NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer
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 tha...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-10-01
|
| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI166295 |
| _version_ | 1827768125802676224 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Shahanshah Khan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:53Z |
| format | Article |
| id | doaj.art-9a592545d1e544fd83a73d0b494e19c0 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:07:53Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-9a592545d1e544fd83a73d0b494e19c02023-11-07T16:20:55ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-10-0113319NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancerShahanshah KhanYoun-Tae KwakLan PengShuiqing HuBrandi L. CantarelCheryl M. LewisYunpeng GaoRam S. ManiThirumala-Devi KannegantiHasan ZakiColorectal 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.https://doi.org/10.1172/JCI166295Gastroenterology |
| spellingShingle | 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 NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer The Journal of Clinical Investigation Gastroenterology |
| title | NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer |
| title_full | NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer |
| title_fullStr | NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer |
| title_full_unstemmed | NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer |
| title_short | NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer |
| title_sort | nlrp12 downregulates the wnt β catenin pathway via interaction with stk38 to suppress colorectal cancer |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/JCI166295 |
| work_keys_str_mv | AT shahanshahkhan nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT yountaekwak nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT lanpeng nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT shuiqinghu nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT brandilcantarel nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT cherylmlewis nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT yunpenggao nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT ramsmani nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT thirumaladevikanneganti nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer AT hasanzaki nlrp12downregulatesthewntbcateninpathwayviainteractionwithstk38tosuppresscolorectalcancer |