Journal
DISEASE MODELS & MECHANISMS
Volume 11, Issue 11, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.035139
Keywords
Prostate cancer; Cancer initiation; NKX3.1; Inflammation; Differentiation
Categories
Funding
- National Cancer Institute [P30 CA013696]
- National Institutes of Health [CA196662, CA193442, CA183929, CA173481]
- American Cancer Society [RP-16-237-06-COUN]
- Swiss National Science Foundation [PBBSP3_146959, P300P3_151158]
- US National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR000040]
- US National Institutes of Health [R35 CA197745, U54 CA209997]
- Rutgers School of Health Professions (Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey) Dean's Research Grant
- Melanoma Research Alliance
- Patrick C. Walsh Prostate Cancer Research Fund (Johns Hopkins University)
- One-in-Six Foundation (Akron Community Foundation)
- Prostate Cancer Foundation
- Swiss National Science Foundation (SNF) [P300P3_151158, PBBSP3_146959] Funding Source: Swiss National Science Foundation (SNF)
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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.
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