Genes involved in the immediate early response and epithelial-mesenchymal transition are regulated by adipocytokines in the female reproductive tract

Obesity increases the risk of female reproductive tract cancers, but the underlying mechanistic link between the two is ill-defined. Thus, the objective of the current study was to identify obesity-dependent changes in the expression of immediate early (IE) genes that contribute to cell proliferation and differentiation, and epithelialmesenchymal transition (EMT) genes that promote cell migration. When HeLa cells were treated for 048?hr with IGF-1, leptin, TNFa, or IL-6, each individual adipocytokine altered the abundance of IE (cJUN, cFOS, and cMYC) and EMT (SNAI1, SNAI2, and TWIST1) mRNA abundance. For example, IGF-1 increased cJUN and cFOS and decreased cMYC; leptin increased cFOS; IL-6 increased cFOS and cMYC; and TNFa increased cJUN and cFOS mRNA abundance. Likewise, EMT gene expression was altered by IGF-1, TNFa, and IL-6. SNAI1 was increased by IGF-1 and IL-6; SNAI2 was increased by IGF-1 and TNFa; and TWIST1 was increased by TNFa and IL-6. Chronic exposure to adipocytokines also altered EMT gene expression in the whole uterus of obese compared to normal-weight mice. Specifically, there was no difference in cJun, cFos, or cMyc mRNA abundance between normal-weight and obese animals. Snai1, Snai2, and Twist1 mRNA abundance, however, was increased in the uterus of obese females and correlated with increased circulating IGF-1 levels. These data indicate that obesity-dependent alterations in adipocytokine levels regulate the expression of genes associated with cell proliferation and migration, and therefore may provide a plausible mechanism for obesity-dependent increases in cancers of the female reproductive tract. Mol. Reprod. Dev. 79:128137, 2012. (C) 2011 Wiley Periodicals, Inc.