Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival.
Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival.
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前梯度2在胰腺癌的发展过程中表达和分泌，并促进癌细胞的存活。
DOI：
10.1158/0008-5472.can-08-1320
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Logsdon CD
中科院分区：
文献类型：
--
作者：
Ramachandran V;Arumugam T;Wang H;Logsdon CD
胰腺癌由于其侵袭性的生长和转移，是一个主要的肿瘤学挑战。在目前的研究中，我们研究了前梯度2(AGR2)在这些过程中的作用。用实时定量逆转录聚合酶链式反应(Q-RT-PCR)检测，胰腺癌组织中AGR2基因的表达水平是正常胰腺组织和胰腺炎组织的14倍。免疫组织化学显示AGR2在肿瘤细胞中高表达，在胰腺癌中阳性表达为98%(56/57)，在正常胰腺组织和胰腺炎组织中表达极低。AGR2在早期胰腺上皮内瘤变中也有表达。RT-PCR和Western blotting显示在9个胰腺癌细胞系中有7个细胞株AGR2表达升高。在癌细胞的条件培养液中检测到的AGR2表明它是分泌的。采用小干扰RNA沉默和短发夹状RNA沉默的方法评价AGR2对胰腺癌细胞的影响。沉默AGR2显著降低细胞增殖(MTS实验)和侵袭(Boyden小室实验)，并提高吉西他滨的敏感性(荧光激活细胞分类分析)。来自AGR2沉默的细胞的条件培养液刺激胰腺癌细胞增殖的能力降低，这表明分泌的AGR2是活跃的。在体内，通过非侵入性生物发光成像评估，在MPanc-96细胞中沉默AGR2导致肿瘤生长显著减少，并增加了吉西他滨治疗的有效性。综上所述，AGR2在胰腺癌发生发展过程中表达和分泌，对癌细胞的生长和存活起重要作用。这些观察表明，AGR2可能是胰腺癌的一个有用的分子靶点。
Pancreatic cancer is a major oncological challenge due to its aggressive growth and metastasis. In the current study, we investigated the role of anterior gradient 2 (AGR2) in these processes. AGR2 mRNA, as assessed by quantitative real-time reverse transcription–PCR (Q-RT-PCR), was 14-fold higher in pancreatic cancer compared with normal and pancreatitis tissues. Immunohistochemistry revealed high expression of AGR2 in neoplastic cells with 98% (56 of 57) positivity on pancreatic cancer and minimal staining in normal and pancreatitis tissues. AGR2 was also expressed in early pancreatic intraepithelial neoplastic lesions. RT-PCR and Western blotting showed elevated AGR2 expression in seven of nine pancreatic cancer cell lines. AGR2, as detected in conditioned media from cancer cells, indicated that it was secreted. The influence of AGR2 on pancreatic cancer cells was evaluated by silencing with small interfering RNA and short hairpin RNA. Silencing of AGR2 significantly reduced cell proliferation (MTS assay) and invasion (Boyden chamber assay) and improved gemcitabine sensitivity (fluorescence-activated cell sorting analysis). Conditioned media from cells in which AGR2 was silenced had a reduced ability to stimulate proliferation of pancreatic cancer cells, suggesting that secreted AGR2 was active. In vivo, silencing of AGR2 in MPanc-96 cells led to a significant reduction of tumor growth and increased the effectiveness of gemcitabine treatments in orthotopic tumor models evaluated by noninvasive bioluminescence imaging. In summary, AGR2 is expressed and secreted during pancreatic cancer development and plays an important role in cancer cell growth and survival. These observations suggest that AGR2 may be a useful molecular target in pancreatic cancer.