The monocyte chemoattractant protein-induced protein (MCPIP) family consists of 4 members (MCPIP1–4) encoded by theZC3h12A-Dgenes, which are located at different loci. The common features of MCPIP proteins are the zinc finger domain, consisting of three cysteines and one histidine (CCCH), and the N-terminal domain of the PilT protein (PilT-N-terminal domain (PIN domain)). All family members act as endonucleases controlling the half-life of mRNA and microRNA (miRNA). The best-studied member of this family is MCPIP1 (also known as Regnase-1).In this review, we discuss the current knowledge on the role of MCPIP1 in cancer-related processes. Because the characteristics of MCPIP1 as a fundamental negative regulator of immune processes have been comprehensively described in numerous studies, we focus on the function of MCPIP1 in modulating apoptosis, angiogenesis and metastasis.

Background: Squamous 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.Methods: We 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 tumorigenesisin vivo, we established a mouse model of chemically induced carcinogenesis.Results: Skin 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 (Mcpip1^eKO). Papillomas that developed in Mcpip1^eKOmouse 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.Conclusions: Overall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.

The pathogenesis of hidradenitis suppurativa (HS) is yet to be fully understood. However, inflammation is a key element in the development of skin lesions. The aim of this study was to evaluate the expression of monocyte chemotactic protein-1-induced protein-1 (MCPIP1) in the skin of patients suffering from HS. Skin biopsies of 15 patients with HS and 15 healthy controls were obtained and processed for immunohistochemistry, western blot, and real time PCR. The highest mean MCPIP1 mRNA expression was found in the inflammatory lesional skin of HS patients. It was significantly higher than MCPIP1 mRNA expression in the biopsies from both healthy controls and non-lesional skin of HS patients. Western blot analysis indicated that expression of MCPIP1 was elevated within both lesional and non-lesional skin compared to the healthy control. The increased MCPIP1 mRNA and protein expression level in HS lesions may indicate its possible role in the disease pathogenesis.

Background: Monocyte chemoattractant protein-induced protein 3 (MCPIP3), also called Regnase-3 and encoded by the ZC3H12C gene, is a member of the MCPIP family of RNases. Previous studies showed that MCPIP1 in keratinocytes plays a pivotal role in the maintenance of skin integrity and immunological function. Given that the expression of MCPIP3, similar to that of MCPIP1, is increased in psoriatic lesions compared with uninvolved skin, a role of MCPIP3 in the regulation of keratinocyte and epidermal biology was hypothesized. Methods: This study aimed to investigate the specific function of the MCPIP3 protein in the skin. The expression pattern of MCPIP3 was studied in normal human epidermal keratinocytes (NHEKs) subjected to in vitro differentiation and upon stimulation with proinflammatory factors. Mice with keratinocyte-specific deletion of MCPIP3 (Mcpip3^loxP/loxPKrt14^Cre; MCPIP3^EKO) were generated and characterized. The response of the skin of MCPIP3^EKO mice to imiquimod (IMQ) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated. The expression levels of key modulators of keratinocyte proliferation and differentiation were measured in MCPIP3^EKO model mice and in NHEKs transiently transfected with MCPIP3-specific siRNA. Reporter assays were used to identify direct targets of MCPIP3 nucleolytic activity. Results: In human keratinocytes, the expression of ZC3H12C/MCPIP3 was rapidly induced by stimulation with TPA, IL-17a, IL-36α, and TNF-α. Although mice with keratinocyte-specific deletion of MCPIP3 (MCPIP3^EKO) did not develop skin inflammation, they displayed abnormalities in skin morphology. Stimulation with IMQ and TPA exacerbated epidermal hyperplasia caused by keratinocyte-specific deficiency of MCPIP3 and led to abnormal epidermal differentiation. The expression levels of keratinocyte proliferation and differentiation markers, such as keratin-14, cyclin B1, involucrin, and the S100 calcium-binding proteins S100A7/A9, were increased in NHEKs in which MCPIP3 expression was silenced. MCPIP3 negatively regulates the level of cyclin B1 mRNA via direct nucleolytic cleavage within its 3’ untranslated region. Conclusions: The MCPIP3 protein modulates the balance of keratinocyte proliferation and differentiation and functions as a regulator of epidermal morphology in vivo.