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Dis Model Mech. 2018 Nov 16;11(11). pii: dmm035139. doi: 10.1242/dmm.035139.

Cooperation of loss of NKX3.1 and inflammation in prostate cancer initiation.

Author information

1
Departments of Medicine and Urology, Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
2
Department of Pathology and Cell Biology, Columbia University Medical Center, NY 10032, USA.
3
Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
4
Department of Health Informatics, Rutgers School of Health Professions, Rutgers, The State University of New Jersey, Newark, NJ 07101, USA.
5
Graduate Program in Pathobiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Department of Medicine, Columbia Center for Translational Immunology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
7
Departments of Systems Biology and Biochemistry and Molecular Biophysics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
8
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
9
Departments of Urology, Medicine, Pathology & Cell Biology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA cabateshen@columbia.edu.

Abstract

Although it is known that inflammation plays a critical role in prostate tumorigenesis, the underlying processes are not well understood. Based on analysis of genetically engineered mouse models combined with correlative analysis of expression profiling data from human prostate tumors, we demonstrate a reciprocal relationship between inflammation and the status of the NKX3.1 homeobox gene associated with prostate cancer initiation. We find that cancer initiation in aged Nkx3.1 mutant mice correlates with enrichment of specific immune populations and increased expression of immunoregulatory genes. Furthermore, expression of these immunoregulatory genes is similarly increased in human prostate tumors having low levels of NKX3.1 expression. We further show that induction of prostatitis in Nkx3.1 mutant mice accelerates prostate cancer initiation, which is coincident with aberrant cellular plasticity and differentiation. Correspondingly, human prostate tumors having low levels of NKX3.1 have de-regulated expression of genes associated with these cellular processes. We propose that loss of function of NKX3.1 accelerates inflammation-driven prostate cancer initiation potentially via aberrant cellular plasticity and impairment of cellular differentiation.This article has an associated First Person interview with the first author of the paper.

KEYWORDS:

Cancer initiation; Differentiation; Inflammation; NKX3.1; Prostate cancer

PMID:
30266798
PMCID:
PMC6262819
DOI:
10.1242/dmm.035139
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interestsA.C. is founder, equity holder, consultant and director of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc. C.G.D. has ownership interests in Compugen, Harpoon, Kleo, Potenza and Tizona; has served in a consulting or advisory role for Agenus, Dendreon, Janssen, Lilly, Merck, Medimmune, Pierre Fabre and Roche/Genentech; has received research funding from Aduro Biotech, Bristol Myers Squibb and Janssen; and holds patents, receives royalties or has other intellectual property interests with Bristol Myers Squibb, AstraZeneca Medimmune and Janssen. The other authors declare no competing or financial interests

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