Fuentes Maren K, Nigavekar Shraddha S, Arumugam Thiruvengadam, Logsdon Craig D, Schmidt Ann Marie, Park Juliet C, Huang Emina H
Program in Cellular & Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Dis Colon Rectum. 2007 Aug;50(8):1230-40. doi: 10.1007/s10350-006-0850-5.
Colon cancer is the third most prevalent cancer in the United States. However, the molecular mechanisms involved in the development and progression of colon cancer are incompletely understood. This study was initiated to explore the potential role of the receptor for advanced glycation end-products and S100P in modulation of key properties of human colon cancer cells.
Western blot, reverse transcription-polymerase chain reaction, and quantitative polymerase chain reaction were performed for detection of the receptor for advanced glycation end-products and S100P in colon cancer and matched normal colon. The influence of exogenously added S100P was analyzed on SW480 colon cancer cell line proliferation, migration, phosphorylation of mitogen activated protein kinases, and NFkappaB activation. To identify the mechanisms involved in these responses, coimmunoprecipitation examining the S100P/Receptor for advanced glycation end-products interaction and the effects of receptor for advanced glycation end-products inhibition in this interaction were analyzed.
Although the receptor for advanced glycation end-products was present in normal and malignant colon specimens, only the malignant specimens expressed S100P. Treatment of SW480 cells with S100P increased proliferation and cell migration. Addition of exogenous S100P stimulated both ERK1/2 phosphorylation and NFkappaB activity. The interaction between S100P and the receptor for advanced glycation end-products was demonstrated by coimmunoprecipitation of these molecules from SW480 cells. Antagonism of the receptor for advanced glycation end-products blocked this interaction and the biologic effects of S100P on these cells.
These data indicate that S100P is expressed at greater levels in colon cancer than matched normal tissue and that S100P stimulates colon cancer cell growth, migration, Erk phosphorylation, and NFkappaB activation in vitro, suggesting that this ligand/receptor pair may be targeted for the development of new therapies.
结肠癌是美国第三大常见癌症。然而，结肠癌发生和发展所涉及的分子机制尚未完全明确。本研究旨在探讨晚期糖基化终末产物受体（RAGE）和S100P在调节人结肠癌细胞关键特性中的潜在作用。
采用蛋白质免疫印迹法、逆转录-聚合酶链反应和定量聚合酶链反应检测结肠癌组织及配对正常结肠组织中晚期糖基化终末产物受体和S100P的表达。分析外源性添加S100P对SW480结肠癌细胞系增殖、迁移、丝裂原活化蛋白激酶磷酸化及核因子κB（NFκB）激活的影响。为确定这些反应所涉及的机制，通过免疫共沉淀检测S100P/晚期糖基化终末产物受体相互作用，并分析晚期糖基化终末产物受体抑制在该相互作用中的效应。
虽然晚期糖基化终末产物受体在正常和恶性结肠标本中均有表达，但只有恶性标本表达S100P。用S100P处理SW480细胞可增加细胞增殖和迁移。外源性添加S100P可刺激细胞外信号调节激酶1/2（ERK1/2）磷酸化和NFκB活性。通过对SW480细胞中的这些分子进行免疫共沉淀，证实了S100P与晚期糖基化终末产物受体之间的相互作用。晚期糖基化终末产物受体的拮抗剂可阻断这种相互作用以及S100P对这些细胞的生物学效应。
这些数据表明，S100P在结肠癌中的表达水平高于配对的正常组织，且S100P在体外可刺激结肠癌细胞生长、迁移、Erk磷酸化和NFκB激活，提示该配体/受体对可能成为新治疗方法开发的靶点。
