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B Signaling Via Down-Regulation of Fas-Associated Factor 1 in Asbestos-Induced Mesotheliomas from Arf Knockout Mice

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B Signaling Via Down-Regulation of Fas-Associated Factor 1 in Asbestos-Induced Mesotheliomas from Arf Knockout Mice Activated TNF-␣/NF-␬B signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice Deborah A. Altomarea,1, Craig W. Mengesa,1, Jianming Peia, Lili Zhanga, Kristine L. Skele-Stumpa, Michele Carboneb, Agnes B. Kanec, and Joseph R. Testaa,2 aHuman Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111; bDepartment of Pathology, Cancer Research Center of Hawaii, Honolulu, HI 96813; and cDepartment of Pathology and Laboratory Medicine, Brown University, Providence, RI 02912 Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, and approved January 5, 2009 (received for review September 4, 2008) The human CDKN2A locus encodes 2 distinct proteins, p16(INK4A) human MM cell lines has been shown to induce G1-phase cell cycle and p14(ARF) [mouse p19(Arf)], designated INK4A (inhibitor of arrest and apoptotic cell death (8), suggesting that ARF, like INK4A, cyclin dependent kinase 4) and ARF (alternative reading frame) is an important target of 9p21 deletions in MM. here, that are translated from alternatively spliced mRNAs. Human Arf knockout mice represent an invaluable resource to test the ARF is implicated as a tumor suppressor gene, mainly in association relevance of ARF to MM pathogenesis. The Arf mouse model used with the simultaneous deletion of INK4A. However, questions here was generated by replacing the exon 1␤ of Arf with a remain as to whether loss of ARF alone is sufficient to drive Pgk-Neomycin cassette, leaving Ink4a sequences intact (9). Arf null tumorigenesis. Here, we report that mice deficient for Arf are (Ϫ/Ϫ) mice are highly prone to tumors, developing undifferentiated susceptible to accelerated asbestos-induced malignant mesotheli- sarcomas, carcinomas, and tumors of the nervous system within 1 oma (MM). MMs arising in Arf (؉/؊) mice consistently exhibit year of age; heterozygous Arf (ϩ/Ϫ) mice develop tumors at a lower biallelic inactivation of Arf, but, unexpectedly, do not acquire rate (20%) and longer latency. additional recurrent genetic alterations that we previously iden- Here, we show that Arf (ϩ/Ϫ) mice exposed to asbestos are tified in asbestos-induced MMs arising in Nf2 (؉/؊) mice. Array predisposed to MM, with a significantly shorter tumor latency CGH analysis was used to detect a recurrent deletion at chromo- compared with wild-type littermates. The murine MMs exhibit some 4C6 in MMs from Arf (؉/؊) mice. A candidate gene in this biallelic inactivation of the remaining wild-type Arf allele, although region, Faf1 (FAS-associated factor 1), was further explored, be- they do not exhibit the typical profile of tumor suppressor gene cause it encodes a protein implicated in tumor cell survival and in inactivation observed in human MMs. Array (a)CGH analysis led the pathogenesis of some human tumor types. We confirmed us to identify hemizygous loss of the Faf1 (FAS-associated factor 1) hemizygous loss of Faf1 and down-regulation of Faf1 protein in a locus, resulting in aberrant TNF-␣-induced NF-␬B signaling, a ؉ ؊ series of MMs from Arf ( / ) mice, and we then showed that Faf1 pathway previously implicated in asbestos-induced oncogenesis and ␣ ␬ regulates TNF- -mediated NF- B signaling, a pathway previously MM cell survival (10, 11). implicated in asbestos-induced oncogenesis of human mesothelial cells. Collectively, these data indicate that Arf inactivation has a Results significant role in driving MM pathogenesis, and implicate Faf1 as .Arf (؉/؊) Mice Are Susceptible to Asbestos-Induced MM ␣ ␬ After a key component in the TNF- /NF- B signaling node that has now repeated injections of crocidolite asbestos, we found markedly been independently implicated in asbestos-induced oncogenesis. accelerated MM development in asbestos-treated Arf (ϩ/Ϫ) mice, compared with wild-type littermates (Fig. 1A), whereas none of the array-CGH ͉ tumor suppressors control TiO2-treated mice developed MM. The median latency for detection of MM in Arf (ϩ/Ϫ) mice was 42 weeks after initial he CDKN2A (INK4a/ARF) locus encodes 2 distinct proteins asbestos exposure, compared with 56 weeks in wild-type mice. A Ttranslated from alternatively spliced mRNAs; p16(INK4A), log-rank test demonstrated that Arf (ϩ/Ϫ) mice had decreased designated as INK4A (inhibitor of cyclin dependent kinase 4) here, survival times, compared with wild-type mice (P ϭ 4.63E-13). ␣ is encoded by exons 1 , 2, and 3. The alternate product p14(ARF), Epithelial, mixed, and sarcomatoid histologies were observed in dubbed ARF (alternative reading frame protein) here, is specified asbestos-treated Arf (ϩ/Ϫ) and wild-type mice, although epithelial ␤ by exons 1 , 2, and 3 (1, 2). Amino acid sequences of