Adrenomedullin is expressed in pancreatic cancer and stimulates cell proliferation and invasion in an autocrine manner via the adrenomedullin receptor, ADMR
Adrenomedullin is expressed in pancreatic cancer and stimulates cell proliferation and invasion in an autocrine manner via the adrenomedullin receptor, ADMR
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DOI：
10.1158/0008-5472.can-06-3362
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Logsdon, Craig D.
中科院分区：
文献类型：
--
作者：
Ramachandran, Vijaya;Arumugam, Thiruvengadam;Logsdon, Craig D.
目前的研究调查了肾上腺髓质素作为一种潜在的胰腺癌细胞功能的自分泌调节因子。免疫组织化学检测结果显示，90%(43/48)的人胰腺癌组织中有肾上腺髓质素的表达，逆转录-聚合酶链式反应(RT-PCR)检测结果显示，100%(8/8)的胰腺癌细胞表达肾上腺髓质素。用ELISA法测定，胰腺癌细胞株也能分泌肾上腺髓质素到培养上清液中(5/5)。外源性肾上腺髓质素作用于体外培养的PANC-1、BxPC3和MPanc96细胞，可刺激细胞增殖、侵袭和核因子kappaB活性，表明细胞对肾上腺髓质素的反应能力。用肾上腺髓质素拮抗剂处理细胞可抑制基础水平的增殖和核因子kappaB的活性，从而支持该分子的自分泌功能。此外，通过基因转移到PANC-1细胞而增加肾上腺髓质素水平，而在MPanc96细胞中肾上腺髓质素小发夹RNA沉默抑制了体内肿瘤的生长和转移。肾上腺髓质素至少通过两种不同的受体发挥作用，即肾上腺髓质素受体(ADMR)和降钙素受体样受体(CRLR)。逆转录-聚合酶链式反应和Western blotting结果表明，胰腺癌细胞只表达ADMR，不表达CRLR。相反，在肿瘤微环境中发现的细胞，原代人胰腺星状和内皮细胞(HUVEC)，同时表达ADMR和CRLR。胰腺癌细胞中ADMR的小发夹RNA沉默阻断了肾上腺髓质素诱导的生长和侵袭，表明该受体参与了肾上腺髓质素的自分泌作用。这些数据表明，通过ADMR作用的肾上腺髓质素增加了胰腺癌细胞的侵袭力，并表明这些分子可能是有用的治疗靶点。
The current study investigated adrenomedullin as a potential autocrine regulator of pancreatic cancer cell function. Adrenomedullin was localized in the neoplastic epithelium of 90% (43 of 48) of human pancreatic adenocarcinomas analyzed by immunohistochemistry and was expressed by 100% (8 of 8) of pancreatic cancer cell tines analyzed by reverse transcription-PCR. Pancreatic cancer cell lines also secreted adrenomedullin into the culture medium as determined by ELISA (5 of 5). Exogenous adrenomedullin treatment of Panc-1, BxPC3, and MPanc96 cells in vitro stimulated cell proliferation, invasion, and nuclear factor kappa B activity, indicating the ability of the cells to respond to adrenomedullin. Treatment of the cell cultures with an adrenomedullin antagonist inhibited basal levels of proliferation and nuclear factor kappa B activity, supporting the autocrine function of this molecule. Furthermore, increasing adrenomedullin levels by gene transfer to Panc-1 cells increased, whereas adrenomedullin small hairpin RNA silencing in MPanc96 cells inhibited tumor growth and metastasis in vivo. Adrenomedullin is able to act through at least two different receptors, adrenomedullin receptor (ADMR) and calcitonin receptor-like receptor (CRLR). Reverse transcription-PCR and Western blotting indicated that pancreatic cancer cells expressed only ADMR but not CRLR. In contrast, cells found in the tumor microenvironment, primary human pancreatic stellate and endothelial (HUVEC) cells, expressed both ADMR and CRLR. Small hairpin RNA silencing of ADMR in pancreatic cancer cells blocked adrenomedullin-induced growth and invasion, indicating that this receptor is involved in the autocrine actions of adrenomedullin. These data indicate that adrenomedullin acting via ADMR increases the aggressiveness of pancreatic cancer cells and suggests that these molecules may be useful therapeutic targets.