WNT2–SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer

Abstract Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and propagation. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that WNT2 was overexpressed in GCSCs and positively regulated by its transcription factor SOX4. SOX4 was in turn upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSC self-renewal and tumorigenicity. Furthermore, blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2–SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2–SOX4 positive feedback loop as a mechanism for GCSC-induced chemo-drugs resistance and suggested that the WNT2–SOX4 axis may be a potential therapeutic target for gastric cancer treatment.