The selenoprotein P–LRP5/6–WNT3A complex promotes tumorigenesis in sporadic colorectal cancer
K. Sandeep Prabhu
K. Sandeep Prabhu
Published July 3, 2023
Citation Information: J Clin Invest. 2023;133(13):e171885. https://doi.org/10.1172/JCI171885.
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The selenoprotein P–LRP5/6–WNT3A complex promotes tumorigenesis in sporadic colorectal cancer

Abstract

Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor–related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.

Authors

K. Sandeep Prabhu

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Figure 1

SELENOP increases canonical WNT signaling to promote Apc-dependent tumorigenesis in the intestine.

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SELENOP increases canonical WNT signaling to promote Apc-dependent tumor...
Loss of the tumor suppressor gene Apc results in activation of WNT signaling. Increased expression of SELENOP throughout the progression from conventional adenomas to carcinoma drives carcinogenesis in sporadic CRC. A 42 amino acid domain in SELENOP situated between the third and fourth Sec residues activates canonical WNT signaling via direct interaction with WNT3A and its coreceptor LRP5/6 to increase β-catenin–dependent expression of protumorigenic genes. Notably, treatment with heparin can prevent the interaction between SELENOP and LRP5/6.