Serine-threonine Kinase Receptor-Associated Protein is a Critical Mediator of APC Mutation–Induced Intestinal Tumorigenesis Through a Feed-Forward Mechanism

Background & Aims

Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation–induced intestinal tumor initiation and progression.

Methods

We generated Strap intestinal epithelial knockout mice (Strap^ΔIEC) by crossing mice containing floxed alleles of Strap (Strap^fl/fl) with Villin-Cre mice. Then we generated Apc^Min/+;Strap^fl/fl;Vill-Cre (Apc^Min/+;Strap^ΔIEC) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor–derived organoids for STRAP knockdown and knockout and overexpression experiments.

Results

Strap deficiency extended the average survival of Apc^Min/+ mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter.

Conclusions

STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis.