期刊
ONCOGENE
卷 30, 期 20, 页码 2345-2355出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.605
关键词
IL-6; STAT3; tumorigenesis; EMT; IGF-IR; prostate
资金
- National Institute of Health (NIH) [1K01CA116002, NIH 1R01CA149405, PO1 CA085859, P01 CA104177]
- DOD-USARMC IDEA Development Award [W81XWH-06-1-0014]
- Pacific Northwest Prostate Cancer [SPORE P50-CA097186]
As an established mediator of inflammation, interleukin-6 (IL-6) is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. However, whether IL-6 has a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates the autocrine IL-6 loop and autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer the tumorigenic property and also that activation of signal transducer and activator of transcription 3 (STAT3) is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6-mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands, namely IGF-I and IGF-II. These findings indicate that IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer. Oncogene (2011) 30, 2345-2355; doi: 10.1038/onc.2010.605; published online 24 January 2011
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