Dysregulation of upstream and downstream transforming growth factor-β transcripts in livers of children with biliary atresia and fibrogenic gene signatures.
Dysregulation of upstream and downstream transforming growth factor-β transcripts in livers of children with biliary atresia and fibrogenic gene signatures.
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DOI：
10.1016/j.jpedsurg.2013.03.047
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发表时间：
2013-10
影响因子：
2.4
通讯作者：
Nadler, Evan P.
中科院分区：
文献类型：
--
作者：
Iordanskaia, Tatiana;Hubal, Monica J.;Koeck, Emily;Rossi, Christopher;Schwarz, Kathleen;Nadler, Evan P.
我们的前期工作表明，转化生长因子β（transforming-growth factor，TGF β）通路在实验性胆道闭锁（biliary atresia，BA）相关的肝纤维化中起着重要作用。为了在人类中证实这些发现，我们对来自患有BA的儿童的肝脏标本的公开可用的微阵列数据进行了计算机模拟分析，假设TGF β途径将失调。我们分析了47名BA婴儿的公开肝脏基因表达微阵列数据。我们重新分析了微阵列图像文件和临床数据，以比较在初始研究中确定的纤维化和炎症队列之间的基因表达差异。使用BA的动物模型确认来自微阵列分析的靶标。方差分析（ANOVA）检测到6903个转录物（2822个不同基因）在组间差异调节（p<0.01;倍数变化>1.2）。我们使用靶向方法鉴定了24种TGF β相关转录物的亚组。在纤维化组中，前胶原转录物的表达增加（1.2倍至1.4倍）;基质金属蛋白酶（MMP）-7的表达同样增加2倍，而MMP-9和纤溶酶原激活物抑制剂-1分别减少2倍和3倍。整合素β5（1.18倍）和β8（1.84倍）在纤维化组中也表现出表达增加。在实验BA中证实了β5（3倍）和β8（5倍）以及Smad-3（4倍）和Smad相互作用蛋白（SIP）-1（3.5倍）mRNA的表达增加。实验组中磷酸化的Smad 3蛋白也是对照组的近两倍，进一步暗示了TGF-β通路。已知的上游和下游TGF-β介质的基因转录本在患有BA和纤维化基因特征的儿童的肝脏标本中差异表达。在我们的动物BA模型中也发现在人类样本中失调的相同整联蛋白上调，TGF-β途径中的其他中间体也是如此。进一步调查是否这些介质可能是未来治疗BA儿童的有吸引力的目标是必要的。
Our previous work demonstrated that the transforming-growth factor (TGF) β pathway plays a central role in the liver fibrosis associated with experimental biliary atresia (BA). To confirm these findings in humans, we performed an in silico analysis of publicly available microarray data from liver specimens from children with BA, with the hypothesis that the TGF β pathway would be dysregulated. We analyzed publicly available liver gene expression microarray data from 47 infants with BA. We re-analyzed the microarray image files and clinical data to compare gene expression differences between the fibrogenic and inflammatory cohorts identified in the initial study. Targets from the microarray analysis were confirmed using the animal model of BA. Analysis of variance (ANOVA) detected 6903 transcripts (2822 distinct genes) differentially regulated between groups (p<0.01; fold change >1.2). We used a targeted approach to identified a subgroup of 24 TGF β-related transcripts. Expressions for procollagen transcripts were increased in the fibrogenic group (1.2 fold to 1.4 fold); expression of matrix metalloproteinase (MMP)-7 was similarly increased 2-fold, while MMP-9 and plasminogen activator inhibitor-1 were decreased 2-fold and 3-fold respectively. Integrins β5 (1.18 fold) and β8 (1.84 fold) also demonstrated increased expression in the fibrogenic group. Increased expression of β5 (3-fold) and β8 (5-fold) as well as Smad-3 (4-fold) and Smad interacting protein (SIP)-1 (3.5 fold) mRNA were confirmed in experimental BA. Phosphorylated Smad 3 protein in the experimental group was also nearly twice that of the control group, further implicating the TGF-β pathway. Gene transcripts for known upstream and downstream TGF-β mediators are differentially expressed in liver specimens from children with BA and a fibrogenic gene signature. The same integrins that were dysregulated in the human specimens were also found to be upregulated in our animal BA model, as were other intermediaries in the TGF-β pathway. Further investigation into whether these mediators may be attractive targets for future therapy in children with BA is warranted.
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作者：
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DOI：
10.1016/j.jss.2009.10.038
发表时间：
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期刊：
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发表时间：
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