**3. Chemically induced keratinocyte proteome alterations**

Chemically induced tumors in experimental models can mimic all the clinical cancer progress phases being useful in the evaluation of new drugs, studying biological context or in decoding molecular mechanisms responsible for tumor initiation and development. Among chemical carcinogens commonly applied in cancer models are the following: environmental contaminants, N-nitroso compounds, food additives, antineoplastic agents, natural and synthetic substances, etc.

comparison to normal skin, such as S100A4 /A8 /A9 /A10 [30]. The over-expression of this protein family was found also in other inflammatory diseases as well as in psoriatic keratinocytes [31, 32]. Over-expression of mast cell proteins was also found in inflamed keratinocytes, namely activation proteins, mast cell b-tryptase, and so on [29]. Mast cell b-tryptase can further induce tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6) and interleukin-1b (IL-1b) upregulating and also collagen type I and fibronectin expression [33]. Another pro-inflammatory protein found overexpressed in inflammatory keratinocytes, macrophage migration inhibitory factor (MIF), can be involved in the amplification of the inflammatory responses

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Components of the skin's extracellular matrix (ECM), like the small leucine-rich proteoglycan family members, asporin and decorin, are inhibited by direct binding of the transforming growth factor β (TGF-β) activity [34]. In inflamed keratinocytes, high asporin expression was reported and this overexpression is probably due to the inflammatory response in human

Differences in the proteomic pattern between normal and inflammatory keratinocytes reside in several important classes of overexpressed proteins. These are appending to the inflammation, tumor suppression, and fibrosis processes. The dynamic expression of these proteins can

Recent studies have compared non-advanced SCC to advanced SCC, in order to identify pathways that are activated in SCC progression. Considering the fact that SCC develops on skin areas exposed to sunlight, UV radiation is found to be responsible for activating signal transduction pathways in the processes of apoptosis, inflammation, proliferation, and differentia-

Molecular marker studies that reflect the initial changes in skin carcinogenesis have shown that the most important gene involved in the ultraviolet radiation effects is the p53 tumor suppressor gene, which plays an important role in apoptosis, cell proliferation, DNA differentiation and repairing process. Mutations of the p53 tumor suppressor gene result in the occurrence of other mutations in cascade with the loss of control of aberrant cell growth, leading to

Also, several biomarkers, such as E-cadherin, Ki-67 and cyclin D1, have been shown to correlate with malignancy in NMSC [37]. Thus, designed to maintain the stability of epithelial tissues, E-cadherin is a Ca(2+) dependent intercellular adhesion molecule, whose downregulation is closely related to the increased potential for tumor invasiveness and metastasis. In SCC, a decrease in E-cadherin expression in the primary lesion is correlated with the development of regional lymph node metastases [38]. Ki-67 is a marker of the cell proliferation and a representative in fast and frequent recurrent aggressive tumors [39]. An important regulator of the cell cycle, cyclin D1 is a proto-oncogene which is essential in the development of skin

cancer leading to the organization and abnormal differentiation of tissues [40].

developed during wound healing.

be important in depicting the therapeutic target potential.

**5. SCC progression and aggressiveness**

tion, necessary for SCC development [2].

the formation of cancer cells [35, 36].

dermal wounds [29].

Combining chemically induced cancer models with innovative molecular imaging techniques may help to advance new anticancer diagnostics and therapeutics protocols [22]. By studying skin carcinogenesis, phases of early alterations in the skin layers and of the mechanisms beneath are highlighted. These mouse models share common mechanisms with human skin tumorigenesis, and moreover, there are similarities in terms of genetic milieu caused by carcinogens and pro-inflammatory cytokines and chemokines that favor tumor progression [23].

Different carcinogens imprint different changes on skin cells, including on the keratinocyte proteome pattern. Mancozeb—*ethylene (bis)dithiocarbamate*—is a fungicide and a multipotent carcinogen whose underlying mechanism of action is mostly unknown. By a two-dimensional gel electrophoresis and mass spectrometry analysis, a proteomic profile of mice skin exposed to mancozeb (200 mg/kg body weight) was generated. By comparison with control samples, two significantly upregulated proteins were found, Calcyclin (S100A6) and Calgranulin-B (S100A9); these two proteins are well-known markers of keratinocyte differentiation and proliferation, suggesting their role in neoplastic alterations induced by Mancozeb. The same approach in human keratinocyte carcinogenesis model with HaCaT cells revealed that upregulation of S100A6 and S100A9 confirms the neoplastic potential of Mancozeb. The authors conclude that S100A6 and S100A9 modulate the ERK1/2 signaling pathway underlying in this way the Mancozeb-induced neoplastic potential in human skin [24], and thus, a certain proteome milieu prescribe keratinocyte behavior in a chemically triggered carcinogenesis.
