Journal Article

NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer

Peng, Lan, Kanneganti, Thirumala-Devi, Gao, Yunpeng, Khan, Shahanshah, Kwak, Youn-Tae, Cantarel, Brandi L., Mani, Ram S., Lewis, Cheryl M., Zaki, Hasan, Hu, Shuiqing

2023

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adenocarcinoma / Animals / beta Catenin - genetics / beta Catenin - metabolism / Biomedical research / Carcinogenesis - genetics / Cell activation / Cell death / Cell Line, Tumor / Cell Movement / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - pathology / Down-regulation / Epithelial cells / Gastroenterology / Gene Expression Regulation, Neoplastic / Glycogen Synthase Kinase 3 beta - genetics / Humans / Inflammation / Inflammatory bowel disease / Intestine / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Kinases / Metastasis / Mice / Microbiota / Organoids / Pathogenesis / Phosphorylation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteomics / Signal transduction / Therapeutic targets / Tumorigenesis / Tumors / Wnt protein / Wnt Signaling Pathway / β-Catenin