Department of Paediatric Surgery, Kanchi Kamakoti CHILDS Trust Hospital, CHILDS Trust Medical Research Foundation, Chennai, India.
Institute of Liver Disease & Transplantation, Gleneagles Global Health City, Chennai, India.
Mol Biol Rep. 2019 Oct;46(5):5123-5130. doi: 10.1007/s11033-019-04969-3. Epub 2019 Jul 24.
The disease phenotype in biliary atresia (BA) is caused by a fibro-inflammatory process leading to destruction of cholangiocytes, obstruction of ductular pathways and eventual progression to liver cirrhosis. The first line of management is a Kasai portoenterostomy (KPE) followed by liver transplantation (LT) in some children. Several factors have been postulated to affect the outcome of KPE and/or the subsequent progression of liver disease. However, no biomarkers have been identified in the liver for BA. We aimed to address this deficit. Whole transcriptome mRNA sequencing was performed for 29 samples (25 BA and 4 Controls) to identify the candidate genes predicting the prognosis of KPE. These results were further confirmed with quantitative Realtime PCR (qPCR). Analysis from RNA-sequencing data identified matrix metalloproteinase7 (MMP7) and phosphoenolpyruvate carboxykinase (PCK1) as potential determinants of the outcome of KPE. MMP7 expression was significantly elevated in patients who failed to clear jaundice after KPE as well as in patients with End Stage Liver Disease (ESLD). In contrast, PCK1 level was upregulated in patients who had successful KPE, while there was a significant down regulation in patients who failed KPE. MMP7 and PCK1 expression patterns had an inverse relation to the outcome of KPE and hence could potentially be used as biomarkers to predict KPE outcome and disease progression, enabling clinicians to design new treatment strategies for BA.
胆道闭锁（BA）的疾病表型是由纤维炎症过程引起的，导致胆管细胞破坏、胆管途径阻塞，最终进展为肝硬化。一线治疗方法是进行 Kasai 门腔分流术（KPE），随后一些患儿需要进行肝移植（LT）。有多种因素被认为会影响 KPE 的结果和/或随后的肝病进展。然而，在 BA 的肝脏中尚未发现生物标志物。我们旨在解决这一缺陷。对 29 个样本（25 个 BA 和 4 个对照）进行了全转录组 mRNA 测序，以鉴定预测 KPE 预后的候选基因。这些结果通过定量 Realtime PCR（qPCR）进一步证实。来自 RNA-seq 数据的分析表明，基质金属蛋白酶 7（MMP7）和磷酸烯醇丙酮酸羧激酶 1（PCK1）是 KPE 结果的潜在决定因素。MMP7 的表达在 KPE 后未能清除黄疸的患者以及终末期肝病（ESLD）患者中显著升高。相比之下，PCK1 水平在 KPE 成功的患者中上调，而在 KPE 失败的患者中则显著下调。MMP7 和 PCK1 的表达模式与 KPE 的结果呈反比，因此它们可能被用作预测 KPE 结果和疾病进展的生物标志物，使临床医生能够为 BA 设计新的治疗策略。
