EACR25-1950

Modification of β-Catenin by MCPIP1 endonuclease Activity regulates the metastatic potential of ccRCC

J. Górka¹, P. Marona¹, M. Główczyk², R. Myrczek^1,3, J. Ryś⁴, J. Jura¹, K. Miękus¹

¹Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Department of General Biochemistry, Cracow, Poland
²School of Medicine, University of Virginia, Department of Pathology, Charlottesville, United States
³Jagiellonian University, Doctoral School of Exact and Natural Sciences, Cracow, Poland
⁴Centre of Oncology Maria Skłodowska-Curie Memorial Institute, Cracow Branch, Department of Tumor Pathology, Cracow, Poland

Introduction:

Renal cell carcinoma (RCC) is one of the most common urological neoplasms in the world, with ccRCC being the most common subtype, accounting for approximately 75% of RCC cases. Among the many pathways implied in ccRCC, the Wnt/β-catenin pathway has emerged as a key contributor. To overcome these challenges, acquiring a comprehensive understanding of the underlying biology of ccRCC is crucial. Among the endonucleases, the ZC3H12a gene encoding Monocyte Chemoattractant Protein-1 Induced Protein, has a suppressive effect in renal cell carcinoma. Our recent study revealed that MCPIP1 may act as a tumor suppressor in ccRCC that prevents EMT by stabilizing Wnt inhibitors and decreasing the levels of active β-catenin and EMT inducers.

Material and method:

To investigate the role of MCPIP1 in ccRCC development and progression, we used in vivo, in vitro models and the samples from patients. We conducted a comprehensive analysis, including the assessment of crucial genes and proteins of the Wnt/β-Catenin pathway, using Western blot, microarray analysis, quantitative PCR, immunofluorescence, and immunohistochemistry staining.

Result and discussion:

In this study we demonstrate that the endonuclease activity of MCPIP1 may mediate tumor progression by controlling the transcriptional and post-transcriptional modification of β-catenin. We found that MCPIP1 regulates of the level of genes binding to the CTNNB1 gene promoter, which encodes β-catenin. Moreover, MCPIP1 influences not only on the level of β-catenin, but also on its post-transcriptional modifications, including phosphorylations of Y654 and S675 which regulate its activity. Furthermore, we observed a dramatic decrease in the level of inactive, degradation-promoted, phosphorylated β-catenin (Ser45) in advanced stages of ccRCC compared to early clinical stages. In contrast, the level of active, phosphorylated β-catenin significantly increases with the progression of the disease. Microarray analysis indicated that the expression of genes binding to the CTNNB1 gene promoter, encoding β-catenin, may affect the progression of ccRCC.

Conclusion:

Our studies suggest that MCPIP1 plays a significant role in the progression of ccRCC by regulating the post-transcriptional modifications of β-catenin. The level and location of phosphorylated β-catenin may be crucial at every stage of ccRCC development.