title: ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma.
abstract: Non-small-cell lung carcinoma (NSCLC) is among the deadliest of human cancers. The CDKN2A locus, which houses the INK4a and ARF tumor suppressor genes, is frequently altered in NSCLC. However, the specific role of ARF in pulmonary tumorigenesis remains unclear. KRAS and other oncogenes induce the expression of ARF, thus stabilizing p53 activity and arresting cell proliferation. To address the role of ARF in Kras-driven NSCLC, we compared the susceptibility of NIH/Ola strain wild-type and Arf-knockout mice to urethane-induced lung carcinogenesis. Lung tumor size, malignancy and associated morbidity were significantly increased in Arf(-/-) compared with Arf(+/+) animals at 25 weeks after induction. Pulmonary tumors from Arf-knockout mice exhibited increased cell proliferation and DNA damage compared with wild-type mice. A subgroup of tumors in Arf(-/-) animals presented as dedifferentiated and metastatic, with many characteristics of pulmonary sarcomatoid carcinoma, a neoplasm previously undocumented in mouse models. Our finding of a role for ARF in NSCLC is consistent with the observation that benign adenomas from Arf(+/+) mice robustly expressed ARF, while ARF expression was markedly reduced in malignant adenocarcinomas. ARF expression also frequently colocalized with the expression of p21(CIP1), a transcriptional target of p53, arguing that ARF induces the p53 checkpoint to arrest cell proliferation in vivo. Taken together, these findings demonstrate that induction of ARF is an early response in lung tumorigenesis that mounts a strong barrier against tumor growth and malignant progression.
authors.affiliation: 1] Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Busch
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Moser
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Gurley
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Kelly-Spratt
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Liggitt
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kemp
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology; D018450:Disease Progression; D011905:Genes, ras; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53