Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

Abstract

Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H 2 O 2 -induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo. Vitiligo is a disfiguring dermatosis with an incidence rate of approximately 0.5-1.0% in the populations worldwide. 1 Characterized by patchy depigmentation of the skin, the disease can affect the patients' self-image, or even cause depression, thus substantially decreasing life quality among vitiligo patients. 2 Although several etiological theories, including genetic predisposition, 3-5 autoimmunity, 6,7 melanocytorrhagy 8,9 and toxic metabolites 10 have been proposed to participate in the pathogenesis of vitiligo, the exact mechanism of melanocyte degeneration in depigmented lesions still remains unclear.The generation of oxidative stress has long been demonstrated to have a crucial role in the onset and progression of vitiligo. 11,12 Owing to the pro-oxidant state generated during melanin synthesis, melanocytes are particularly vulnerable to oxidative stress. 13 In vitiligo, accumulation of toxic intermediates such as 6-and 7-BH4 and catecholamine, 14,15 concomitant with reduced levels and activity of catalase and several other antioxidant enzymes [16][17][18] have been demonstrated in patients' epidermis. Because of these intracellular metabolic disorder and compromised intrinsic antioxidant defenses, hydrogen peroxide (H 2 O ...

Intrinsic and extrinsic regulation of human skin melanogenesis and pigmentation

“…They also evidenced that the overexpression of miR‐25 conducted to melanocyte dysfunction, to the inhibition of tyrosinase activity and the decrease in melanin content, probably due to the targeting of MITF by miR‐25. Besides, miR‐25 inhibited the production and the secretion of SCF and bFGF from keratinocytes, thus inhibiting their paracrine effect on the survival of melanocytes under oxidative stress . A second study in the Alpaca identified miR‐508‐3p as a regulator of melanogenesis via direct MITF targeting .…”

MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo

“…Dysregulated miRNA expression is associated with the pathogenesis of various inflammatory skin disorders such as psoriasis, atopic dermatitis, and allergic contact dermatitis (Sonkoly E et al , 2008), and there is some evidence implicating miRNAs in vitiligo. Gene expression microarray studies have revealed aberrant miRNA expression in the skin and serum of patients with vitiligo (Mansuri et al , 2014, Shi et al , 2014, Shi et al , 2013), with upregulation of miR-224-3p, miR-4712-3p, and miR-3940-5p in peripheral blood mononuclear cells (Wang et al , 2015), miR-25 upregulated in serum (Shi et al , 2016) and miR-99b, miR-125-b, miR-155, and miR-199a-3p upregulated in the skin (Šahmatova et al , 2016) of vitiligo patients. Little is known, however, about the exact role of miRNAs, their targets, and their mechanism of action in the pathophysiology of vitiligo.…”

Novel approaches to vitiligo treatment via modulation of mTOR and NF-κB pathways in human skin melanocytes

“…It has been recognized that this unique type of skin disorder is associated with melanocyte and possibly other skin cell apoptosis5, 6. Melanocyte death is related to reactive oxygen species, cytokines7, 8, and more complicatedly, autoimmunity3, 9-13.…”