RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis
Marina Lesina, … , Roland Michael Schmid, Hana Algül
Marina Lesina, … , Roland Michael Schmid, Hana Algül
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):2919-2932. https://doi.org/10.1172/JCI86477.
View: Text | PDF
Research Article Oncology

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

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.

Authors

Marina Lesina, Sonja Maria Wörmann, Jennifer Morton, Kalliope Nina Diakopoulos, Olga Korneeva, Margit Wimmer, Henrik Einwächter, Jan Sperveslage, Ihsan Ekin Demir, Timo Kehl, Dieter Saur, Bence Sipos, Mathias Heikenwälder, Jörg Manfred Steiner, Timothy Cragin Wang, Owen J. Sansom, Roland Michael Schmid, Hana Algül

×

Figure 7

Pancreas-specific inactivation of CXCR2 is sufficient to bypass OIS.

Options: View larger image (or click on image) Download as PowerPoint
Pancreas-specific inactivation of CXCR2 is sufficient to bypass OIS. (A)...
(A) H&E staining, expression of Ki-67, and SA-β-Gal activity in pancreata from 18-week-old *Kras and *Kras Cxcr2 mice. Scale bars: 500 μm, 100 μm. Representative images are shown. (B) Kaplan-Meier curves documenting a median survival of 195 days in *Kras Cxcr2 mice (n = 7; green line) and of 162 days in *Kras CXCR2null mice (n = 40; blue line) versus 291 days in *Kras mice (n = 18; magenta line); P = 0.0488 and P = 0.0011 by Mantel-Cox log rank test. n, number of mice. (C) IHC analysis of human pancreatic cancer and tumor-adjacent tissue illustrates positive staining for CXCR2 in low-grade hPanIN (asterisk) and weak staining in high-grade hPanIN (circle) lesions. Scale bars: 20 μm. Representative images are shown. (D) Real-time PCR expression analysis of mRNA from microdissected human (h) low-grade (LG) PanIN cells and tumor ductal cells (hPDAC) for Cxcl1, Cxcl2, Cxcl5, Cxcl6, Cxcl8, and Ccl3. Mean ± SD; n ≥ 11; *P < 0.05, **P < 0.005, ***P < 0.0005 by Mann-Whitney test; n, number of samples.