Targeting lncRNA H19/miR-29b/COL1A1 Axis Impedes Myofibroblast Activities of Precancerous Oral Submucous Fibrosis

Abstract

Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. Among these regulators, profibrotic lncRNA <i>H19</i> has been found to be overexpressed in several fibrosis diseases. Here, we examined the expression of <i>H19</i> in OSF specimens and its functional role in fibrotic buccal mucosal fibroblasts (fBMFs). Our results indicate that the aberrantly overexpressed <i>H19</i> contributed to higher myofibroblast activities, such as collagen gel contractility and migration ability. We also demonstrated that <i>H19</i> interacted with <i>miR</i>-<i>29b</i>, which suppressed the direct binding of <i>miR</i>-<i>29b</i> to the 3'-untranslated region of type I collagen (COL1A1). We showed that ectopic expression of <i>miR</i>-<i>29b</i> ameliorated various myofibroblast phenotypes and the expression of α-smooth muscle actin (α-SMA), COL1A1, and fibronectin (FN1) in fBMFs. In OSF tissues, we found that the expression of <i>miR</i>-<i>29b</i> was downregulated and there was a negative correlation between <i>miR</i>-<i>29b</i> and these fibrosis markers. Lastly, we demonstrate that arecoline stimulated the upregulation of <i>H19</i> through the transforming growth factor (TGF)-β pathway. Altogether, this study suggests that increased TGF-β secretion following areca nut chewing may induce the upregulation of <i>H19</i>, which serves as a natural sponge for <i>miR</i>-<i>29b</i> and impedes its antifibrotic effects.