Abstract
BackgroundAccumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. Leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in EMT. However, the potential mechanism remains unknown. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism.MethodsWith the assessment of EMT-associated marker expression in MCF-7, SK-BR-3, and MDA-MB-468 cells, the effect of leptin on breast cancer cells was analyzed. Besides, an array of pathway inhibitors as well as RNA interference targeting pyruvate kinase M2 (PKM2) were used to clarify the underlying mechanism of leptin-mediated EMT in vitro and in vivo.ResultsThe results demonstrated that leptin promoted breast cancer cells EMT, visibly activated the PI3K/AKT signaling pathway, and upregulated PKM2 expression. An antibody against the leptin receptor (anti-ObR) and the PI3K/AKT signaling pathway inhibitor LY294002 significantly abolished leptin-induced PKM2 expression and EMT-associated marker expression. SiRNA targeting PKM2 partially abolished leptin-induced migration, invasion, and EMT-associated marker expression. In vivo xenograft experiments indicated that RNA interference against PKM2 suppressed breast cancer growth and metastasis.ConclusionsOur data suggest that leptin promotes EMT in breast cancer cells via the upregulation of PKM2 expression as well as activation of PI3K/AKT signaling pathway, and PKM2 might be one of the key points and potential targets for breast cancer therapy.
Highlights
Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis
Besides IL-8 which is involved in leptin-induced EMT, this study has found that pyruvate kinase M2 (PKM2) is another critical molecule affecting tumor progression
Data showed that leptin upregulated vimentin, fibronectin and Twist expression, but downregulated E-cadherin expression. This effect was weakened after the addition of PKM2-siRNA (Fig. 3e). These findings indicated that PKM2 had an effect on the upregulation of Twist, and it was essential for leptin-induced EMT in MCF-7 and SK-BR-3 cells
Summary
Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. A key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is involved in EMT. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism. Wei et al Journal of Experimental & Clinical Cancer Research (2016) 35:166 of food intake, energy balance, immune, and endocrine systems, as well as ontogenesis. Most of these functions are involved in leptin-induced signals which comprise several pathways triggered by many cytokines (i.e., canonical signaling pathways: JAK2/STAT, MAPK/ERK, and PI3K/AKT kinase) [10]. Leptin/ObRs are expressed at low levels in the epithelial cells of normal human mammary glands, but overexpressed in breast cancer cells [9, 11, 12]
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