p19 ^Arf Suppresses Growth, Progression, and Metastasis of Hras-Driven Carcinomas through p53-Dependent and -Independent Pathways

Abstract

Ectopic expression of oncogenes such as Ras induces expression of p19 ^Arf, which, in turn, activates p53 and growth arrest. Here, we used a multistage model of squamous cell carcinoma development to investigate the functional interactions between Ras, p19 ^Arf, and p53 during tumor progression in the mouse. Skin tumors were induced in wild-type, p19 ^Arf -deficient, and p53-deficient mice using the DMBA/TPA two-step protocol. Activating mutations in Hras were detected in all papillomas and carcinomas examined, regardless of genotype. Relative to wild-type mice, the growth rate of papillomas was greater in p19 ^Arf- deficient mice, and reduced in p53-deficient mice. Malignant conversion of papillomas to squamous cell carcinomas, as well as metastasis to lymph nodes and lungs, was markedly accelerated in both p19  ^Arf- and p53-deficient mice. Thus, p19 ^Arf inhibits the growth rate of tumors in a p53-independent manner. Through its regulation of p53, p19 ^Arf also suppresses malignant conversion and metastasis. p53 expression was upregulated in papillomas from wild-type but not p19 ^Arf -null mice, and p53 mutations were more frequently seen in wild-type than in p19 ^Arf -null carcinomas. This indicates that selection for p53 mutations is a direct result of signaling from the initiating oncogenic lesion, Hras, acting through p19 ^Arf.

Abstract

A squamous cell carcinoma model shows Ras mutation not only initiates tumor development but, through Arf and p53, directly influences the subsequent evolutionary trajectory of the tumors