The endonuclease MCPIP1 protects against liver cancer development in a sex-dependent manner by modulating β-catenin and CREB1

Background & Aims: Monocyte chemoattractant protein-induced protein 1 (MCPIP1), encoded by ZC3H12A, is a negative regulator of inflammation and tumorigenesis. While its role has been implicated in various cancers, the function of MCPIP1 in hepatocellular carcinoma (HCC) remains poorly understood. This study explored the contribution of hepatocyte-specific MCPIP1 loss to HCC pathogenesis, highlighting its role in overcoming the inherent tumor resistance observed in female mice. Methods: Liver tissues (N≥5 per group) and primary hepatocytes (N≥3 per group) were evaluated using Western blot, immunohistochemistry, immunofluorescence, RNA-seq and pathway enrichment analysis. The expression levels of MCPIP1 in HCC were measured by qRT-PCR. The results are presented as mean ± SD, student's t or Mann-Whitney U tests were used for statistical analysis of two groups. For more than two groups, ordinary two-way ANOVA was used. Results: The hepatocyte-specific loss of MCPIP1 markedly promoted fibrosis and tumorigenesis, particularly in female mice, disrupting the normal sex-related protection observed in the diethylnitrosamine (DEN) model. As determined by next-generation sequencing and bioinformatics analysis, oncogenic and fibrotic programs, including the EMT, Wnt/β-catenin, and JAK/STAT3 pathways, were activated in MCPIP1 knockout livers. These molecular events activated β-catenin, c-Met, and IL-6/STAT3/NFκB signaling, and they enhanced fibrotic remodeling. In MCPIP1-deficient hepatocytes, active β-catenin and CREB1 accumulated in the nucleus, and the expression of protumorigenic targets, such as Spp1, Tgfb2, and Adam17 increased. Moreover, MCPIP1 expression was significantly downregulated in human HCC tissues and correlated with tumor progression. Conclusions: MCPIP1 plays a protective role against inflammation-driven hepatocarcinogenesis, particularly in females, by restraining fibrotic remodeling and oncogenic signaling. The downregulation of MCPIP1 expression promotes a tumor-promoting microenvironment through the coordinated activation of the β-catenin, STAT3, and CREB1 pathways.