Adrenomedullin is induced by hypoxia and enhances pancreatic cancer cell invasion
Adrenomedullin is induced by hypoxia and enhances pancreatic cancer cell invasion
复制标题
DOI：
10.1002/ijc.22596
复制
发表时间：
2007-07-01
影响因子：
6.4
通讯作者：
Kleeff, Joerg
中科院分区：
文献类型：
--
作者：
Keleg, Shereen;Kayed, Hany;Kleeff, Joerg
肾上腺髓质素（ADM）由不同类型的细胞合成，并通过结合降钙素受体样受体（CRLR）和受体活性修饰蛋白（RAMP）家族成员发挥作用。本研究旨在探讨ADM及其信号通路在胰腺癌中的表达及其功能。通过QRT-PCR，与正常胰腺组织相比，PDAC组织中ADM和CRLR的中位mRNA水平分别高1.5倍和2.4倍。免疫组化显示ADM、CRLR、RAMP 1和RAMP 2在胰腺癌细胞中表达，而RAMP 3不表达。与健康对照组和慢性胰腺炎（CP）患者相比，PDAC患者的ADM血清水平显著升高，ROC曲线下面积分别为0.83和0.98。在30.6 ng/ml的临界水平下，ADM区分PDAC与对照组和CP患者的特异性分别为85.5%和83.6%，敏感性分别为80%和100%。所有5个评估的胰腺癌细胞系均表达ADM、CRLR、RAMP 1和RAMP 2，而RAMP 3仅在115个胰腺癌细胞系中表达。ADM在315人胰腺癌细胞中被缺氧强烈诱导，并显著增加侵袭力。CRLR的阻断降低了4/5人胰腺癌细胞的侵袭力。此外，在315细胞系中，rADM轻微上调血管内皮生长因子的分泌。综上所述，ADM在PDAC中被缺氧诱导并过度表达，因此可能作为一种潜在的肿瘤标志物。此外，ADM增加了一些胰腺癌细胞的侵袭性，并可能影响血管生成，这表明阻断该途径可能具有治疗潜力。(C)2007 Wiley-Liss，Inc.
Adrenomedullin (ADM) is synthesized by different types of cells and acts by binding calcitonin receptor-like receptor (CRLR) and members of the receptor activity-modifying protein (RAMP) family. In this study, the expression and functional role of ADM and its signaling components were investigated in pancreatic adenocarcinoma (PDAC). By QRT-PCR, median mRNA levels of ADM and CRLR were 1.5- and 2.4-fold higher, respectively, in PDAC tissues compared to normal pancreatic tissues. By immunohistochemistry, ADM, CRLR, RAMP1 and RAMP2, but not RAMP3, were expressed in pancreatic cancer cells. ADM serum levels were significantly increased in PDAC patients compared to healthy controls and chronic pancreatitis (CP) patients, with an area under the ROC curve of 0.83 and 0.98, respectively. At a cut-off level of 30.6 ng/ml, the specificity of ADM to differentiate PDAC from controls and CP patients was 85.5 and 83.6%, with a sensitivity of 80 and 100%. All 5 evaluated pancreatic cancer cells lines expressed ADM, CRLR, RAMP1 and RAMP2, whereas RAMP3 was expressed in only 115 pancreatic cancer cell lines. ADM was strongly induced by hypoxia and significantly increased invasiveness in 315 human pancreatic cancer cells. Blocking of CRLR decreased invasiveness in 4/5 human pancreatic cancer cells. In addition, rADM slightly up-regulated vascular endothelial growth factor secretion in 315 cell lines. In conclusion, ADM is induced by hypoxia and over-expressed in PDAC and might therefore serve as a potential tumor marker. Furthermore, ADM increases invasiveness of some pancreatic cancer cells and might influence angiogenesis, suggesting that blocking this pathway might have a therapeutic potential. (C) 2007 Wiley-Liss, Inc.