Leptin induces proliferation and anti-apoptosis in human hepatocarcinoma cells by up-regulating cyclin D1 and down-regulating Bax via a Janus kinase 2-linked pathway

Abstract

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)-b1 caused HCC cells degradation of poly(ADPribose) polymerase and consequential apoptosis; whereas, leptin protected cells from apoptosis by reversing TGF-b1-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.

Differential roles of leptin in regulating cell migration in thyroid cancer cells

“…Conversely, leptin inhibits the cell growth of Mia-PaCa and PANC-1 pancreatic cancer cells through unknown mechanisms (10). In line with other studies, we have demonstrated that leptin stimulates proliferation of breast cancer and hepatoma cells (11,12). Furthermore, among patients with breast cancer, serum leptin concentrations were higher in women with high-grade tumors (13).…”

“…It is plausible that leptin signaling in transformed epithelial cells is different from that in normal thyroid follicular cells. Although the in vivo role of leptin in carcinogenesis has not been well characterized, leptin promotes in vitro cell proliferation in many, but not all, types of cancer (8)(9)(10)(11)(12). In pancreatic cancer cells, leptin inhibits cell growth in a dosedependent manner (10).…”

Lentivirus mediated shRNA interference targeting MAT2B induces growth-inhibition and apoptosis in hepatocellular carcinoma

“…LV-shMAT2B could induce apoptosis of HCC cells but had no impact on normal liver cells, the reason might be that there was no expression of the MAT2B gene in normal liver cells. It was demonstrated that induction mRNA of bcl-x S by SAMe in HepG2 cells resulted in apoptosis, but SAMe had no effect on expression of bcl-x L [29] . We discovered that the protein level of bcl-x S was increased and the expression of bcl-x L was down-regulated by LV-shMAT2B.…”

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

“…Clinical trials have shown that adipocytokine disorders, including increased levels of leptin and decreased levels of adiponectin in the serum, are implicated in hepatocarcinogenesis (7,8). Leptin induces proliferation and inhibits apoptosis in human HCC cells (9). These findings suggest that adipocytokine dysbalance may play an important role in the development and progression of HCCs.…”