Application of Bioinformatics Methodologies in the Fields of Skin Biology and Dermatology

Bioinformatics is a research field that uses computer‐based tools to investigate life sciences questions employing “big data” results from large‐scale DNA sequencing, whole genomes, transcriptomes, metabolomes, populations, and biological systems, which can only be comprehensively viewed in silico. The epidermis was among the earliest targets of bioinformatics studies because it represents one of the most accessible targets for research. An additional advantage of working with the epidermis is that the sample can even be recovered using tape stripping, an easy, noninvasive protocol. Consequently, bioinformatics methods in the fields of skin biology and dermatology generated a fairly large volume of bioinformatics data, which led us to originate the term “skinomics.” Skinomics data are directed toward epidermal differentiation, malignancies, inflammation, allergens, and irritants, the effects of ultraviolet (UV) light, wound healing, the microbiome, stem cells, etc. Cultures of cutaneous cell types, keratinocytes, fibroblasts, melanocytes, etc., as well as skin from human volunteers and from animal models, have been extensively experimented on. Here, we review the development of the skinomics, its methodology, current achievements, and future potentials

Nuclear Proteins Involved in Transcription of the Human K5 Keratin Gene

Keratin K5 is expressed in the basal layer of stratified epithelia in mammals and its synthesis is regulated by hormones and vitamins such as retinoic acid. The molecular mechanisms that regulate K5 expression are not known. To initiate analysis of the protein factors that interact with the human K5 keratin gene upstream region, we have used gel-retardation and DNA-mediated cell-transfection assays. We found five DNA sites that specifically bind nuclear proteins. DNA-protein interactions at two of the sites apparently increase transcription levels, at one decrease it. The importance of the remaining two sites is, at present, unclear. In addition, the location of the retinoic acid and thyroid hormone nuclear receptor action site has been determined, and we suggest that it involves a cluster of five sites similar to the consensus recognition elements. The complex constellation of protein binding sites upstream from the K5 gene probably reflects the complex regulatory circuits that govern the expression of the K5 keratin in mammalian tissues

Differential transcriptional effects of EGFR inhibitors.

EGF and its receptor EGFR serve as a paradigm for signaling in cell, molecular and tumor biology. EGFR inhibitors, drugs targeting the intracellular kinase activity and antibodies targeting the extracellular ligand binding, are used to treat breast, lung, colon and other cancers. Nominally affecting the same target, inhibitors have different effects, suggesting that use of inhibitor combinations may provide beneficial in cancer treatment. To explore the specific and the common transcriptional effects of EGFR inhibitors, we present metaanalysis of 20 individual studies comprising 346 microarrays. We identified specific gene subsets regulated by kinase inhibitors, those regulated using antibodies and by suppressing EGFR expression using miR-7. Unreported before, the inhibitors prominently induce lysosome components. All inhibitors rely on related sets of transcription factors and protein kinases, both for transcriptional induction and suppression. However, we find that Gefitinib suppresses apoptosis inhibitors, while inducing cell-cycle inhibitors; conversely, Erlotinib suppresses cell-cycle and cell migration genes, while inducing proapoptotic genes. EGFR-targeting antibodies specifically suppress cell motility, developmental and differentiation processes, while inducing the contractile apparatus. miR-7, distinctively, suppresses cell-cycle genes, while inducing transcription machinery. These metaanalysis results suggest that different inhibitors have overlapping but quite distinct effects in target cells. Judicial use of EGFR-targeting combinations, i.e., simultaneous use of antibodies and multiple kinase inhibitors, may provide more effective cancer treatments with fewer side-effects and avoid development of resistance. We expect, moreover, that specific drug combination treatments can be fine-tuned to achieve specific, personalized results

Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

Human skin cancers, the most common type of tumors, represent a significant health burden. The deadliest is unquestionably melanoma. Half of melanomas have an activating mutation in the BRAF gene, prompting development of novel drugs, vemurafenib and dabrafenib, specifically targeting mutated BRAF. Trametinib and cobimetinib, which block MEK, a BRAF effector protein, have been used in combination with BRAF inhibitors. A promising new melanoma treatment is immunotherapy, approach that boosts patient's own immune system to attack cancer. Pembrolizumab and nivolumab inhibit PD-1, whereas Ipilimumab targets CTLA-4, another immunity check point, to boost the immune response. Here we focus on pathways, mechanisms, targets and treatments of human skin cancers, with particular emphasis on the new developments in the research on melanomas

Human Skin Cancer, Potential Biomarkers and Therapeutic Targets

Skin cancers, basal and squamous cell carcinomas, malignant melanomas, and Merkel cell carcinomas, constitute arguably the most common and increasingly prevalent human neoplasms. Here we discuss the epigenetic changes in DNA and chromatin, which are increasingly associated with melanoma. Several chapters focus on the posttranscriptional modification of the proteins at the melanocyte cell surface, their role in tumorigenesis, and their potential as therapeutic targets. Specifically, extracellular modifications of integrins, glycosylation of cell surface proteins, and changes of cadherins are presented. In a very interesting approach, a potential to target the mitochondria of melanoma cells is investigated. In conclusion, this volume presents various aspects of human skin cancers, components of the large worldwide effort to combat and eradicate this growing health concern