Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma.
Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma.
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DOI：
10.1038/modpathol.2011.191
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发表时间：
2012-05
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醛酮还原酶家族1B 10（AKR 1B 10）具有较强的脂类底物特异性（包括法尼醛、香叶基香叶醛、视黄醛和羰基化合物），这些脂类底物的代谢在促进肿瘤发生中起着至关重要的作用。AKR 1B 10的过表达已经在吸烟相关的癌症如肺癌中被鉴定。由于胰腺癌的发生与吸烟密切相关，本研究的目的是检查AKR 1B 10在胰腺癌中的表达和致癌作用。采用免疫组织化学方法分析了50例石蜡包埋的临床胰腺癌标本中AKR 1B 10的表达。利用Western blotting和siRNA技术检测AKR 1B 10在胰腺癌细胞中的致瘤作用，主要是细胞凋亡和蛋白质异戊二烯化，包括KRAS蛋白及其下游信号。免疫组化分析显示，AKR 1B 10在70%（35/50）的胰腺腺癌和大多数胰腺上皮内瘤变中过表达，但在邻近形态正常的胰腺组织中不表达。与正常胰腺导管上皮细胞（HPDE 6 E7）相比，所有6种培养的胰腺癌细胞系均具有AKR 1B 10的过表达，这与酶活性的增加相关。siRNA介导的胰腺癌细胞中AKR 1B 10表达的沉默导致1）细胞凋亡增加，2）非法尼基化HDJ 2蛋白增加，和3）膜结合异戊二烯化KRAS蛋白及其下游信号分子（包括磷酸化ERK和MEK以及膜结合E-钙粘蛋白）减少。我们的研究结果提供了第一时间的证据，AKR 1B 10是一个独特的酶参与胰腺癌的发生可能通过调节细胞凋亡和蛋白质异戊二烯化。
Aldo-keto reductase family 1B10 (AKR1B10) exhibits more restricted lipid substrate specificity (including farnesal, geranylgeranial, retinal and carbonyls), a n d metabolizing these lipid substrates plays a crucial role in promoting carcinogenesis. Overexpression of AKR1B10 has been identified in smoking-related carcinomas such as lung cancer. As development of pancreatic cancer is firmly linked to smoking, the aim of the present study was to examine the expression and oncogenic role of AKR1B10 in pancreatic adenocarcinoma. AKR1B10 expression was analyzed in 50 paraffin-embedded clinical pancreatic cancer samples using immunohistochemistry. Oncogenic function of AKR1B10 was examined in pancreatic carcinoma cells in vitro using western blotting and siRNA approaches, mainly on cell apoptosis and protein prenylation including KRAS protein and its downstream signals. Immunohistochemistry analysis revealed that AKR1B10 over-expressed in 70% (35/50) of pancreatic adenocarcinomas and majority of pancreatic intraepithelial neoplasia, but not in adjacent morphologically normal pancreatic tissue. Compared to a normal pancreatic ductal epithelial cell (HPDE6E7), all of six cultured pancreatic adenocarcinoma cell lines had a over-expression of AKR1B10 using immunoblotting, which correlated with increase of enzyme activity. siRNA-mediated silencing of AKR1B10 expression in pancreatic cancer cells resulted in 1) increased cell apoptosis, 2) increased non-farnesyled HDJ2 protein, and 3) decreased membrane-bound prenylated KRAS protein and its downstream signaling molecules including phosphorylated ERK and MEK and membrane-bound E-cadherin. Our findings provide first time evidence of that AKR1B10 is a unique enzyme involved in pancreatic carcinogenesis possibly via modulation of cell apoptosis and protein prenylation.
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