Concomitant Activation of the JAK/STAT, PI3K/AKT, and ERK Signaling Is Involved in Leptin-Mediated Promotion of Invasion and Migration of Hepatocellular Carcinoma Cells

Abstract

Various epidemiologic studies have shown that obesity is associated with hepatocellular carcinoma. Leptin, the key player in the regulation of energy balance and body weight control, also acts as a growth factor on certain organs in both normal and disease states. It is plausible that leptin acts to promote hepatocellular carcinogenesis directly affecting malignant properties of liver cancer cells. However, a direct role for leptin in hepatocellular carcinoma has not been shown. In this study, we analyzed the role of leptin and the mechanism(s) underlying its action in hepatocellular carcinoma cells, which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of both HepG2 and Huh7 cells and involves activation of signal transducers and activators of transcription 3 (STAT3), AKT, and extracellular signal-regulated kinase (ERK) signaling pathways. Leptin-induced phosphorylation of ERK and AKT was dependent on Janus-activated kinase (JAK)/STAT activation. Intriguingly, we also found that leptin potently induces invasion of hepatocellular carcinoma cells in Matrigel invasion and electric cell-substrate impedancesensing assays. Leptin-stimulated invasion was effectively blocked by pharmacologic inhibitors of JAK/STAT and, to a lesser extent, by ERK and phosphatidylinositol 3-kinase (PI3K) inhibition. Importantly, leptin also induced the migration of both HepG2 and Huh7 cells on fibronectin matrix. Inhibition of JAK/STAT, ERK, and PI3K activation using pharmacologic inhibitors effectively blocked leptin-induced migration of HepG2 and Huh7 cells. Taken together, these data indicate that leptin promotes hepatocellular carcinoma growth, invasiveness, and migration and implicate the JAK/STAT pathway as a critical mediator of leptin action. Our findings have potential clinical implications for hepatocellular carcinoma progression in obese patients. [Cancer Res 2007;67(6):2497-507]

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

“…To our knowledge, the activation of all three (PI3K/Akt, JAK/STAT, and ERK) pathways in neural stem cells in response to LIF signaling has not been reported previously although concomitant activation of these three pathways have been demonstrated in carcinoma cells where they are involved in promotion of growth, invasion, and migration [84,85]. Here, we have shown that, during differentiation of NP cells, LIF activated PI3K/AKT as well as STAT3 signaling (Fig.…”

Leptin induces migration and invasion of glioma cells through MMP‐13 production

“…In this study, we found that malignant C6 glioma cells indeed expressed more leptin and leptin receptor than non-malignant astrocytes RBA1 and NRA, indicating that leptin and/or leptin receptor play a significant role in neoplastic cells. It has been reported that leptin increases the migration and invasion of hepatocellular carcinoma cells and prostate cancer cells (Frankenberry et al 2004;Saxena et al 2007). Here we found that exogenous application of human recombinant leptin enhanced the migration and invasion ability of C6 glioma cells.…”

“…On the other hand, stromal cells derived from endometriotic lesions express significantly high amounts of leptin under both normoxic and hypoxic conditions (44.3 ± 11.8 pg/ml and 191.5 ± 31.4 pg/ml, respectively) (Wu et al 2007). To take obesity as 20 GLIA-00145-2008 another example, plasma leptin is an excellent index of obesity and correlated with some obesity-related diseases, such as diabetes, coronary heart disease, and obesity-linked carcinoma (Sader et al 2003;Saxena et al 2007). The extracellular space is quite small so that the local extracellular concentration of leptin may reach a much higher concentration in the brain.…”

“…A variety of evidence indicates that leptin is highly correlated with obesity-related carcinoma, such as breast cancer (Rose et al 2002) and hepatocellular carcinoma (Saxena et al 2007). High leptin levels are associated with advanced tumor stage and higher tumor grade in breast cancer (Goodwin et al 2005).…”

Histomorphological and immunophenotypic features of pill-induced esophagitis

“…Pill-induced esophagitis and reflux esophagitis account for more than 1/5 th and 2/3 rd esophageal ulceration cases, respectively [18]. Recent reports suggest that intraepithelial eosinophil infiltration within the esophagus is induced throughout multiple signaling pathways, including extracellular signal-related kinase (ERK) [19][20][21], leptin [22] and leptin signaling-related proteins, such as the signal transducer and activator of transcription 3 (STAT3) and the mammalian target of rapamycin (mTOR) [23][24][25][26].…”