MCPIP1 modulates the miRNA‒mRNA landscape in keratinocyte carcinomas.

J Exp Clin Cancer Res

Faculty of Biochemistry, Biophysics and Biotechnology, Department of General Biochemistry, Jagiellonian University, Gronostajowa 7, Krakow, 30-387, Poland.

Published: October 2024

AI Article Synopsis

  • MCPIP1 is a protein that helps control inflammation and may prevent tumors; mice lacking this protein are more prone to developing skin tumors from certain chemical exposures.
  • The study used advanced sequencing techniques to explore how MCPIP1 regulates specific microRNAs and their effect on gene expression in skin tumors induced by chemicals.
  • Findings revealed significant changes in gene expression with 2400 different protein-coding genes and 33 microRNAs affected, highlighting the direct impact of MCPIP1 on microRNA levels and its role in promoting skin cancer cell growth.

Article Abstract

Background: Monocyte Chemotactic Protein 1-Induced Protein 1 (MCPIP1, also called Regnase-1) is a negative modulator of inflammation with tumor-suppressive properties. Mice with keratinocyte-specific deletion of the Zc3h12a gene, encoding MCPIP1, (Mcpip1 mice) are more susceptible to the development of epidermal papillomas initiated by 7,12-dimethylbenz[a]-anthracene (DMBA) and promoted by 2-O-tetradecanoylphorbol-13-acetate (TPA).

Methods: The aim of this study was to investigate the MCPIP1 RNase-dependent microRNA (miRNA)‒mRNA regulatory network in chemically induced squamous cell carcinoma (SCC)-like skin papillomas. Next-generation sequencing (NGS) coupled with bioinformatic analysis was used to shortlist the MCPIP1-dependent changes in protein-coding genes and miRNAs. The expression levels of the selected miRNAs were analyzed by quantitative PCR in human keratinocytes with MCPIP1 silencing. Functional studies were performed in human keratinocytes transfected with appropriate miRNA mimics. The DIANA-microT-CDS algorithm and DIANA-TarBase v7 database were used to predict potential target genes and identify the experimentally validated targets of differentially expressed (DE) miRNAs.

Results: RNA sequencing (RNA-Seq) analysis of control and Mcpip1 DMBA/TPA-induced papillomas revealed transcriptome changes, with 2400 DE protein-coding genes and 33 DE miRNAs. The expression of miR-223-3p, miR-376c-3p, and miR-139-5p was confirmed to be dependent on MCPIP1 activity in both murine and human models. We showed that MCPIP1 directly regulates the expression of miR-376c-3p via direct cleavage of the corresponding precursor miRNA. The pro-proliferative activity of miR-223-3p, miR-376c-3p, and miR-139-5p was experimentally confirmed in SCC-like keratinocytes. Bioinformatic prediction of the mRNA targets of the DE-miRNAs revealed 416 genes as putative targets of the 18 upregulated miRNAs and 425 genes as putative targets of the 15 downregulated miRNAs. Further analyses revealed the murine interactions that are conserved in humans. Functional analysis indicated that during the development of cutaneous SCC, the most important pathways/processes mediated by the miRNA‒mRNA MCPIP1-dependent network are the regulation of inflammatory processes, epithelial cell proliferation, Wnt signaling, and miRNA transcription.

Conclusions: Loss of MCPIP1 modulates the expression profiles of 33 miRNAs in chemically induced Mcpip1 papillomas, and these changes directly affect the miRNA‒mRNA network and the modulation of pathways and processes related to carcinogenesis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492624PMC
http://dx.doi.org/10.1186/s13046-024-03211-8DOI Listing

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