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American journal of cancer research. 2014 Sep 6. pmc: PMC4163613

STAT3β controls inflammatory responses and early tumor onset in skin and colon experimental cancer models.

Marino F¹, Orecchia V², Regis G³, Musteanu M⁴, Tassone B⁵, Jon C⁶, Forni M⁷, Calautti E⁸, Chiarle R⁹, Eferl R¹⁰, Poli V¹¹

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¹Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
²Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
³Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
⁴Spanish National Cancer Research Centre (CNIO) 28029 Madrid, Spain.
⁵Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
⁶Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
⁷Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
⁸Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.
⁹Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy ; Departmen of Pathology, Children's Hospital Boston and Harvard Medical School 02115 Boston, USA.
¹⁰Medical University Vienna & Comprehensive Cancer Center (CCC), Institute for Cancer Research A-1090 Vienna, Austria.
¹¹Department of Molecular Biotechnology and Health Sciences, University of Turin Turin, 10126, Italy.

Abstract

Chronic inflammation is a well-recognized pathogenic factor in tumor initiation and progression. Mice lacking the pro-oncogenic transcription factor STAT3 were shown to be protected from both colitis-associated and epidermal cancers induced by the AOM/DSS and DMBA/TPA protocols, respectively. However, these murine models did not distinguish between the two STAT3 isoforms, the full-length STAT3α, believed to exert most pro-oncogenic functions attributed to STAT3, and the shorter STAT3β, often referred to as a dominant-negative, but possessing specific transcriptional activities. Here we assessed the contribution of STAT3β to inflammation-driven tumorigenesis making use of mice lacking this isoform, but still expressing STAT3α (STAT3(Δβ/Δβ)). We show that the lack of STAT3β leads to exacerbated acute responses to both TPA and DSS, thus confirming its anti-inflammatory role. Enhanced inflammation correlates with earlier tumor onset in both the epidermis and the intestine in STAT3(Δβ/Δβ) mice. In contrast, overall tumor development and final tumor burden were unaffected. These results suggest that STAT3β, by limiting inflammation during the initial phases of tumorigenesis, contributes to tissue homeostasis and counteracts malignant transformation and initial tumor growth. Accordingly, the balance between the two STAT3 isoforms, likely determined by the complex signaling networks shaping the tumor microenvironment and driving tumor transformation and progression, is apparently crucial to determine the initial tumor transformation rates in inflammation-associated cancers.

KEYWORDS: AOM/DSS protocol, DMBA/TPA protocol, STAT3 isoforms, STAT3β, colitis-associated cancer, genetically modified mice, inflammation, inflammation-driven tumorigenesis, skin tumorigenesis

Publikations ID: 25232490
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