INK4A and morphology predominated (Fig. 1B). The growth and histological ␣ ␤ ARF are unrelated, because exons 1 and 1 show no homology features of the MMs in this series of Arf (ϩ/Ϫ) mice are similar to and exon 2/3 sequences are translated in different reading frames. asbestos-induced tumors in previous chronic carcinogenicity assays The CDKN2A locus is among the most commonly mutated in wild-type and Tp53-deficient (ϩ/Ϫ) mice (12, 13). Epithelial genomic sites in human cancer (2). Point mutations or deletions MMs frequently presented with tumor ascites, spheroids, and specifically affecting exon 1␣ of INK4A are not uncommon, al- though intragenic mutations affecting exon 1␤ of ARF are seldom, if ever, observed (2, 3). Overall, the high frequency of concurrent Author contributions: D.A.A., C.W.M., A.B.K., and J.R.T. designed research; D.A.A., C.W.M., INK4A and ARF loss has made it difficult to assess the contribution J.P., L.Z., K.L.S.-S., and A.B.K. performed research; D.A.A., C.W.M., J.P., M.C., A.B.K., and of ARF to human tumorigenesis. J.R.T. analyzed data; and D.A.A., C.W.M., and J.R.T. wrote the paper. We previously demonstrated that the CDKN2A locus is homozy- The authors declare no conflict of interest. gously deleted in most malignant mesothelioma (MM) cell lines and This article is a PNAS Direct Submission. in many MM tumor specimens (4). FISH analysis revealed a high Freely available online through the PNAS open access option. incidence (Ϸ50 to 75%) of homozygous deletions in frozen MM Data deposition: Microarray data reported in this paper has been deposited in the Gene specimens or MM cells cultured for Յ5 days (5, 6). Reexpression Expression Omnibus (GEO) database (accession no. GSE12419). of INK4A in MM cells resulted in cell cycle arrest, cell death, as well 1D.A.A. and C.W.M contributed equally to this work. as tumor suppression and regression (7). In contrast to the estab- 2To whom correspondence should be addressed. E-mail: [email protected]. lished role of INK4A, the involvement of ARF in MM is less This article contains supporting information online at www.pnas.org/cgi/content/full/ understood. However, adenovirus-mediated transfer of ARF in 0808816106/DCSupplemental. 3420–3425 ͉ PNAS ͉ March 3, 2009 ͉ vol. 106 ͉ no. 9 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0808816106 Downloaded by guest on September 23, 2021 Fig. 1. Arf (ϩ/Ϫ) mice exhibit decreased MM latency compared with wild-type littermates. (A) Comparison of survival in asbestos-treated Arf (ϩ/Ϫ) and wild-type mice, depicted by Kaplan–Meier survival curves. Arf (ϩ/Ϫ) mice showed significantly shorter survivals than wild-type mice based on the log-rank test (P ϭ 4.63e-13). One Arf (ϩ/Ϫ) mouse and 5 wild-type mice had no ob- vious tumors and were excluded as censored observa- tions. (B) Summary of MMs arising in asbestos-treated Arf (ϩ/Ϫ) and wild-type mice. (C) Representative histo- pathology of MMs from Arf (ϩ/Ϫ) mice treated with asbestos. (Top) Noninvasive epithelial MM growing on the abdominal surface of the diaphragm. Malignant cells exfoliate from the surface of the tumor. (Middle) Bloody tumor ascites. Malignant epithelial MM cells grow in suspension within the peritoneal cavity. (Bottom) MMs grow as solid tumor spheroids within the peritoneal cavity and may attach to the parietal and visceral serosal linings. Sections were stained with hematoxylin and eosin. diffuse peritoneal seeding on the serosal lining (Fig. 1C). In general, band C6, which was identified in all 4 MM cultures. This region is the MMs in Arf (ϩ/Ϫ) mice did not show extensive invasion of the distal to a homozygous loss of the Cdk2na locus observed in MM lymphatics and skeletal muscle, unlike tumors from Tp53 (ϩ/Ϫ)or cells from wild-type mouse 104 (Fig. 3A), identified in Fig. 2 as Nf2 (ϩ/Ϫ) mice. Overall, 8 of 25 MMs from the asbestos-treated Arf having loss of Ink4a/Arf DNA, RNA, and protein. Closer exami- (ϩ/Ϫ) mice exhibited invasion into the lymphatics or muscle tissue, and the incidence of invasion was equivalent to that of MMs from wild-type mice (9 of 22 MMs). MMs from Arf (؉/؊) Mice Exhibit Biallelic Inactivation. MM cells from ascites or peritoneal lavage were cultured. We found biallelic inactivation of Arf in MMs from Arf (ϩ/Ϫ) mice, demonstrated by the loss of the wild-type allele in all 11 primary MM cultures analyzed, along with the fact that the mutant knockout allele was retained (not deleted) in 10 of the same 11 tumors (Fig. 2A). In comparison, loss of both wild-type Arf alleles was observed in 3 of 7 MMs from asbestos-treated wild-type mice, and down-regulation of Arf expression was observed in 2 additional MMs in this series, bringing the total to 5 of 7 (71%) MMs from wild-type littermates with loss of functional Arf (Fig. 2A). Immunoblot analysis of a subset of tumor cell lysates from Arf (ϩ/Ϫ) and wild-type mice confirmed the RT-PCR results (Fig.
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