RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

Lesina, M. et al. (2016) RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis. Journal of Clinical Investigation, 126(8), pp. 2919-2932. (doi: 10.1172/jci86477) (PMID:27454298)

Abstract

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.

• Item Type: Articles
• Additional Information: This work was supported by grants from Deutsche Forschungsgemeinschaft (AL 1174/5-1 and LE 3222/1-1) and Deutsche Krebshilfe (111646).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Sansom, Professor Owen
• Authors: Lesina, M., Wörmann, S. M., Morton, J., Diakopoulos, K. N., Korneeva, O., Wimmer, M., Einwächter, H., Sperveslage, J., Demir, I. E., Kehl, T., Saur, D., Sipos, B., Heikenwälder, M., Steiner, J. M., Wang, T. C., Sansom, O. J., Schmid, R. M., and Algül, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Clinical Investigation
• Publisher: American Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238
• Copyright Holders: Copyright © 2016 ASCI
• First Published: First published in Journal of Clinical Investigation 126(8): 2919-2932
• Publisher Policy: Reproduced in accordance with the publisher copyright policy