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

• Type of Material: Article
• Authors: Neeraj K. Saxena, Emory University; Dipali Sharma, Emory University; Xiaokun Ding, Emory University; Songbai Lin, Emory University; Fabio Marra, University of Florence; Didier Merlin, Emory University; Frank A Anania, Emory University
• Language: English
• Date: 2007-03-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2007 American Association for Cancer Research.
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/67/6/2497
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 67
• Issue: 6
• Start Page: 2497
• End Page: 2507
• Grant/Funding Information: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK; IH grants DK 062092 (F.A. Anania), DK061941 (D. Merlin), and DK071594 (D. Merlin); Digestive Diseases Research Development Centers grant R24DK064399 (Division of Digestive Diseases); U.S. Army Medical Research and Material Command grant BC-030963 (D. Sharma); The Susan G. Komen BCRF grant BCTR 0503526 (D. Sharma); and Italian Ministry of University and Research (F. Marra).
• Research Categories: Health Sciences, Oncology

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 impedance-sensing 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.