TY - JOUR
T1 - Lack of immunomodulatory interleukin-27 enhances oncogenic properties of mutant p53 in vivo
AU - Dibra, Denada
AU - Mitra, Abhisek
AU - Newman, Melisa
AU - Xia, Xueqing
AU - Cutrera, Jeffry J.
AU - Gagea, Mihai
AU - Kleinerman, Eugenie S.
AU - Lozano, Guillermina
AU - Li, Shulin
N1 - Funding Information:
This study was supported by NIH R01 CA120985. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 AACR.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Purpose: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported. Experimental Design: IL27RA-/- mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA-/- p53H/+ and IL27RA-/- p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis. Results: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age. Conclusions: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo.
AB - Purpose: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported. Experimental Design: IL27RA-/- mice were bred with mutant p53 heterozygous (p53R172H/+) mice to obtain IL27RA-/- p53H/+ and IL27RA-/- p53H/H mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis. Results: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age. Conclusions: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo.
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U2 - 10.1158/1078-0432.CCR-15-2052
DO - 10.1158/1078-0432.CCR-15-2052
M3 - Article
C2 - 26979394
AN - SCOPUS:84980011834
SN - 1078-0432
VL - 22
SP - 3876
EP - 3883
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -