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 epithelial-mesenchymal transition (EMT) genes that promote cell migration. When HeLa cells were treated for 0-48hr with IGF-1, leptin, TNFα, 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 TNFα increased cJUN and cFOS mRNA abundance. Likewise, EMT gene expression was altered by IGF-1, TNFα, and IL-6. SNAI1 was increased by IGF-1 and IL-6; SNAI2 was increased by IGF-1 and TNFα; and TWIST1 was increased by TNFα 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.