| First Author | Khan S | Year | 2023 |
| Journal | J Clin Invest | Volume | 133 |
| Issue | 19 | PubMed ID | 37581937 |
| Mgi Jnum | J:344564 | Mgi Id | MGI:7578736 |
| Doi | 10.1172/JCI166295 | Citation | Khan S, et al. (2023) NLRP12 downregulates the Wnt/beta-catenin pathway via interaction with STK38 to suppress colorectal cancer. J Clin Invest 133(19) |
| abstractText | 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/beta-catenin pathway, but not NF-kappaB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates beta-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 beta-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3beta, leading to the degradation of beta-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3beta and beta-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/beta-catenin pathway, and the NLRP12/STK38/GSK3beta signaling axis could be a promising therapeutic target for CRC. |
