The emerging role of RUNX3 in cancer metastasis

Metastasis remains the major driver of mortality in patients with cancer. The multistep metastatic process starts with the dissemination of tumor cells from a primary site and leading to secondary tumor development in an anatomically distant location. Although significant progress has been made in understanding the molecular characteristics of metastasis, many questions remain regarding the intracellular mechanisms governing transition through the various metastatic stages. The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-beta (TGF-beta) signaling pathway, and has critical roles in the regulation of cell death by apoptosis, and in angiogenesis, epithelial-to-mesenchymal transition (EMT), cell migration and invasion. RUNX3 functions as a bona fide initiator of carcinogenesis by linking the Wnt oncogenic and TGF-beta tumor suppressive pathways. RUNX3 is frequently inactivated in human cancer cell lines and cancer samples by hemizygous deletion of the Runx3 gene, hypermethylation of the Runx3 promoter, or cytoplasmic sequestration of RUNX3 protein. Inactivation of RUNX3 makes it a putative tumor suppressor in human neoplasia. In the present review, we summarize the proposed roles of RUNX3 in metastasis and, when applicable, highlight the mechanism by which they function.