Herranz-Montoya Irene, Angulo-Aguado Mariana, Perna Cristian, Zagorac Sladjana, García-Jimeno Luis, Park Solip, Djouder Nabil
Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, 28034, Madrid, Spain.
Nat Commun. 2025 Apr 26;16(1):3934. doi: 10.1038/s41467-025-59282-4.
Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC loss activates MYC to transcriptionally upregulate URI, which modulates MDM2 activity, triggering p53 proteasomal degradation, essential for tumour initiation and mutation burden accrual in CRC mice. Remarkably, reinstating p53 levels via genetic URI depletion or p53 super-expression in CRC mice with WNT pathway activation prevents tumour initiation and extends lifespan. Our data reveal a "two-hit" genetic model central to APC loss-driven CRC initiation, wherein MYC/URI axis intricately controls p53 degradation, offering mechanistic insights into transitional mutation acquisition essential for CRC progression.
结直肠癌（CRC）的发病率可能由于驱动其起始和进展的不同机制而不断上升。费伦和沃格尔斯坦提出的初始模型将其视为一种多步骤肿瘤形成过程，起源于由WNT激活诱导的腺瘤性息肉，最终通过p53缺失发展为侵袭性肿瘤。通过整合人类数据和小鼠遗传学，我们重新定义了这一模式，强调了MYC、致癌性URI和p53降解在结直肠癌起始过程中的关键作用。早期APC缺失会激活MYC，从而转录上调URI，后者调节MDM2活性，触发p53蛋白酶体降解，这对于CRC小鼠的肿瘤起始和突变负担积累至关重要。值得注意的是，在激活WNT通路的CRC小鼠中，通过基因敲除URI或超表达p53来恢复p53水平，可预防肿瘤起始并延长寿命。我们的数据揭示了一种“双打击”遗传模型，该模型是APC缺失驱动的CRC起始的核心，其中MYC/URI轴复杂地控制着p53降解，为CRC进展所必需的过渡性突变获得提供了机制性见解。
