Jiang Nan, Sun Rongtong, Sun Qing
Shandong University School of Medicine, Jinan, Shandong Province, People's Republic of China.
Weihai Municipal Hospital, Weihai, Shandong Province, People's Republic of China.
Drug Des Devel Ther. 2014 Nov 14;8:2295-302. doi: 10.2147/DDDT.S69004. eCollection 2014.
Previous reports indicate that over 13 different tumors, including hepatocellular carcinoma (HCC), are related to obesity. Obesity-associated inflammatory, metabolic, and endocrine mediators, as well as the functioning of the gut microbiota, are suspected to contribute to tumorigenesis. In obese people, proinflammatory cytokines/chemokines including tumor necrosis factor-alpha, interleukin (IL)-1 and IL-6, insulin and insulin-like growth factors, adipokines, plasminogen activator inhibitor-1, adiponectin, and leptin are found to play crucial roles in the initiation and development of cancer. The cytokines induced by leptin in adipose tissue or tumor cells have been intensely studied. Leptin-induced signaling pathways are critical for biological functions such as adiposity, energy balance, endocrine function, immune reaction, and angiogenesis as well as oncogenesis. Leptin is an activator of cell proliferation and anti-apoptosis in several cell types, and an inducer of cancer stem cells; its critical roles in tumorigenesis are based on its oncogenic, mitogenic, proinflammatory, and pro-angiogenic actions. This review provides an update of the pathological effects of leptin signaling with special emphasis on potential molecular mechanisms and therapeutic targeting, which could potentially be used in future clinical settings. In addition, leptin-induced angiogenic ability and molecular mechanisms in HCC are discussed. The stringent binding affinity of leptin and its receptor Ob-R, as well as the highly upregulated expression of both leptin and Ob-R in cancer cells compared to normal cells, makes leptin an ideal drug target for the prevention and treatment of HCC, especially in obese patients.
先前的报告表明，超过13种不同的肿瘤，包括肝细胞癌（HCC），都与肥胖有关。肥胖相关的炎症、代谢和内分泌介质，以及肠道微生物群的功能，被怀疑与肿瘤发生有关。在肥胖人群中，发现促炎细胞因子/趋化因子，包括肿瘤坏死因子-α、白细胞介素（IL）-1和IL-6、胰岛素和胰岛素样生长因子、脂肪因子、纤溶酶原激活物抑制剂-1、脂联素和瘦素，在癌症的发生和发展中起关键作用。脂肪组织或肿瘤细胞中由瘦素诱导的细胞因子已得到深入研究。瘦素诱导的信号通路对于肥胖、能量平衡、内分泌功能、免疫反应和血管生成以及肿瘤发生等生物学功能至关重要。瘦素是几种细胞类型中细胞增殖和抗凋亡的激活剂，也是癌症干细胞的诱导剂；其在肿瘤发生中的关键作用基于其致癌、促有丝分裂、促炎和促血管生成作用。本综述提供了瘦素信号通路病理效应的最新进展，特别强调了潜在的分子机制和治疗靶点，这些可能在未来的临床环境中得到应用。此外，还讨论了瘦素在肝癌中诱导的血管生成能力和分子机制。瘦素与其受体Ob-R的严格结合亲和力，以及与正常细胞相比癌细胞中瘦素和Ob-R的高度上调表达，使瘦素成为预防和治疗肝癌的理想药物靶点，尤其是在肥胖患者中。
