TY  - JOUR
AU  - Lesina, Marina
AU  - Wörmann, Sonja Maria
AU  - Morton, Jennifer
AU  - Diakopoulos, Kalliope Nina
AU  - Korneeva, Olga
AU  - Wimmer, Margit
AU  - Einwächter, Henrik
AU  - Sperveslage, Jan
AU  - Demir, Ihsan Ekin
AU  - Kehl, Timo
AU  - Saur, Dieter
AU  - Sipos, Bence
AU  - Heikenwälder, Mathias
AU  - Steiner, Jörg Manfred
AU  - Wang, Timothy Cragin
AU  - Sansom, Owen J
AU  - Schmid, Roland Michael
AU  - Algül, Hana
TI  - RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis.
JO  - The journal of clinical investigation
VL  - 126
IS  - 8
SN  - 1558-8238
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2017-05046
SP  - 2919 - 2932
PY  - 2016
AB  - Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.
KW  - Chemokine CXCL1 (NLM Chemicals)
KW  - Cxcl1 protein, mouse (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Receptors, Interleukin-8B (NLM Chemicals)
KW  - Rela protein, mouse (NLM Chemicals)
KW  - Transcription Factor RelA (NLM Chemicals)
KW  - ras Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27454298
C2  - pmc:PMC4966329
DO  - DOI:10.1172/JCI86477
UR  - https://inrepo02.dkfz.de/record/129041
ER  -