Carcinogenesis Advance Access originally published online on April 5, 2006
Carcinogenesis 2006 27(7):1507-1515; doi:10.1093/carcin/bgl018
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Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line
1 Cancer Prevention Fellowship Program, Division of Cancer Prevention, 2 Laboratory of Biosystems and Cancer, National Cancer Institute, Bethesda, MD, USA and 3 Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA
* To whom correspondence and request for reprints should be addressed at: Cancer Prevention Fellowship Program, NCI, Division of Cancer Prevention, 6130 Executive Boulevard, MSC 7361 Bethesda, MD 20892-7361, USA Email: imigjeni{at}msu.edu
Increased visceral adipose tissue results in elevated plasma leptin, which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (ApcMin/+; IMCE) colon epithelial cells but not normal (Apc+/+; YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells but not in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (P < 0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and associated STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipoctye-specific cytokine leptin and obesity-associated colon cancer.
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