Jovanovic Ivan, Zivkovic Maja, Kostic Mirjana, Krstic Zoran, Djuric Tamara, Kolic Ivana, Alavantic Dragan, Stankovic Aleksandra
Laboratory for Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia.
Nephrology and Urology Departments, University Children's Hospital, Belgrade, Serbia.
J Transl Med. 2016 Jun 30;14(1):193. doi: 10.1186/s12967-016-0955-0.
The genetic cause of most congenital anomalies of the kidney and urinary tract (CAKUT) cases remains unknown, therefore the novel approaches in searching for the common disease denominators are required. miRs regulate gene expression in humans and therefore have potentially therapeutic and biomarker properties. No studies thus far have attempted to explore the miRs in human CAKUT. We applied a new strategy to identify most specific miRs associated with CAKUT, in pediatric patients.
Data from the whole genome expression, gathered from ureter tissue samples of 19 patients and 7 controls, were used for the bioinformatic prediction of miRs activity in CAKUT. We integrated microarray gene expression data and miR target predictions from multiple prediction algorithms using Co-inertia analysis (CIA) in conjunction with correspondence analysis and between group analysis, to produce a ranked list of miRs associated with CAKUT. The CIA included five different sequence based miR target prediction algorithms and the Co-expression Meta-analysis of miR Targets. For the experimental validation of expression of miRs identified by the CIA we used tissue from 36 CAKUT patients and 9 controls. The results of gene ontology (GO) analysis on co-expressed targets of miRs associated with CAKUT were used for the selection of putative biological processes relevant to CAKUT.
We identified 7 miRs with a potential role in CAKUT. The top ranked miRs from miRCos communities 4, 1 and 7 were chosen for experimental validation of expression in CAKUT tissue. The 5.7 fold increase of hsa-miR-144 expression in human tissue from CAKUT patients compared to controls (p = 0.005) was observed. From the GO we selected 7 biological processes that could contribute to CAKUT, which genes are potentially influenced by hsa-miR-144. The hsa-miR-200a, hsa-miR-183 and hsa-miR-375 weren't differentially expressed in CAKUT.
This study shows that integrative approach applied here was useful in identification of the miRs associated with CAKUT. The hsa-miR-144, first time identified in CAKUT, could be connected with biological processes crucial for normal development of kidney and urinary tract. Further functional analysis must follow to reveal the impact of hsa-miR-144 on CAKUT occurrence.
大多数先天性肾和尿路畸形（CAKUT）病例的遗传病因仍不清楚，因此需要寻找常见疾病共性的新方法。微小RNA（miR）在人类中调节基因表达，因此具有潜在的治疗和生物标志物特性。迄今为止，尚无研究试图探索人类CAKUT中的miR。我们应用了一种新策略来鉴定儿科患者中与CAKUT相关的最特异的miR。
从19例患者和7例对照的输尿管组织样本中收集的全基因组表达数据，用于CAKUT中miR活性的生物信息学预测。我们使用共惯性分析（CIA）结合对应分析和组间分析，整合了来自多种预测算法的微阵列基因表达数据和miR靶标预测，以生成与CAKUT相关的miR排名列表。CIA包括五种基于序列的不同miR靶标预测算法和miR靶标的共表达荟萃分析。为了对CIA鉴定出的miR表达进行实验验证，我们使用了36例CAKUT患者和9例对照的组织。对与CAKUT相关的miR的共表达靶标的基因本体（GO）分析结果用于选择与CAKUT相关的推定生物学过程。
我们鉴定出7种在CAKUT中具有潜在作用的miR。从miRCos群落4、1和7中排名靠前的miR被选用于CAKUT组织中表达的实验验证。观察到与对照相比，CAKUT患者人体组织中hsa-miR-144表达增加了5.7倍（p = 0.005）。从GO中我们选择了7种可能导致CAKUT的生物学过程，这些基因可能受hsa-miR-144影响。hsa-miR-200a、hsa-miR-183和hsa-miR-375在CAKUT中无差异表达。
本研究表明，此处应用的综合方法有助于鉴定与CAKUT相关的miR。首次在CAKUT中鉴定出的hsa-miR-144可能与肾脏和尿路正常发育的关键生物学过程有关。必须进行进一步的功能分析以揭示hsa-miR-144对CAKUT发生的影响。
