Gastrointestinal (GI) cancer is characterized by its aggressiveness, but the underlying mechanism is not fully
understood. Studies reveal that epithelial to mesenchymal transition (EMT), which is regulated by a series of transcription
factors and signaling pathways, is strongly associated with GI cancer cell proliferation, invasion and metastasis.
Importantly, EMT is a product of crosstalk between signaling pathways. Krüppel-like factor 4 (KLF4), a zinc finger-type
transcription factor, is decreased or lost in most GI cancers. By transcriptionally regulating its downstream target genes,
KLF4 plays important roles of GI cancer tumorigenesis, proliferation and differentiation. In this review, we focus on the
mechanism of KLF4 in GI cancer EMT, and demonstrate that through crosstalk with TGF-β, Notch, and Wnt signaling
pathways, KLF4 negatively regulates EMT of GI cancers. Finally, we indicate the challenging new frontiers for KLF4
which contributes to better understanding of the mechanism of GI cancer aggressiveness.