NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer
Shahanshah Khan, Youn-Tae Kwak, Lan Peng, Shuiqing Hu, Brandi L. Cantarel, Cheryl M. Lewis, Yunpeng Gao, Ram S. Mani, Thirumala-Devi Kanneganti, Hasan Zaki
Shahanshah Khan, Youn-Tae Kwak, Lan Peng, Shuiqing Hu, Brandi L. Cantarel, Cheryl M. Lewis, Yunpeng Gao, Ram S. Mani, Thirumala-Devi Kanneganti, Hasan Zaki
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Research Article Gastroenterology

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

Abstract

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.

Authors

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

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Figure 1

NLRP12 suppresses invasive adenocarcinoma and downregulates genes involved in proliferation, epithelial-mesenchymal transition (EMT), and invasion.

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NLRP12 suppresses invasive adenocarcinoma and downregulates genes involv...
Colorectal tumorigenesis was induced in WT and Nlrp12–/– mice (n = 16/group) using the AOM plus DSS regimen. (A and B) Mice were sacrificed 12 weeks after AOM, and tumor burden was counted. (C and D) Tumor-bearing colon sections (n = 7) were stained with H&E and examined histopathologically. (C) Representative images of H&E-stained colons. The arrow indicates the invasion of the tumor into the stroma. Scale bars: 100 μm. (D) Semiquantitative scoring for low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive adenocarcinoma. Data represent mean ± SEM. Experiments were repeated at least 3 times, and data from a representative experiment are presented. (E) RNA isolated from tumors was used for RNA-seq analysis. The heatmap shows the expression of selected genes. (F–H) The expression of MMPs (F), EMT markers (G), and Wnt target genes (H) in the tumor was measured by real-time RT-PCR. Data represent mean ± SEM. Experiments were repeated 2 times, and data from a representative experiment are presented. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by unpaired, 2-tailed Student’s t test.