Transcription Factors Runx1 and Runx3 Suppress Keratin Expression in Undifferentiated Keratinocytes.

The Runt-related transcription factor (Runx) family has been suggested to play roles in stem cell regulation, tissue development, and oncogenesis in various tissues/organs. In this study, we investigated the possible functions of Runx1 and Runx3 in keratinocyte differentiation. Both Runx1 and Runx3 proteins were detected in primary cultures of mouse keratinocytes. Proteins were localized in the nuclei of undifferentiated keratinocytes but translocated to the cytoplasm of differentiated cells. The siRNA-mediated inhibition of Runx1 and Runx3 expression increased expression of keratin 1 and keratin 10, which are early differentiation markers of keratinocytes. In contrast, overexpression of Runx1 and Runx3 suppressed keratin 1 and keratin 10 expression. Endogenous Runx1 and Runx3 proteins were associated with the promoter sequences of keratin 1 and keratin 10 genes in undifferentiated but not differentiated keratinocytes. In mouse skin, the inhibition of Runx1 and Runx3 expression by keratinocyte-specific gene targeting increased the ratios of keratin 1- and keratin 10-positive cells in the basal layer of the epidermis. On the other hand, inhibition of Runx1 and Runx3 expression did not alter the proliferation capacity of cultured or epidermal keratinocytes. These results suggest that Runx1 and Runx3 likely function to directly inhibit differentiation-induced expression of keratin 1 and keratin 10 genes but are not involved in the regulation of keratinocyte proliferation.

AHR and NRF2 in Skin Homeostasis and Atopic Dermatitis.

Skin is constantly exposed to environmental insults, including toxic chemicals and oxidative stress. These insults often provoke perturbation of epidermal homeostasis and lead to characteristic skin diseases. AHR (aryl hydrocarbon receptor) and NRF2 (nuclear factor erythroid 2-related factor 2) are transcription factors that induce a battery of cytoprotective genes encoding detoxication and antioxidant enzymes in response to environmental insults. In addition to their basic functions as key regulators of xenobiotic and oxidant detoxification, recent investigations revealed that AHR and NRF2 also play critical roles in the maintenance of skin homeostasis. In fact, specific disruption of AHR function in the skin has been found to be associated with the pathogenesis of various skin diseases, most prevalently atopic dermatitis (AD). In this review, current knowledge on the roles that AHR and NRF2 play in epidermal homeostasis was summarized. Functional annotations of genetic variants, both regulatory and nonsynonymous SNPs, identified in the AHR and NRF2 loci in the human genome were also summarized. Finally, the possibility that AHR and NRF2 serve as therapeutic targets of AD was assessed.

Aryl Hydrocarbon Receptor Directly Regulates Artemin Gene Expression.

Transgenic mice expressing a constitutively active form of the aryl hydrocarbon receptor in keratinocytes (AhR-CA mice) develop severe dermatitis that substantially recapitulates the pathology of human atopic dermatitis. The neurotrophic factor artemin (Artn) is highly expressed in the epidermis of AhR-CA mice and causes hypersensitivity to itch (alloknesis) by elongating nerves into the epidermis. However, whether the Artn gene is regulated directly by AhR or indirectly through complex regulation associated with AhR remains unclear. To this end, we previously conducted chromatin immunoprecipitation-sequencing analyses of the Artn locus and found a xenobiotic response element (XRE) motif located far upstream (52 kb) of the gene. Therefore, in this study, we addressed whether the XRE actually regulates the Artn gene expression by deleting the region containing the motif. We generated two lines of ArtnΔXRE mice. In the mouse epidermis, inducible expression of the Artn gene by the AhR agonist 3-methylcholanthrene was substantially suppressed compared to that in wild-type mice. Importantly, in AhR-CA::ArtnΔXRE mice, Artn expression was significantly suppressed, and alloknesis was improved. These results demonstrate that the Artn gene is indeed regulated by the distal XRE-containing enhancer, and alloknesis in AhR-CA mice is provoked by the AhR-mediated direct induction of the Artn gene.

Eccrine porocarcinoma shares dermoscopic characteristics with eccrine poroma: A report of three cases and review of the published work.

Eccrine porocarcinoma (EPC) is a rare malignant skin tumor presumably arising from the intraepidermal ductal portion of the sweat gland. EPC occasionally mimics eccrine poroma (EP), seborrhea keratosis (SK), basal cell carcinoma (BCC), pyogenic granuloma (PG) and amelanotic melanoma with its clinical appearance as a pink nodule. Dermoscopy is an invaluable technique in diagnosing skin tumors. However, few cases of EPC have been reported using dermoscopic images, and their details were not well examined. Here, we present three histopathologically proven cases of EPC and summarize their dermoscopic findings together with five previously reported cases. None of the eight cases showed dermoscopic evidence indicative of SK (comedo-like openings, milia-like cysts, fissures and ridges, and hairpin vessels with white halo), BCC (blue-gray ovoid nests, multiple blue-gray globules, wheel-like structures, shiny white areas, leaf-like areas and arborizing vessels) or PG (reddish homogeneous area with collarette and white rail lines). A milky red area, which was suggestive of amelanotic melanoma, was not detectable in any cases. Seven cases exhibited a polymorphous vascular pattern mainly consisting of hairpin, linear-irregular and dotted vessels. A combination of round-to-oval pink-white structureless areas and white-to-pink halo was observed in five of eight cases, with one case showing the white-to-pink halo alone. Our investigation revealed that the dermoscopic characteristic of EP was also observed in discrete areas of EPC lesions. Thus, it is possible that the histopathological architecture of EPC contains portions of benign EP-like components. Awareness of this dermoscopic aspect of EPC may be helpful when diagnosing pink nodules.