestinal tissue of necrotizing enterocolitis (NEC). The objective of this study was to identify the target gene of miR‐431 and to investigate the role of the miR‐431‐FOXA1 axis in the pathophysiology of NEC. The target gene of miR‐431 was identified by in silico target prediction bioinformatics, luciferase assay, and Western blotting. Effects of miR‐431 on downstream expression signals, cell proliferation, and apoptosis were investigated by overexpression in Caco‐2 cells upon stimulation by LPS or lipoteichoic acid (LTA). FOXA1 was identified as the target gene of miR‐431. Overexpression of miR‐431 in Caco‐2 cells significantly inhibited FOXA1, ESRRG, and HNF4A and activated IL‐6, LGR5, NFKB2, PLA2G2A, PRKCZ, and TNF. IL‐8 and ‐10 were enhanced when costimulated with LPS or LTA. These potential downstream genes were also significantly dysregulated in primary NEC tissues compared with surgical‐control tissues. Overexpression of miR‐431 significantly decreased proliferation and increased apoptosis of Caco‐2 cells. A proposed network of miR‐431‐FOXA1 interaction with LPS and LTA receptors demonstrates dysregulation of transcription factors, inflammatory mediators, epithelium tight junction regulators, and cell proliferation and apoptosis signals. The miR‐431‐FOXA1 axis could in part be responsible for the intensification of the inflammatory response in NEC tissues and contribute to the proinflammatory pathophysiology.—Wu, Y. Z., Chan, K. Y. Y., Leung, K. T., Lam, H. S., Tam, Y. H., Lee, K. H., Li, K., Ng, P. C. Dysregulation of miR‐431 and target gene FOXA1 in intestinal tissues of infants with necrotizing enterocolitis. FASEB J. 33, 5143–5152 (2019). http://www.fasebj.org

Chromatin regulatory dynamics of early human small intestinal development using a directed differentiation model

“…FOXA1 has been reported to regulate allocation of murine SI secretory lineage [53] and proper gene expression in murine intestinal epithelium [54]. Recently, dysregulation of intestinal FOXA1 also has been linked to necrotizing enterocolitis in infants [55]. The observations made in this study as well as previous reports together underscores the functional importance of FOXA1 in human gut development.…”

Systematic large-scale meta-analysis identifies miRNA-429/200a/b and miRNA-141/200c clusters as biomarkers for necrotizing enterocolitis in newborn

“…The miR-141/200c cluster and the miR-429/200a/b cluster are critical members of the miR-200 family, which are gathered at two locations in the genome [9]. Recently, several miRNAs including miR-1290 and miR-431 have been reported to be associated with the diagnosis and treatment of NEC [10,11]. Vascular endothelial growth factor (VEGFA) and its receptors 1 fms-related tyrosine kinase 1 (FLT1) and kinase insert domain receptor (KDR) have been newly recognized as critical regulators of angiogenesis and inflammation in colorectal cancer [12].…”

Signification of forkhead box A1 (FOXA1) expression in thyroid cancers

“…Therefore, the authors claimed that miR-132 acts as a tumor suppressor targeting FOXA1 in thyroid papillary carcinoma [23]. Similarly, in other human diseases, FOXA1 expression has been found to be inhibited by miR-30a-5p and miR-212 in hepatocellular carcinomas [24,25], by miR-212 in osteosarcomas [26], by miR-194 in non-small cell lung cancers [27], and by miR-431 in necrotizing enterocolitis [28]. The current study included only one case of undifferentiated sarcoma of the thyroid.…”