Journal article
SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions
The Journal of clinical investigation, Vol.133(13), pp.1-15
07/01/2023
DOI: 10.1172/JCH65988
Abstract
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 (Ape) 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.
Details
- Title: Subtitle
- SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions
- Creators
- Jennifer PilatRachel BrownZhengyi ChenNathaniel BerleAdrian OthonM WashingtonShruti AnantSuguru KurokawaVictoria NgJoshua ThompsonJustin JacobseJeremy GoettelEthan LeeYash ChoksiKen LauSarah ShortChristopher Williams
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.133(13), pp.1-15
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCH65988
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 07/01/2023
- Academic Unit
- Internal Medicine; Hematology, Oncology, and Blood & Marrow Transplantation
- Record Identifier
- 9984443159802771
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