The homeodomain-only protein homeobox (HOPX) is the smallest known member of the homeodomain-containing protein family, atypically unable to bind DNA. HOPX is widely expressed in diverse tissues, where it is critically involved in the regulation of proliferation and differentiation. In human skin, HOPX controls epidermal formation through the regulation of late differentiation markers, and HOPX expression correlates with the level of differentiation in cutaneous pathologies. In mouse skin, Hopx was additionally identified as a lineage tracing marker of quiescent hair follicle stem cells. This review discusses current knowledge of HOPX structure and function in normal and pathological conditions.
Differentiation of proliferative nodules in giant congenital nevi from melanoma arising within such nevi is an important diagnostic challenge. DNA methylation is a well-established epigenetic modification already observed in the earliest stages of carcinogenesis, which increases during melanoma progression. The ten-eleven translocation enzymes catalyze the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), which has recently been reported as an epigenetic hallmark associated with tumor aggressiveness and poor prognosis in a wide variety of cancers. In this study, we analyzed 12 proliferative nodules and 13 melanomas both arising in giant congenital nevi and matched results with a control group including 67 benign and malignant melanocytic lesions. Proliferative nodules displayed high 5-hmC expression levels (90.65%) compared with melanomas with almost complete loss of this marker (7.87%). We showed that low 5-hmC levels in melanomas correlate with downregulation of isocitrate dehydrogenase and ten-eleven translocation families of enzymes implicated in the cytosine methylation cycle. Simultaneously, these enzymes were overexpressed in proliferative nodules leading to strong 5-hmC expression. We emphasize the significance of 5-hmC loss for discrimination of melanomas from benign proliferative nodules arising within giant congenital nevi, and for establishing the correct diagnosis in ambiguous cases when histological and immunohistochemical characteristics are not sufficiently specific.
The influence of inhibitors of different lipoxygenases (LOX) on the growth of human tumor cells with different profiles of synthesized eicosanoids was studied. The studied LOX inhibitors had virtually no influence on the growth of A549 cells actively synthesizing cyclooxygenase and lipoxygenase metabolites of arachidonic acid (AA). The inhibitor of 12-LOX, baicalein, significantly inhibited proliferation in cultures of A431 epidermoid carcinoma cells with a characteristic domination of the major lipoxygenase metabolite of AA, 12-hydroxyeicosatetraenoic acid (12-HETE), in the profile of synthesized eicosanoids and reduced to 70% the incorporation of [3H]thymidine into DNA. Treatment of these cultures with 12-HETE virtually restored the growth potential of the tumor cells. The findings suggest that the lipoxygenase metabolite of AA, 12-HETE, is a growth-limiting factor for tumor cells of definite type.
Cutaneous squamous cell carcinomas (SCCs) are frequent heterogeneous tumors arising from sun-exposed regions of the skin and characterized by complex pathogenesis. HOPX is a member of the homeodomaincontaining superfamily of proteins holding an atypical homeodomain unable to bind to DNA. First discovered in the heart as a regulator of cardiac development, in the skin, HOPX modulates the terminal differentiation of keratinocytes. There is a particular interest in studying HOPX in squamous skin carcinogenesis because it has the atypical structure and the functional duality as an oncogene and a tumor suppressor gene, reported in different malignancies. In this study, we analyzed the effects of HOPX knockdown and overexpression on SCC tumorigenicity in vitro and in vivo. Our data show that HOPX knockdown in SCC cells inhibits their proliferative and invasive activity through the acceleration of apoptosis. We established that methylation of two alternative HOPX promoters leads to differential expression of HOPX transcripts in normal keratinocytes and SCC cells. Importantly, we report that HOPX acts as an oncogene in the pathogenesis of SCC probably through the activation of the second alternative promoter and the modulation of apoptosis.
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