Rac1-Mediated DNA Damage and Inflammation Promote Nf2 Tumorigenesis but Also Limit Cell-Cycle Progression.
Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing reactive oxygen species that, on one hand, induce nuclear factor κB signaling and expression of inflammatory cytokines, and on the other activate p53 checkpoint and senescence programs dampening the cyclin D1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Yuhao
Y
Shi
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Saumya R
SR
Bollam
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Shannon M
SM
White
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Sean Z
SZ
Laughlin
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Garrett T
GT
Graham
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Mandheer
M
Wadhwa
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Hengye
H
Chen
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Chan
C
Nguyen
Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Jeremie
J
Vitte
Department of Head and Neck Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Marco
M
Giovannini
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Jeffery
J
Toretsky
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: cy232@georgetown.edu.
Chunling
C
Yi
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics; D054337:Cell Dedifferentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006529:Hepatomegaly / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009442:Neurilemmoma / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000378:metabolism*; D009929:Organ Size; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D015415:Biomarkers; D016328:NF-kappa B; D025581:Neurofibromin 2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020830:rac1 GTP-Binding Protein
DNA damage response; NF2; ROS; Rac1; Yap; inflammation; senescence