Activated TNF-α/NF-κB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice

The humanCDKN2A locus encodes 2 distinct proteins, p16(INK4A) and p14(ARF) [mouse p19(Arf)], designated INK4A (inhibitor of cyclin dependent kinase 4) and ARF (alternative reading frame) here, that are translated from alternatively spliced mRNAs. HumanARF is implicated as a tumor suppressor gene, mainly in association with the simultaneous deletion ofINK4A . However, questions remain as to whether loss ofARF alone is sufficient to drive tumorigenesis. Here, we report that mice deficient forArf are susceptible to accelerated asbestos-induced malignant mesothelioma (MM). MMs arising inArf (+/−) mice consistently exhibit biallelic inactivation ofArf , but, unexpectedly, do not acquire additional recurrent genetic alterations that we previously identified in asbestos-induced MMs arising inNf2 (+/−) mice. Array CGH analysis was used to detect a recurrent deletion at chromosome 4C6 in MMs fromArf (+/−) mice. A candidate gene in this region,Faf1 (FAS-associated factor 1), was further explored, because it encodes a protein implicated in tumor cell survival and in the pathogenesis of some human tumor types. We confirmed hemizygous loss ofFaf1 and down-regulation of Faf1 protein in a series of MMs fromArf (+/−) mice, and we then showed that Faf1 regulates TNF-α-mediated NF-κB signaling, a pathway previously implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these data indicate thatArf inactivation has a significant role in driving MM pathogenesis, and implicate Faf1 as a key component in the TNF-α/NF-κB signaling node that has now been independently implicated in asbestos-induced oncogenesis.