MCPIP1 inhibits Wnt/\u03b2-catenin signaling pathway activity and modulates epithelial-mesenchymal transition during clear cell renal cell carcinoma progression by targeting miRNAs

Judyta Gorka,Jurek W Dobrucki,Jolanta Jura,Oliwia Kwapisz,Katarzyna Miekus,Agnieszka Waligórska,Ewelina Pospiech,Janusz Rys,Paulina Marona

doi:10.1038/s41388-021-02062-3

Judyta Gorka, Jurek W Dobrucki + Show 7 more

Open Access

https://doi.org/10.1038/s41388-021-02062-3

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Journal: Oncogene	Publication Date: Oct 16, 2021
Citations: 21	License type: open-access

Affiliation: Jagiellonian University

Abstract

Epithelial-mesenchymal transition (EMT) refers to the acquisition of mesenchymal properties in cells participating in tumor progression. One hallmark of EMT is the increased level of active β-catenin, which can trigger the transcription of Wnt-specific genes responsible for the control of cell fate. We investigated how Monocyte Chemotactic Protein-1-Induced Protein-1 (MCPIP1), a negative regulator of inflammatory processes, affects EMT in a clear cell renal cell carcinoma (ccRCC) cell line, patient tumor tissues and a xenotransplant model. We showed that MCPIP1 degrades miRNAs via its RNase activity and thus protects the mRNA transcripts of negative regulators of the Wnt/β-catenin pathway from degradation, which in turn prevents EMT. Mechanistically, the loss of MCPIP1 RNase activity led to the upregulation of miRNA-519a-3p, miRNA-519b-3p, and miRNA-520c-3p, which inhibited the expression of Wnt pathway inhibitors (SFRP4, KREMEN1, CXXC4, CSNK1A1 and ZNFR3). Thus, the level of active nuclear β-catenin was increased, leading to increased levels of EMT inducers (SNAI1, SNAI2, ZEB1 and TWIST) and, consequently, decreased expression of E-cadherin, increased expression of mesenchymal markers, and acquisition of the mesenchymal phenotype. This study revealed that MCPIP1 may act as a tumor suppressor that prevents EMT by stabilizing Wnt inhibitors and decreasing the levels of active β-catenin and EMT inducers.

Highlights

The Wnt signaling pathway is a key molecular cascade that regulates cell fate in animals
To confirm that Monocyte Chemotactic Protein-1-Induced Protein-1 (MCPIP1) protects against the acquisition of the mesenchymal phenotype, we performed a study in Foxn1nu/Foxn1nu and NOD-SCID mice subcutaneously injected with clear cell renal cell carcinoma (ccRCC) cells overexpressing the MCPIP1 protein (MCPIP1) or its RNase-depleted form (MCPIP1-D141) or silencing MCPIP1 (Fig. 1D, Supplementary Fig. S1F)
A low level of MCPIP1 in ccRCC cells increases the levels of vimentin and β-catenin and decreases that of E-cadherin, indicating that MCPIP1 may control the acquisition of mesenchymal features [24]

Summary

Introduction

The Wnt signaling pathway is a key molecular cascade that regulates cell fate in animals. In the canonical Wnt pathway, β-catenin is the key effector responsible for signal transduction to the nucleus and the activation of Wnt-specific genes responsible for the control of cell fate [1]. When Wnt signaling is inactive, active β-catenin is recruited to a destruction complex, in which casein kinase 1 (CK1) phosphorylates β-catenin at serine 45 (S45), priming β-catenin for subsequent phosphorylation by glycogen synthase kinase 3 (GSK3). These phosphorylation events mark β-catenin for subsequent ubiquitination and proteasomal degradation and prevent β-catenin from translocating to the nucleus [2,3,4]. Active β-catenin directly binds to transcription factors associated with the promoters of the key epithelial-mesenchymal transition (EMT)

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