UNC5 dependence receptor family in human cancer: A controllable double-edged sword.

UNC5 receptor family (UNC5A-D) have been identified as dependence receptors whose functions depend on the availability of their ligand netrin-1. Through binding to netrin-1, these receptors transmit signals for cell survival, migration and differentiation, and participate in diverse physiological and pathological processes. In the lack of netrin-1, however, these receptors initiate apoptosis-inducing signal. Accumulating evidence reveals that netrin-1 and its receptors play a role in tumorigenesis and tumor progression. The expression of UNC5 receptor family is down-regulated in a variety of human tumors. Expression aberrance of UNC5 receptor family in tumors is caused by diverse mechanisms including genomic, epigenetic, transcriptional and post-transcriptional regulation. Notably, blocking netrin-1 binding to its receptors induces apoptotic cell death in tumor cells. In this review, we describe the characters and roles of UNC5 family members in tumorigenesis and tumor progression, discussing the regulatory mechanisms underlying down-regulation of UNC5 family members as well as recent implications of targeting netrin-1/UNC5 on potential clinical application for cancer treatment.