Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells.
Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells.
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DOI：
10.1002/ijc.23887
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发表时间：
2008-12-15
影响因子：
6.4
通讯作者：
Gonzalez, Ruben R.
中科院分区：
文献类型：
--
作者：
Carino, Cecilia;Olawaiye, Alexander B.;Cherfils, Salandre;Serikawa, Takehiro;Lynch, Maureen P.;Rueda, Bo R.;Gonzalez, Ruben R.
关键词：
子宫内膜癌中涉及的几种促血管生成/促炎因子受瘦素调节，但负责这些瘦素诱导作用的信号传导机制在很大程度上是未知的。在此我们报道了在良性（原发性和HES）和癌性子宫内膜上皮细胞中，EEC（An 3Ca、SK-UT 2和石川）瘦素以剂量依赖性方式调节血管内皮生长因子（VEGF）、白细胞介素-1 β（IL-1β）、白血病抑制因子（LIF）及其各自的受体VEGFR 2、IL-1 R tI和LIFR。值得注意的是，瘦素在癌症中比在良性细胞中诱导VEGF/VEGFR 2和LIF水平更大的增加。而IL-1β仅在良性原发性EEC中被leptin升高。癌-EEC表达更高水平的瘦素受体（全长OB-Rb和短亚型），而良性原发性EEC。瘦素介导的JAK 2（janus kinase 2）激活位于PI-3 K（phosphatidylinositol-3 kinase）和/或MAPK（mitogen activated protein kinase）信号通路激活的上游。瘦素诱导的细胞因子/受体通常涉及JAK 2和MAPK激活，但PI-3 K磷酸化需要瘦素增加LIF，IL-1/IL-1 R tI。瘦素介导的mTOR（雷帕霉素的哺乳动物靶蛋白）活化，主要与MAPK相关，在瘦素调节所有细胞因子和受体中发挥核心作用。这些结果表明，瘦素的作用是细胞特异性的，可以赋予增殖或细胞存活的优势，或可能促进子宫内膜厚度。瘦素对促血管生成分子的影响在恶性细胞与良性细胞中更为明显，这可能意味着在子宫内膜癌细胞中瘦素诱导的细胞信号通路存在潜在的转变。
Several pro-angiogenic/pro-inflammatory factors involved in endometrial cancer are regulated by leptin but the signaling mechanisms responsible for these leptin induced actions are largely unknown. Here we report that in benign (primary and HES) and cancer endometrial epithelial cells, EEC (An3Ca, SK-UT2 and Ishikawa) leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1β); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1β was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on pro-angiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin induced cell signaling pathways in endometrial cancer cells.
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DOI：
10.1073/pnas.93.13.6231
发表时间：
1996-06-25
影响因子：
11.1
作者：
Ghilardi, N;Ziegler, S;Skoda, RC
通讯作者：
Skoda, RC
影响因子：
5.3
作者：
Hübschle, T;Thom, E;Meyerhof, W
通讯作者：
Meyerhof, W
影响因子：
4.8
作者：
Gera, JF;Mellinghoff, IK;Lichtenstein, AK
通讯作者：
Lichtenstein, AK
影响因子：
4.8
作者：
Giraudo, E;Primo, L;Bussolino, F
通讯作者：
Bussolino, F
影响因子：
20.1
作者：
Bouloumié, A;Drexler, HCA;Busse, R
通讯作者：
Busse, R