Institute of Immunology, Witten/Herdecke University, Stockumer Strasse 10, 58448 Witten, Germany.
Endocr Relat Cancer. 2010 Feb 18;17(1):179-89. doi: 10.1677/ERC-09-0225. Print 2010 Mar.
Active migration of tumor cells is a prerequisite for the development of metastasis and tumor progression, and is regulated by a variety of extracellular ligands. Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5- to 2-fold with obesity-associated colon cancer accounting for 14-35% of total incidence. In obese individuals, serum levels of leptin are markedly increased, and therefore, we have investigated the impact of this adipocytokine on the migration of various human colon carcinoma cell lines such as SW480, SW620, and HCT116. Leptin significantly enhanced the migratory activity of all three cell lines, and the strongest effect was observed in SW480 cells, which increased their locomotor activity from 28% spontaneously locomoting cells to 50%. The intracellular signal transduction regulating this pro-migratory effect involves the activation of the transcription factor signal transducer and activator of transcription-3 via Janus kinases, but also the activity of src tyrosine kinases, focal adhesion kinase, exclusively protein kinase Cdelta, and the phosphatidyl-inositol-3-kinase, as proven by the use of particular inhibitors and target-specific small interfering RNAs. Herein, we deliver new evidence for a modulatory role of leptin in the regulation of colon cancer progression by stimulating tumor cell migration. Thus, our findings have potential clinical implications, because understanding the impact of leptin on tumor cell migration and the underlying signal transduction mechanisms is mandatory for future development of novel therapeutics to treat obesity-associated colorectal cancer.
肿瘤细胞的主动迁移是转移和肿瘤进展发展的前提，受到多种细胞外配体的调控。流行病学研究表明，肥胖使结肠癌的风险增加 1.5-2 倍，肥胖相关的结肠癌占总发病率的 14-35%。在肥胖个体中，瘦素的血清水平明显升高，因此，我们研究了这种脂肪细胞因子对各种人结肠癌细胞系（如 SW480、SW620 和 HCT116）迁移的影响。瘦素显著增强了这三种细胞系的迁移活性，在 SW480 细胞中观察到最强的作用，其自发迁移细胞的运动活性从 28%增加到 50%。调节这种促迁移作用的细胞内信号转导涉及通过 Janus 激酶激活转录因子信号转导和转录激活因子 3，但也涉及 src 酪氨酸激酶、粘着斑激酶、独特的蛋白激酶 Cdelta 和磷脂酰肌醇-3-激酶的活性，如通过使用特定的抑制剂和针对特定靶点的小干扰 RNA 所证明的那样。在此，我们提供了新的证据，证明瘦素通过刺激肿瘤细胞迁移在调节结肠癌进展中具有调节作用。因此，我们的发现具有潜在的临床意义，因为了解瘦素对肿瘤细胞迁移的影响及其潜在的信号转导机制，对于未来开发治疗肥胖相关结直肠癌的新疗法是必要的。
