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Mesothelioma is a fatal tumor of the pleura and is strongly associated with asbestos exposure. The molecular mechanisms underlying the long latency period of mesothelioma and driving carcinogenesis are unknown. Moreover, late diagnosis means that mesothelioma research is commonly focused on end-stage disease. Although disruption of the CDKN2A (INK4A/ARF) locus has been reported in end-stage disease, information is lacking on the status of this key tumor suppressor gene in pleural lesions preceding mesothelioma. Manufactured carbon nanotubes (CNTs) are similar to asbestos in terms of their fibrous shape and biopersistent properties and thus may pose an asbestos-like inhalation hazard. Here we show that instillation of either long CNTs or long asbestos fibers into the pleural cavity of mice induces mesothelioma that exhibits common key pro-oncogenic molecular events throughout the latency period of disease progression. Sustained activation of pro-oncogenic signaling pathways, increased proliferation, and oxidative DNA damage form a common molecular signature of long-CNT- and long-asbestos-fiber-induced pathology. We show that hypermethylation of p16/Ink4a and p19/Arf in CNT- and asbestos-induced inflammatory lesions precedes mesothelioma; this results in silencing of Cdkn2a (Ink4a/Arf) and loss of p16 and p19 protein, consistent with epigenetic alterations playing a gatekeeper role in cancer. In end-stage mesothelioma, silencing of p16/Ink4a is sustained and deletion of p19/Arf is detected, recapitulating human disease. This study addresses the long-standing question of which early molecular changes drive carcinogenesis during the long latency period of mesothelioma development and shows that CNT and asbestos pose a similar health hazard.
Pubmed ID: 29112861 RIS Download
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View all literature mentionsSoftware that allows users to manually or automatically design custom primers and probes for gene quantitation and allelic discrimination (SNP) real-time PCR applications. It supports assays based on TaqMan and SYBR Green I dye chemistries.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis monoclonal targets STAT3, phospho (Tyr705 / Ser727)
View all literature mentionsThis monoclonal targets Truncated N-term AA 1-181 of human WT-1 protein
View all literature mentionsThis polyclonal targets KRT10
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (197G2) Rabbit mAb
View all literature mentionsThis monoclonal targets Ly6g
View all literature mentionsThis monoclonal targets Mesothelioma antibody [HBME-1]
View all literature mentionsThis polyclonal targets AKT1 (phospho S473)
View all literature mentionsThis polyclonal targets Frap1
View all literature mentionsThis polyclonal targets Src (phospho Y418)
View all literature mentionsThis polyclonal targets CDKN2A/p19ARF
View all literature mentionsThis monoclonal targets Mouse CD3
View all literature mentionsThis polyclonal targets CD68 antibody
View all literature mentionsThis polyclonal targets CD45 antibody
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis monoclonal targets synthetic peptide corresponding to residues near the carboxy terminus of human Src.
View all literature mentionsThis polyclonal targets Phospho-Src Family (Tyr416)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473) (193H12) Rabbit mAb
View all literature mentionsThis recombinant monoclonal targets Stat3
View all literature mentionsThis polyclonal targets Ki67 antibody - Proliferation Marker
View all literature mentionsThis monoclonal targets Histone H3, phospho (Ser10)
View all literature mentionsMus musculus with name C57BL/6NCrl from IMSR.
View all literature mentionsThis monoclonal targets Truncated N-term AA 1-181 of human WT-1 protein
View all literature mentionsThis polyclonal targets KRT10
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (197G2) Rabbit mAb
View all literature mentionsThis monoclonal targets Ly6g
View all literature mentionsThis monoclonal targets Mesothelioma antibody [HBME-1]
View all literature mentionsThis polyclonal targets AKT1 (phospho S473)
View all literature mentionsThis polyclonal targets Frap1
View all literature mentionsThis polyclonal targets Src (phospho Y418)
View all literature mentionsThis polyclonal targets CDKN2A/p19ARF
View all literature mentionsThis recombinant monoclonal targets Stat3
View all literature mentionsThis monoclonal targets Mouse CD3
View all literature mentionsThis polyclonal targets CD68 antibody
View all literature mentionsThis polyclonal targets CD45 antibody
View all literature mentionsThis monoclonal targets β-Actin
View all literature mentionsThis monoclonal targets synthetic peptide corresponding to residues near the carboxy terminus of human Src.
View all literature mentionsThis polyclonal targets Phospho-Src Family (Tyr416)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473) (193H12) Rabbit mAb
View all literature mentionsThis polyclonal targets Ki67 antibody - Proliferation Marker
View all literature mentionsThis monoclonal targets Histone H3, phospho (Ser10)
View all literature mentionsThis monoclonal targets STAT3, phospho (Tyr705 / Ser727)
View all literature mentionsMus musculus with name C57BL/6NCrl from IMSR.
View all literature mentionsThis monoclonal targets STAT3, phospho (Tyr705 / Ser727)
View all literature mentionsThis monoclonal targets STAT3, phospho (Tyr705 / Ser727)
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