Loss of myeloid Mcpip1 suppresses hair growth and development of epidermal papilloma of the skin

Skin cancer is one of the most common type of cancer. In the course of skin carcinogenesis, the interaction between malignant keratinocytes and the tumor microenvironment, specifically immune cells, is critical. Monocyte chemotactic protein-1-induced protein 1 (MCPIP1), coded by ZC3H12A gene, is an RNase that negatively regulates stability of transcripts coding for proinflammatory cytokines (such as IL-1β, IL-6), thereby acts as a key negative regulator of inflammation. Expression of MCPIP1 is impaired in several types of cancer, such as breast cancer and neuroblastoma. We previously showed that mice deficient of keratinocyte Mcpip1 (Mcpip1-EKO) developed chemically-induced (DMBA/TPA model) SCC-like (squamous cell carcinoma) tumors faster and with more aggressive morphology, compared to control mice. Here, we investigated the effect of myeloid Mcpip1 deficiency (Mcpip1-MKO) in the DMBA/TPA-induced skin carcinogenesis model. In contrast to control mice, which developed numerous papillomas as expected, none of the Mcpip1-MKO mice developed SCC-like tumors. However, all of the Mcpip1-MKO mice developed multiple pigmented nevi, and strikingly completely lost hair on the entire body subjected to the treatment. On the histological level, we observed strong accumulation of melanin around hair follicles remnants and infiltration of immune cells, mostly macrophages. Next, we performed RNA-sequencing from lesions (nevi/papilloma) and non-lesional skin of control and Mcpip1-MKO mice, which showed upregulated inflammation-related processes in Mcpip1-MKO mice skin, such as response to interferon-gamma. In contrary, epithelial cell proliferation and Wnt-signaling pathways were downregulated. In this study, observed suppression of hair growth and papilloma development in Mcpip1-MKO mice was in contrast to the previously determined Mcpip1-EKO mice phenotype. Overall, our study suggests a distinct and critical role for keratinocyte- and myeloid-Mcpip1 in the course of skin carcinogenesis. The research has been supported by a grant from the Priority Research Area BioS (to A.L.-C.) under the Strategic Programme Excellence Initiative at Jagiellonian University.