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Hepatic transcriptome in CUGBP1 S302A knock-in mice highlights CUGBP1 degradation by Gankyrin through diethylnitrosamine (DEN) activation, leading to fatty liver and liver cancer

ABSTRACT: Purpose: CUGBP1 is an important regulator of liver homeostasis, through splicing regulation, stability, and mRNA translation. To aim to characterize the transcriptome of DEN-mediated liver cancer in CUGBP1 knock-in mice with Ser302 mutated to Ala (which mimics unphosphorylated CUGBP1 isoform) through RNA sequencing. Specifically, we compared gene expression levels to identify the impact of DEN-driven activation in both wildtype and CUGBP1 Ser302-to-Ala knock-in mice, focusing on downstream CUGBP1 targets and tumor activating pathways. Methods: Hepatic mRNA profiles were obtained through RNA sequencing of flash-frozen samples obtained at time of sacrifice. Results: We observe an augmentation of up- and downregulated cancer-related genes and pathways in CUGBP1 s302a knock-in mice compared to WT mice. We observe not only changes in expression related to oncogenesis, but also in splicing. Reduction of CUGBP1 protein due to the s302a variant leads to higher sensitivity to the development of liver cancer as a result of alterations in expression of down-stream mRNAs at both the splicing and expression levels. Conclusion: CUGBP1 is a strong tumor suppressor in the liver, and reduction of the CUGBP1 protein accelerates the development of liver cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE83240 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA325326

REPOSITORIES: GEO

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