RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and Mediates High-Fat Diet-Induced Colon Carcinogenesis

Sheelarani Karunanithi, Liraz Levi, Jennifer DeVecchio, George Karagkounis, Ofer Reizes, Justin D. Lathia, Matthew F. Kalady, Noa Noy

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

The transmembrane protein, STRA6, functions as a vitamin A transporter and a cytokine receptor when activated by vitamin A-bound serum retinol binding protein 4 (RBP4). STRA6 activation transduces a JAK2-STAT3 signaling cascade and promotes tumorigenesis in a xenograft mouse model of colon cancer. We show here that RBP4 and STRA6 expression is associated with poor oncologic prognosis. Downregulating STRA6 or RBP4 in colon cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, we show that high-fat diet (HFD) increases LGR5 expression and promotes tumor growth in a xenograft model independent of obesity. HFD increased STRA6 levels, and downregulation of STRA6 delays and impairs tumor initiation, tumor growth, and expression of stemness markers. Together, these data demonstrate a key role of STRA6 and RBP4 in the maintenance of colon cancer self-renewal and that this pathway is an important link through which consumption of HFD contributes to colon carcinogenesis.

Original languageEnglish (US)
Pages (from-to)438-450
Number of pages13
JournalStem Cell Reports
Volume9
Issue number2
DOIs
StatePublished - Aug 8 2017
Externally publishedYes

Keywords

  • colon cancer
  • high-fat diet
  • RBP4
  • stem cells
  • stemness
  • STRA6

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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