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

Abstract

Summary: 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. : Karunanithi and colleagues demonstrate that the RBP4-STRA6 pathway is critical for colon cancer stem cell (CSC) maintenance. Downregulating STRA6 or RBP4 in colon cancer cells decreases CSC population and self-renewal. Increased levels of CSC markers and tumor growth in response to high-fat feeding are abrogated upon STRA6 silencing. The RBP4-STRA6 pathway may provide a link between high-fat feeding and colon carcinogenesis. Keywords: STRA6, RBP4, colon cancer, stem cells, high-fat diet, stemness