Evidence that leptin through STAT and CREB signaling enhances cyclin D1 expression and promotes human endometrial cancer proliferation

J Cell Physiol. 2009 Mar;218(3):490-500. doi: 10.1002/jcp.21622.


Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D1 together with a down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D1 promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D1 expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA, Neoplasm / metabolism
  • Down-Regulation / drug effects
  • Endometrial Neoplasms / enzymology
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / pathology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Leptin / pharmacology*
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • RNA, Small Interfering / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Transcriptional Activation / drug effects


  • CCND1 protein, human
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA, Neoplasm
  • Leptin
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Cyclin D1
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases