MicroRNA-7 directly targets Reg1 in pancreatic cells

Abstract

Regenerating islet-derived (Reg) proteins, which were first discovered in the pancreas, are associated with increased proliferation, prevention of apoptosis, and enhanced differentiation in normal and disease states, but very little is known about the regulation of their expression. We hypothesized that Reg expression is influenced by microRNAs. Bioinformatic analysis predicted Reg1 to be a target of microRNA-7 (miR-7), which influences pancreatic β-cell function. To this end, we investigated the effects of miR-7 on Reg1 expression in pancreatic acinar and islet β-cells. High levels of Reg1 were noted by immunostaining and Western blotting in acinar cells in contrast to islet cells. A reciprocal expression pattern was observed for miR-7. Overexpression of miR-7 resulted in Reg1 mRNA suppression and reduction of secreted Reg1 protein. Conversely, miR-7 knockdown led to increases in Reg1. Targeting of Reg1 by miR-7 was confirmed via luciferase activity assays. In contrast, miR-7 did not directly repress the human ortholog of Reg1 REG1A as well as REG1B indicating species differences in the regulation of Reg expression. This is the first account of microRNA modulation of any Reg member warranting studies to fill gaps in our knowledge of Reg protein biology, particularly in disease contexts.

Four Decades After the Discovery of Regenerating Islet-Derived (Reg) Proteins: Current Understanding and Challenges

“…Because miR-7 has roles in β-cell proliferation and function, avenues are opened for exploring possible connections with the regulation of reg1 expression and potentially shining more light on Reg function. The same study (Downing et al, 2019), however, demonstrated that unlike reg1 , the human REG1A and REG1B are not targeted directly by miR-7. This exemplifies further that regulation of Reg expression may not be universal but species-dependent.…”

“…Lastly, the potential regulation of Reg gene expression by microRNAs (miRNAs) has been largely unexplored. Recently, the murine reg1 , which displays a 3′-UTR region that matches the seed of miRNA-7 (miR-7), was shown to be a direct target of this miRNA (Downing et al, 2019). Interestingly enough, miR-7 expression is higher in the islets than in exocrine cells (200:1) (Bravo-Egana et al, 2008; Correa-Medina et al, 2009) whereas Reg1 is abundant in acinar cells but not in normal islets.…”

Nei Endonuclease VIII‐Like1 (NEIL1) Inhibits Apoptosis of Human Colorectal Cancer Cells

“…It has been shown that miRNAs are closely related to various biological processes, including cell proliferation, differentiation, apoptosis, and tissue development, which might also be involved in the occurrence and development of human cancers. miRNA- (miR-) 7 is an evolutionarily conserved miRNA abundantly expressed in the human pancreas and endocrine cells, which plays specific roles in the endocrine cell differentiation and function [ 10 ]. Moreover, it has been shown that miR-7 is associated with the progression of various tumors, including gastric cancer, lung cancer, breast cancer, and glioma [ 11 ].…”

Reg-1α Promotes Differentiation of Cortical Progenitors via Its N-Terminal Active Domain

“…Among the different family members, Reg-1α has been shown to be expressed during embryonic development and protein levels are stage-dependent while mRNA levels are stable. Very recently, it has been shown that microRNA-7 directly targets the murine Reg1 modulating its expression in pancreatic cells (Downing et al, 2019). miR-7 is expressed in various regions of the brain of humans and mice (Farh et al, 2005;Landgraf et al, 2007) and could be affecting the Reg-1α expression in this context.…”