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

Gastroenterology. 2022 Jan;162(1):193-208. doi: 10.1053/j.gastro.2021.09.010. Epub 2021 Sep 11.

Abstract

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 (StrapΔIEC) by crossing mice containing floxed alleles of Strap (Strapfl/fl) with Villin-Cre mice. Then we generated ApcMin/+;Strapfl/fl;Vill-Cre (ApcMin/+;StrapΔIEC) 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 ApcMin/+ 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.

Keywords: Intestinal Cancer; Mouse Models; Tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Disease Progression
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic
  • Genes, APC*
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Tumor Cells, Cultured
  • Wnt Signaling Pathway

Substances

  • RNA-Binding Proteins
  • STRAP protein, human
  • STRAP protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases