PO.TB10.05 · 肿瘤生物学
新型肥胖相关脂肪因子调节子宫内膜癌细胞的恶性表型
Novel obesity-associated adipokine modulates the malignant phenotype of endometrial cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
子宫内膜样子宫内膜癌（EEC）是美国最常见的妇科恶性肿瘤。约60%的EEC女性患者被认为与超重或肥胖相关。随着美国肥胖流行的持续，这部分患者的比例可能会增加。Omentin（ITLN1）是一种新型脂肪因子，表达于覆盖网膜脂肪组织的间皮细胞中。血清omentin水平与体质指数呈负相关，并随体重减轻而升高。我们证明，与健康女性相比，EEC患者的血清omentin水平显著更低。此外，与低脂饮食喂养的免疫功能健全小鼠相比，高脂饮食喂养的小鼠表现出显著更高的肿瘤负荷和更低的循环omentin水平，提示肥胖抑制循环omentin水平并促进EEC进展。为确定omentin在EEC发病机制中的作用，我们用重组omentin处理人和小鼠EEC细胞系，以评估细胞生长和细胞运动性。我们发现，与用PBS处理的对照细胞相比，用重组omentin处理的EEC细胞的细胞增殖率显著降低。与对照细胞相比，omentin处理的EEC细胞的迁移率也显著降低。由于先前有报道omentin结合alpha-v-beta-3（alphavbeta3）整合素以发挥生物学功能，我们用alphavbeta3阻断抗体处理EEC细胞，以观察omentin对细胞生长和运动性的效应是否会被消除。我们发现，与正常小鼠IgG对照相比，alphavbeta3阻断抗体消除了omentin对细胞生长的抑制效应。同样，alphavbeta3阻断抗体抵消了omentin对细胞迁移的效应。这些结果提示，omentin与alphavbeta3整合素的结合抑制了细胞增殖和运动性。此外，Western blot分析显示，omentin下调了关键的alphavbeta3下游信号分子，如p-ERK和p-CREB。在omentin处理的细胞中加入alphavbeta3阻断抗体逆转了omentin对p-ERK的抑制效应，进一步提示omentin/alphavbeta3整合素轴可能在介导omentin的肿瘤抑制效应中发挥重要作用。总之，上述发现提示，omentin可能通过结合alphavbeta3整合素来抑制EEC细胞的生长和迁移。需要进一步研究以表征omentin介导的对EEC细胞抑制所涉及的特定通路，并将omentin开发为针对EEC患者的低毒性化学预防和治疗药物。
查看英文原文 English abstract
Endometrioid Endometrial Cancer (EEC) is the most common gynecologic malignancy in the United States. Around 60% of women with EEC are believed to be associated with being overweight or obese. This fraction of patients is likely to increase as the obesity epidemic continues in the United States. Omentin (ITLN1) is a novel adipokine that is expressed in mesothelial cells covering the omental adipose tissue. The serum omentin level is inversely correlated with Body Mass Index and it increases with weight loss. We demonstrated that serum omentin level is significantly lower in patients with EEC compared to healthy women. Besides, immunocompetent mice fed with high-fat diet demonstrated a significantly higher tumor burden and lower circulating omentin level than those fed with low-fat diet, suggesting that obesity suppresses circulating omentin level and promotes EEC progression. To determine the roles of omentin in EEC pathogenesis, both human and mouse EEC cell lines were treated with recombinant omentin to evaluate cell growth and cell motility. We found that EEC cells treated with recombinant omentin have a significantly lower cell proliferation rate compared to control cells treated with PBS. Omentin-treated EEC cells also resulted in a significantly reduced migration rate compared to control cells. Since omentin was previously reported to bind to alpha-v-beta-3 (alphavbeta3) integrin to exert biological functions, we treated the EEC cells with alphavbeta3 blocking antibody to see if the effects of omentin on cell growth and motility would be abrogated. We found that alphavbeta3 blocking antibody abrogated the suppressive effect of omentin on cell growth compared to normal mouse IgG control. Similarly, alphavbeta3 blocking antibody counteracted the effect of omentin on cell migration. These suggest that omentin binding to the alphavbeta3 integrin inhibited cell proliferation and motility. In addition, Western blot analysis showed that omentin downregulated key alphavbeta3 downstream signaling molecules, such as p-ERK and p-CREB. Addition of alphavbeta3 blocking antibody in omentin-treated cells reversed the suppressive effect of omentin on p-ERK, further suggesting that omentin/alphavbeta3 integrin axis may play an important role in mediating the tumor suppressive effect of omentin.In conclusion, the above findings suggest that omentin suppresses EEC cell growth and migration potentially through binding to alphavbeta3 integrin. Further study is needed to characterize the specific pathways involved in omentin-mediated suppression on EEC cells and to develop omentin as a low toxicity chemopreventive and therapeutic agent for EEC patients
利益披露 Disclosure
C. Au Yeung, None..
G. Binoj, None..
Q. Zhang, None..
Y. Pacheco, None..
S. Mok, None.