Attoub S, Noe V, Pirola L, Bruyneel E, Chastre E, Mareel M, Wymann M P, Gespach C
INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, and IFR65, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
FASEB J. 2000 Nov;14(14):2329-38. doi: 10.1096/fj.00-0162.
Leptin plays a key role regulating food intake, body weight and fat mass. These critical parameters are associated with an increased risk for digestive and mammary gland cancer in the Western population. Here we determined whether leptin contributes to the invasive phenotype of colonic and kidney epithelial cells at various stages of the neoplastic progression. First, leptin potently (EC50 = 10-30 ng/ml) induces invasion of collagen gels by premalignant familial adenomatous colonic cells PC/AA/C1 and nontumorigenic MDCK kidney epithelial cells, their src-transformed counterparts, and the human adenocarcinoma colonic cells LoVo and HCT-8/S11. Leptin and its Ob-Rb receptors were consistently identified by RT-PCR and immunoblotting in these cell lines, as well as in human colonic epithelial crypts, polyps, colonic tumor resections, and adjacent mucosa. Leptin-induced invasion was effectively blocked by pharmacological inhibitors of several downstream signaling pathways involved in cell transformation, namely, JAK2 tyrosine kinase (AG490), phosphoinositide PI3'-kinase (wortmannin and LY294002), mTOR kinase (rapamycin), and protein kinases C (GF109203X, Gö6976). Accordingly, leptin induces transient elevation of the PI3'-kinase lipid products in JAK2 immunoprecipitates prepared from parental MDCK cells. The leptin effect on invasion was potentiated by the activated form of the small GTPase RhoA and was abrogated by dominant negative mutants of RhoA, Rac1, and the p110alpha of PI3'-K. Our data indicate that leptin may exert a local and beneficial effect on migration of normal colonic epithelial cells and reparation of the inflamed or wounded digestive mucosa. We also emphasize a new role for leptin, linking the nutritional and body fat status to digestive cancer susceptibility by stimulating the invasive capacity of colonic epithelial cells at early stages of neoplasia. This finding has potential clinical implications for colon cancer progression and management of obesity.
瘦素在调节食物摄入、体重和脂肪量方面发挥着关键作用。在西方人群中，这些关键参数与消化和乳腺癌风险增加相关。在此，我们确定瘦素是否在肿瘤进展的各个阶段对结肠和肾上皮细胞的侵袭表型有影响。首先，瘦素能有效（半数有效浓度=10-30纳克/毫升）诱导癌前家族性腺瘤性结肠细胞PC/AA/C1和非致瘤性MDCK肾上皮细胞、它们的src转化对应物以及人结肠腺癌细胞LoVo和HCT-8/S11侵袭胶原凝胶。通过逆转录聚合酶链反应（RT-PCR）和免疫印迹在这些细胞系以及人结肠上皮隐窝、息肉、结肠肿瘤切除术标本和相邻黏膜中持续鉴定出瘦素及其Ob-Rb受体。瘦素诱导的侵袭被参与细胞转化的几种下游信号通路的药理学抑制剂有效阻断，即JAK2酪氨酸激酶（AG490）、磷酸肌醇PI3'-激酶（渥曼青霉素和LY294002）、mTOR激酶（雷帕霉素）和蛋白激酶C（GF109203X、Gö6976）。相应地，瘦素诱导从亲本MDCK细胞制备的JAK2免疫沉淀物中PI3'-激酶脂质产物的短暂升高。小GTP酶RhoA的活化形式增强了瘦素对侵袭的作用，而RhoA、Rac1的显性负性突变体和PI3'-K的p110α消除了瘦素的作用。我们的数据表明，瘦素可能对正常结肠上皮细胞的迁移以及炎症或受伤消化黏膜的修复发挥局部有益作用。我们还强调了瘦素的一个新作用，即通过在肿瘤形成早期刺激结肠上皮细胞的侵袭能力，将营养和体脂状态与消化癌易感性联系起来。这一发现对结肠癌进展和肥胖管理具有潜在临床意义。
