NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer
Shahanshah Khan, … , Thirumala-Devi Kanneganti, Hasan Zaki
Shahanshah Khan, … , Thirumala-Devi Kanneganti, Hasan Zaki
Published August 15, 2023
Citation Information: J Clin Invest. 2023;133(19):e166295. https://doi.org/10.1172/JCI166295.
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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 4

Nlrp12 deficiency promotes colorectal tumorigenesis in Apcmin/+ mice.

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Nlrp12 deficiency promotes colorectal tumorigenesis in Apcmin/+ mice. A...
Apcmin/+ and Apcmin/+ Nlrp12–/– mice (n = 15/group) were sacrificed 5 months after birth, and the number of tumors was counted in the small (A) and large intestine (colon) (B). (C) Representative images of H&E-stained small intestine and colons at low (2×) magnifications. Scale bars: 100 μm. (D–G) Homogenates from tumor-bearing small intestines and colons were analyzed for the activation of β-catenin, p-P65, p-IκBα, IκBα, p-ERK, ERK, p-JNK, p-AKT, and β-actin by Western blotting. Band intensities of p-P65, p-ERK, and β-catenin relative to β-actin were measured. Data represent mean ± SEM. (H and I) RNA isolated from small intestine and tumor-bearing colons was measured for the expression of indicated genes by real-time RT-PCR. Data represent mean ± SEM. Experiments were repeated at least 3 times, and data from a representative experiment are presented. *P < 0.05, **P < 0.01, ***P < 0.001 by unpaired, 2-tailed Student’s t test.