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¹ Department of Veterinary Medicine, College of Bio-Resources and Agriculture National Taiwan University, 10617 Taipei, Taiwan ROC
² Department of Surgery, Mackay Memorial Hospital, 10449 Taipei, Taiwan ROC
³ Mackay Medicine, Nursing and Management College, 10449 Taipei, Taiwan ROC
⁴ Department of Surgery, National Taiwan University Hospital, National Taiwan University, 10002 Taipei, Taiwan ROC

(Requests for offprints should be addressed to I-C Guo; Email: iguo{at}ntu.edu.tw)

C Chen and Y-C Chang contributed equally to this work

Obesity serves as an important risk factor for incidences of both cirrhotic and non-cirrhotic hepatocellular carcinoma (HCC), which is the third leading cause of cancer death worldwide. Leptin, the obesity biomarker molecule secreted systemically by body fat mass and locally by activated hepatic stellate cells, is proposed to play a certain role in HCC growth. Here, we show both proliferative and anti-apoptotic effects of leptin in HCC cells. Leptin stimulated cyclin D1 promoter activity to increase cyclin D1 protein expression, which accelerated the cell cycle progression. The reduced ratio between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) Bcl-2 family proteins by transforming growth factor (TGF)-ß 1 caused HCC cells degradation of poly(ADP-ribose) polymerase and consequential apoptosis; whereas, leptin protected cells from apoptosis by reversing TGF-ß 1-reduced Bcl-2/Bax ratio as a result of down-regulating Bax. Any inhibitor specific for Janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1/2 (ERK1/2) blocked these leptin functions. When intrahepatocytic JAK2 was activated by leptin, the active JAK2 afterward triggered a signaling cascade involving activations of PI3K/Akt and MEK/ERK1/2 in order of occurrence. As yet, in most cases, the crosstalks among signaling pathways primarily studied in diverse cancer cell types for mediating somatotropic effect of leptin are not well clarified and seem to be cell-type dependent. For the first time, our results demonstrate the direct effects of leptin on HCC growth and define its signal pathway with a crosstalking JAK2-PI3K/Akt-MEK/ERK1/2 connection. The identified hierarchy of intrahepatocytic leptin signaling pathway provides a clear basis potentially beneficial to make accurate and effectual strategies for facing both cirrhotic and non-cirrhotic liver carcinogenesis.