SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions
Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-07-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI165988 |
| _version_ | 1797634474484170752 |
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| author | Jennifer M. Pilat Rachel E. Brown Zhengyi Chen Nathaniel J. Berle Adrian P. Othon M. Kay Washington Shruti A. Anant Suguru Kurokawa Victoria H. Ng Joshua J. Thompson Justin Jacobse Jeremy A. Goettel Ethan Lee Yash A. Choksi Ken S. Lau Sarah P. Short Christopher S. Williams |
| author_facet | Jennifer M. Pilat Rachel E. Brown Zhengyi Chen Nathaniel J. Berle Adrian P. Othon M. Kay Washington Shruti A. Anant Suguru Kurokawa Victoria H. Ng Joshua J. Thompson Justin Jacobse Jeremy A. Goettel Ethan Lee Yash A. Choksi Ken S. Lau Sarah P. Short Christopher S. Williams |
| author_sort | Jennifer M. Pilat |
| collection | DOAJ |
| description | Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC. |
| first_indexed | 2024-03-11T12:08:19Z |
| format | Article |
| id | doaj.art-f37c3c97bdc44595a82e0f79ef398d19 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:19Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-f37c3c97bdc44595a82e0f79ef398d192023-11-07T16:20:34ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-07-0113313SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactionsJennifer M. PilatRachel E. BrownZhengyi ChenNathaniel J. BerleAdrian P. OthonM. Kay WashingtonShruti A. AnantSuguru KurokawaVictoria H. NgJoshua J. ThompsonJustin JacobseJeremy A. GoettelEthan LeeYash A. ChoksiKen S. LauSarah P. ShortChristopher S. WilliamsAlthough selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.https://doi.org/10.1172/JCI165988Gastroenterology |
| spellingShingle | Jennifer M. Pilat Rachel E. Brown Zhengyi Chen Nathaniel J. Berle Adrian P. Othon M. Kay Washington Shruti A. Anant Suguru Kurokawa Victoria H. Ng Joshua J. Thompson Justin Jacobse Jeremy A. Goettel Ethan Lee Yash A. Choksi Ken S. Lau Sarah P. Short Christopher S. Williams SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions The Journal of Clinical Investigation Gastroenterology |
| title | SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions |
| title_full | SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions |
| title_fullStr | SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions |
| title_full_unstemmed | SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions |
| title_short | SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions |
| title_sort | selenop modifies sporadic colorectal carcinogenesis and wnt signaling activity through lrp5 6 interactions |
| topic | Gastroenterology |
| url | https://doi.org/10.1172/JCI165988 |
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