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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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

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Figure 6

Reinforcement of OIS depends on CXCL1/CXCR2 axis.

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Reinforcement of OIS depends on CXCL1/CXCR2 axis. (A) Representative imm...
(A) Representative immunohistological staining for CXCR2 in mPanIN lesions from Kras pancreatic tissue and in normal ductal epithelium (inset). Scale bar: 20 μm. (B) Kras PDECs treated with vehicle control (DMSO), CXCL1, or a combination of CXCL1 and a CXCR2 inhibitor (SB225002) were plated for the senescence assay. Scale bar: 100 μm. (C) Injection protocol: Each injection contained 0.5 mg CXCR2 inhibitor (SB225002) per kilogram body weight. Mice were treated 2 times a week over 4 weeks. One injection was administrated at each injection day. Animals were euthanized and dissected 4 days after the last injection. (D) Detection of senescence in pancreatic cryosections from 9-week-old Kras mice treated with PBS as vehicle or CXCR2 inhibitor (SB225002), using SA-β-Gal as a marker. Scale bar: 50 μm. Ratio of SA-β-Gal–positive mPanIN cells to the total number of mPanIN cells in low-grade mPanIN (LG mPanIN) in 9-week-old Kras mice treated with PBS as vehicle or CXCR2 inhibitor (SB225002) was counted per ×200 optical high-power field (HPF). Mean ± SEM; n ≥ 4; *P < 0.05 by Mann-Whitney test; n, number of mice. (E) Representative H&E staining of pancreata from 9-week-old Kras mice after treatment with SB225002 or PBS. Scale bar: 50 μm. Number of low-grade (LG) or high-grade (HG) mPanIN in 9-week-old Kras mice treated with SB225002 or PBS per ×200 optical field. Mean ± SD; n ≥ 4; *P < 0.05, **P < 0.005 by unpaired t test; n, number of mice. (F) Representative H&E staining of pancreata from 18-week-old *Kras and *Kras CXCR2null mice. Scale bars: 500 μm, 100 μm. (G) Numbers of low-grade (LG) and high-grade (HG) mPanIN in 18-week-old *Kras (n = 2) and *Kras Cxcr2null (n = 3) mice were counted per ×200 optical field (HPF). Mean ± SD; *P < 0.05 by unpaired t test; N.D., not detectable; n, number of mice.