Additional Factors

Gene Expression Change

The protein levels of melanogenesis-associated factors (tyrosinase, TRP-1, dopa- chrome tautomerase, silver) were increased in the melasma lesions, indicating a higher melanogenic activity in the lesional skin. Interestingly, the lipid metabolism- associated genes (peroxisome proliferator-activated receptor a (PPAR a), arachidonate 15-lipoxygenase (ALOX15), type B (ALOX15B), diacylglycerol

O-acyltransferase2-like 3, and PPAR-y coactivator 1a) were downregulated in the lesional skin. This finding was supported by an impaired barrier function in the lesional skin of melasma.

Wnt signaling-associated factors (Wnt inhibitory factor (WIF)-1, secreted frizzled-related protein 2 (SFRP2), and Wnt5a) were also found to be upregulated in the lesional skin [26]. The Wnt pathway has a critical role in the development of epidermal melanocytes, and microphthalmia-associated transcription factor (MITF) is a nuclear mediator of this pathway [27, 28]. As a consequence of WIF-1 overexpression, the melanin content and tyrosinase activity in normal human epidermal melanocyte were significantly increased. Therefore, WIF-1 may have the physiologic functions in melanocytes as an auto- or paracrine modulator of Wnt signaling [29]. The increased SFRP2 observed around fibroblasts also suggested the possibility of a cross talk between the dermis and epidermis via the Wnt pathway in the development of melasma [26].

Another interesting study showed that H19 downregulation stimulates melano- genesis in melasma patients [30]. H19 gene transcribes a 2.3 kb noncoding RNA that is thought to have a possible role in certain malignancies [31, 32]. H19 knockdown in a mixed cell culture system (keratinocytes and melanocytes) did induce a tyrosinase overexpression as well as an increase of melanosome transfer. A combination of estrogen treatment and H19 RNA knockdown induce more than additive effects on tyrosinase expression in the mixed cell culture system, whereas UV irradiation does not. These suggest that downregulation of H19 and a sufficient dose of estrogen might be involved in the development of melasma [30].

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