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.
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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

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Figure 4

RelA deficiency compromises OIS.

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RelA deficiency compromises OIS. (A) Ratio of SA-β-Gal–positive mPanIN c...
(A) Ratio of SA-β-Gal–positive mPanIN cells to the total number of mPanIN cells in low-grade mPanIN (LG mPanIN) in Kras (6 mice) and Kras RelA (5 mice) was counted per ×200 optical field (high-power field, HPF). Mean ± SD; n ≥ 50; ***P < 0.0001 by Mann-Whitney test; n, number of HPFs. (B) Detection of senescence in pancreatic cryosections from Kras and Kras RelA mice using SA-β-Gal as a marker. Scale bars: 20 μm. Representative images are shown. (C) Real-time PCR expression analysis of indicated genes in pancreatic lysates from Kras (n = 3) and Kras RelA (n = 3) mice. Error bars are shown as SD. Results are the average of 3 independent experiments and are presented as mean ± SD; *P < 0.05, **P < 0.005 by unpaired t test; n, number of mice. (D) Pancreatic extracts were collected from Kras and Kras RelA genotypes and analyzed by immunoblot analysis using antibodies against DCR2, p53, p16, or p19. β-Actin served as loading control. (E) Immunohistological analysis for DCR2, p53, p21, or p19 in Kras (n = 3) and Kras RelA (n = 3) pancreata. Scale bars: 20 μm. Insets denote single-positive cells. Representative images are shown. Quantification of DCR2, p53, p21, and p19 positivity in PanIN cells shown at the bottom. Results are presented as mean ± SD; *P < 0.05, **P < 0.005, ***P < 0.0005 by unpaired t test; n, number of mice. (F) SASP gene set enrichment analysis of pancreatic RNA from Kras (n = 2) and Kras RelA (n = 2) mice. n, number of mice.