Abstract
BackgroundSquamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC.MethodsWe analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis.ResultsSkin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-β). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9.ConclusionsOverall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.
Highlights
Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer
Monocyte chemotactic protein 1-induced protein 1 (MCPIP1) immunoreactivity was higher than that in the adjacent skin, in cells that expressed keratin 10 (KRT10), which is a characteristic for differentiating benign tumors (Fig. 1b)
In the fully developed SCC biopsies, the overall MCPIP1 expression level was low, and MCPIP1 expression was predominantly restricted to keratin pearls, typical structures observed in cutaneous SCC that are composed of well-differentiated neoplastic squamous cells (Fig. 1a)
Summary
Squamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. The skin is the largest organ in the human body and provides a physical barrier against the external environment. It harbors several types of immune cells crucial for host defense and tissue homeostasis. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), called Regnase-1, is an RNase with antiinflammatory properties [6]. It contains a CCCH-type zinc finger motif, which is required for its interaction with RNA, and a PilT N-terminus (PIN) domain, which confers its enzymatic activity [6,7,8]. MCPIP1 degrades hairpin precursors of miRNAs, affecting miRNA biogenesis [14]
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