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
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
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DOI：
10.1158/0008-5472.can-06-3075
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Anania, Frank A.
中科院分区：
文献类型：
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作者：
Saxena, Neeraj K.;Sharma, Dipali;Anania, Frank A.
各种流行病学研究表明，肥胖与肝细胞癌有关。瘦素是调节能量平衡和体重控制的关键因素，也是正常和疾病状态下某些器官的生长因子。这是合理的，瘦素的行为，以促进肝细胞癌的发生，直接影响肝癌细胞的恶性性质。然而，瘦素在肝细胞癌中的直接作用尚未显示。在这项研究中，我们分析了瘦素的作用及其在肝细胞癌细胞中的作用机制，这些细胞表达瘦素受体的短型和长型。用瘦素处理导致HepG 2和Huh 7细胞的增殖增加，并且涉及信号转导和转录激活因子3（STAT 3）、AKT和细胞外信号调节激酶（ERK）信号通路的激活。瘦素诱导的ERK和AKT磷酸化依赖于Janus激活激酶（JAK）/STAT激活。有趣的是，我们还发现瘦素在Matrigel侵袭和电细胞基质阻抗检测中有效地诱导肝癌细胞的侵袭。瘦素刺激的侵袭被JAK/STAT的药理学抑制剂有效地阻断，并且在较小程度上被ERK和磷脂酰肌醇3-激酶（PI 3 K）抑制。重要的是，瘦素还诱导HepG 2和Huh 7细胞在纤连蛋白基质上的迁移。使用药理学抑制剂抑制JAK/STAT、ERK和PI 3 K活化有效地阻断了瘦素诱导的HepG 2和Huh 7细胞迁移。总之，这些数据表明，瘦素促进肝细胞癌的生长，侵袭性和迁移，并牵连JAK/STAT途径作为瘦素作用的关键介质。我们的研究结果对肥胖患者肝细胞癌的进展具有潜在的临床意义。
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.