| First Author | Cataisson C | Year | 2019 |
| Journal | Mol Cancer Res | Volume | 17 |
| Issue | 8 | Pages | 1759-1773 |
| PubMed ID | 31164412 | Mgi Jnum | J:277730 |
| Mgi Id | MGI:6342418 | Doi | 10.1158/1541-7786.MCR-19-0227 |
| Citation | Cataisson C, et al. (2019) T-Cell Deletion of MyD88 Connects IL17 and IkappaBzeta to RAS Oncogenesis. Mol Cancer Res 17(8):1759-1773 |
| abstractText | Cancer development requires a favorable tissue microenvironment. By deleting Myd88 in keratinocytes or specific bone marrow subpopulations in oncogenic RAS-mediated skin carcinogenesis, we show that IL17 from infiltrating T cells and IkappaBzeta signaling in keratinocytes are essential to produce a permissive microenvironment and tumor formation. Both normal and RAS-transformed keratinocytes respond to tumor promoters by activating canonical NF-kappaB and IkappaBzeta signaling, releasing specific cytokines and chemokines that attract Th17 cells through MyD88-dependent signaling in T cells. The release of IL17 into the microenvironment elevates IkappaBzeta in normal and RAS-transformed keratinocytes. Activation of IkappaBzeta signaling is required for the expression of specific promoting factors induced by IL17 in normal keratinocytes and constitutively expressed in RAS-initiated keratinocytes. Deletion of Nfkbiz in keratinocytes impairs RAS-mediated benign tumor formation. Transcriptional profiling and gene set enrichment analysis of IkappaBzeta-deficient RAS-initiated keratinocytes indicate that IkappaBzeta signaling is common for RAS transformation of multiple epithelial cancers. Probing The Cancer Genome Atlas datasets using this transcriptional profile indicates that reduction of IkappaBzeta signaling during cancer progression associates with poor prognosis in RAS-driven human cancers. IMPLICATIONS: The paradox that elevation of IkappaBzeta and stimulation of IkappaBzeta signaling through tumor extrinsic factors is required for RAS-mediated benign tumor formation while relative IkappaBzeta expression is reduced in advanced cancers with poor prognosis implies that tumor cells switch from microenvironmental dependency early in carcinogenesis to cell-autonomous pathways during cancer progression. |
