PI3K/Akt通路相关miRNAs遗传变异与儿童急性淋巴细胞白血病风险及其作为潜在生物标志物的研究

Acute lymphoblastic leukemia (ALL) is the most common malignant tumour in childhood. Abnormal activity of PI3K/Akt pathway has been demonstrated to play key role on the pathogenesis of ALL. Genetic variants of miRNAs, which can regulate important genes in PI3K/Akt pathway, may involved in pathogenesis of childhood ALL through affecting expression levels of miRNAs or disturbing interaction between miRNAs and target genes. In the present studies, we selected miRNAs which has been confirmed to combine with key genes in PI3K/Akt pathway in bioinformatics web. If there was SNPs in the miRNA and its expression level was different between cases and controls, it was included in our study. We plan to investigate the association between SNPs in these miRNAs and risk of childhood ALL in Chinese population. We will also explore the molecular biological functions of those SNPs associated with risk of ALL. Finally, we will detect expression levels of these miRNAs in plasma to evaluate the clinical application future. Our study will provide theory basis for searching biomarker and early intervention of childhood ALL.

急性淋巴细胞白血病（ALL）是儿童时期最常见的恶性肿瘤。磷脂酰肌醇3-激酶/蛋白激酶B（PI3K/Akt）信号通路的活性异常是其发病的关键环节。调节该通路基因的微小RNA（miRNA）遗传变异可能通过改变miRNA的表达水平或与靶基因的结合能力，影响靶基因表达，从而参与儿童ALL的发病过程。本研究经生物信息学网站选择已经实验证实可调节PI3K/Akt通路关键基因的miRNAs，筛选其基因区域存在SNPs且有差异表达的miRNAs作为候选基因，通过分子流行病学病例-对照研究，探讨miRNA基因遗传变异（SNPs）与中国人群儿童ALL发病风险的相关性，进而深入研究具有显著关联性的SNPs的生物学功能，并检测相应miRNAs的血浆表达水平，评估其临床应用价值。最终为寻找儿童ALL发病易感性的生物学标志，实现疾病的早期干预提供理论依据。

急性淋巴细胞白血病（ALL）是儿童时期最常见的恶性肿瘤。调节PI3K/Akt重要信号通路的微小RNA（miRNA）遗传变异可能影响儿童ALL的发生易感性。本研究选择PI3K/Akt通路关键基因相关的miRNAs，筛选其基因区域的SNPs位点，通过分子流行病学病例-对照研究，探讨miRNA基因遗传变异与中国人群儿童ALL发病风险的相关性，进而深入研究具有显著关联性的SNPs以及miRNA的生物学功能，并检测相应miRNA的血浆表达水平。研究结果发现，rs2292832、rs550894和rs543412均与儿童ALL发病风险显著相关，且进一步分层分析明确其在儿童ALL不同亚组中的效应差异。进而分子生物学实验发现，miR-149具有调控PI3K/Akt通路编码基因表达，调节ALL细胞株生物学特性的作用；此外，与野生型相比，含有rs550894位点突变的miR-612过表达质粒，具有促进白血病细胞株增殖的作用，且能够抑制细胞株凋亡。最后，检测发现儿童ALL血浆中miR-149及miR-100表达水平较非肿瘤对照组有显著性差异。本研究为寻找儿童ALL发病易感性的生物学标志，实现疾病的早期干预提供理论依据。