MiRNA Expression in Psoriatic Skin: Reciprocal Regulation of hsa-miR-99a and IGF-1R

Abstract

BackgroundPsoriasis is a complex disease at the cellular, genomic and genetic levels. The role of microRNAs in skin development was shown in a keratinocyte-specific Dicer knockout mouse model. Considering that two main characteristics of psoriasis are keratinocytes hyperproliferation and abnormal skin differentiation, we hypothesized that aberrant microRNA expression contributes to the psoriatic phenotype. Here, we describe the differential expression of miRNAs in psoriatic involved and uninvolved skin as compared to normal skin, revealing an additional aspect of this complex disorder.Methodology/Principal FindingsExpression arrays were used to compare microRNA expression in normal skin versus psoriatic involved and uninvolved skin. Fourteen differentially expressed microRNAs were identified, including hsa-miR-99a, hsa-miR-150, hsa-miR-423 and hsa-miR-197. The expression of these microRNAs was reevaluated by qPCR. IGF-1R, which is involved in skin development and the pathogenesis of psoriasis, is a predicted target of hsa-miR-99a. In an in situ hybridization assay, we found that IGF-1R and miR-99a are reciprocally expressed in the epidermis. Using a reporter assay, we found that IGF-1R is targeted by hsa-miR-99a. Moreover, over expression of miR-99a in primary keratinocytes down-regulates the expression of the endogenous IGF-1R protein. Over expression of miR-99a also inhibits keratinocyte proliferation and increases Keratin 10 expression. These findings suggest that overexpression of hsa-miR-99a in keratinocytes drives them towards differentiation. In primary keratinocytes grown in high Ca++, miR-99a expression increases over time. Finally, we found that IGF1 increases the expression of miR-99a.Conclusions/SignificanceWe identified several microRNAs that are expressed differentially in normal and psoriatic skin. One of these miRNAs is miR-99a that regulates the expression of IGF-1R. Moreover, miR-99a seems to play a role in the differentiation of keratinocytes. We suggest that miR-99a is one of the regulators of the IGF-1R signaling pathway in keratinocytes. Activation of IGF1 signaling results in elevation of miR-99a which represses the expression of IGF-1R.

Retracted: MicroRNA‐181b negatively regulates the proliferation of human epidermal keratinocytes in psoriasis through targeting TLR4

“…In recent years, with the comprehensive genetic analysis on miR, increasing numbers of specific miR have been discovered to be related with the pathology of psoriasis 19, including miR‐21 20, miR‐146a 21, miR‐424 22 and miR‐99a 23. Other previous studies have also shown that miR‐203, miR‐125b, miR‐99a and miR‐197 were relevant to the pathogenesis of psoriasis by regulating target genes 24, 25, 26, 27.…”

Tetrandrine induces microRNA differential expression in human hypertrophic scar fibroblasts in vitro

“…Moreover hsa-miR-125b was observed to regulate cell proliferation and differentiation in both breast cancer and ovarian cancer cell lines and plays an important role in osteoblastic differentiation (Iorio et al, 2005;Mizuno et al, 2008;Guan et al, 2011). Hsa-miR-125a-3p and hsa-miR-125a-5p were found to affect the migration and invasion of lung cancer cells, while hsa-miR-99a was found to affect the differentiation of keratinocytes (Jiang et al, 2010;Lerman et al, 2011). Recent evidence has shown that hsa-miR-155 may promote cell proliferation by regulating its target genes and can regulate the expression of the angiotensin II type 1 receptor in primary human lung fibroblasts (Kong et al, 2010;Martin et al, 2013).…”

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

“…CTMs have been described in mice lacking genes involved in embryonic development [e.g., sonic hedgehog (6), Wnt (83,84), bone morphogenetic protein (85,86), FGFs (87,88)]. Recently, mice with cartilage-specific deletion of Dicer 1 showed abnormal tracheal development because of a lack of ECM deposition (89). Most of these mutant mice die embryonically or shortly after birth because of the severe and complicated embryonic defects.…”