TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):111-123. https://doi.org/10.1172/JCI29900.
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Research Article

TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

Abstract

Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R–deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R–/– mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R–/– animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R–/– mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

Authors

Niklas Finnberg, Andres J.P. Klein-Szanto, Wafik S. El-Deiry

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Figure 4

Expression profiling of Eμ-myc lymphomas suggests that differentially expressed genes are regulated independent of TRAIL-R gene dosage as well as a role for Stat3 in WT lymphomas.

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Expression profiling of Eμ-myc lymphomas suggests that differentially ex...
RNA samples from TRAIL-R+/– and TRAIL-R–/– Eμ-myc lymphomas (n = 5/genotype) were hybridized to MOE430A 2.0 Affymetrix arrays. Differentially expressed genes (upregulated >2-fold) were subjected to statistical analysis. A shows the top 4 genes that showed consistent changes over the different probe sets. Hspa1b, heat-shock protein 70; Socs3, suppressor of cytokine signaling 3; Zfpm1, friend of GATA1 (also known as Fog-1); Cdkn1a, cyclin-dependent kinase inhibitor 1a (p21). *P < 0.05, Student’s t test. (B) Immunoblotting suggests that Tyr705-phosphorylated Stat3 is elevated in WT Eμ-myc lymphomas compared with TRAIL-R–deficient lymphomas. Tyr705-phosphorylated Stat3 is expressed in a subset of cells within the lymphomas, as detected by immunohistochemistry. (C) CD244 is expressed at higher levels in Eμ-myc lymphomas of TRAIL-R+/– animals (Mann-Whitney U test, P < 0.05; n = 5/genotype). Red horizontal lines indicate medians; red crosses indicate means. (D and E) TRAIL-R–deficient lymphomas (n = 3/genotype; Mann-Whitney U test) show frequent infiltration of CD244+/c-myc cells (Cy3, green; Cy2, red) compared with WT lymphomas, suggesting expression of CD244 on nonlymphoma cells. Representative pictures are shown. Original magnification, ×60 (B); ×100 (E).