Fig. 10: A revised model for CRC molecular progression.

CRC develops as a result of the stepwise acquisition of mutations in the intestinal epithelial cells. The loss of APC typically represents the initial “first hit,” triggering the transformation process. This loss leads to β-catenin activation, which in turn activates MYC. MYC drives the transcription of the oncogenic protein URI, which enhances MDM2 activity. Increased MDM2 activity results in p53 ubiquitination and proteasomal degradation, a critical step in initiating tumorigenesis. The downregulation of p53 disrupts cell cycle regulation, allowing uncontrolled proliferation, and predisposing cells to acquire additional mutations necessary for adenoma progression, such as mutations in KRAS or p53 gene loss. The genetic loss of Tp53 often occurs as a later event, facilitating the transition from adenomas to adenocarcinomas. We also show that genetic p53 loss can drive CRC independently of oncogenic URI, but p53 protein degradation remains an initiating event that depends exclusively on the MYC-URI axis during APC loss-driven CRC initiation. Therefore, URI is oncogenic by promoting p53 degradation, but it can also exert oncogenic activities at later stages of CRC that depend on URI targets other than p53.