Background information: Previous studies have revealed that leptin may be involved in epithelial-mesenchymal transition (EMT), a crucial initiator of cancer progression to facilitate metastatic cascade, increase tumor recurrence, and ultimately cause poor prognosis. However, the underlying mechanism remains unclear. The aim of our present study was to investigate the effect of leptin on EMT of breast cancer cells and the underlying mechanism.
Results: Our data demonstrated that leptin significantly increased the phosphorylation of STAT3, Akt, and ERK1/2, elevated the expression of IL-8, and induced breast cancer cells to undergo EMT. The effect of leptin on IL-8 could visibly abolished by the inhibitor of PI3K LY294002. In addition, leptin-induced EMT of breast cancer cells was blocked by anti-IL-8 antibodies. Examination of the expression of ObR, leptin, IL-8 and EMT-related biomarkers in patient specimens demonstrated that malignant breast carcinoma with lymph node metastases (LNM), which represents poor prognosis, expressed higher levels of ObR, leptin, IL-8 than other types of breast cancer, and displayed more obvious EMT transversion. In vivo xenograft experiment revealed that leptin signally promoted tumor growth and metastasis and increased the expressions of IL-8 and EMT-related biomarkers.
Conclusions: Our results support that leptin-induced EMT in breast cancer cells requires IL-8 activation via the PI3K/Akt signal pathway.
Keywords: AKT, Protein Kinase B; COX-2, cyclooxygenase-2; EMT; EMT, epithelial-mesenchymal transition; ERK, extracellular signal-regulated kinase; IFN, interferon; IL-8; IL-8, Interleukin 8; JAK, Junas Kinase; LNM, lymph node metastases; MAPK, Mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-κB, Nuclear factor kappa B; Ob-R, Ob receptor; PI-3K, phosphatidylinositol-3 kinase; PI3K/Akt; STAT, signal transduction and activators of transcription; TGF, transforming growth factor; TNF, tumor necorsis factor; VEGF, vascular endothelial growth factor; breast cancer; leptin; mTOR, Mammalian Target Of Rapamycin; qRT-PCR, quantify reverse transcription-polymerase chain reaction.