| Autor: |
Khan S; Department of Pathology., Kwak YT; Department of Pathology., Peng L; Department of Pathology., Hu S; Department of Pathology., Cantarel BL; Bioinformatics Core Facility, Lyda Hill Department of Bioinformatics, and., Lewis CM; Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA., Gao Y; Department of Pathology., Mani RS; Department of Pathology., Kanneganti TD; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Zaki H; Department of Pathology. |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of clinical investigation [J Clin Invest] 2023 Oct 02; Vol. 133 (19). Date of Electronic Publication: 2023 Oct 02. |
| DOI: |
10.1172/JCI166295 |
| Abstrakt: |
Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/β-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates β-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of β-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3β, leading to the degradation of β-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3β and β-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/β-catenin pathway, and the NLRP12/STK38/GSK3β signaling axis could be a promising therapeutic target for CRC. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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