小核仁RNA　SNORD126的序列特征和促肝癌生长分子机制

SNORD126 is an orphan C/D box snoRNA and highly expressed in hepatocellular carcinoma (HCC) patient samples. Our previous studies identified several characteristics of SNORD126, including the subcellular localization and its binding proteins. We also demonstrated that SNORD126 overexpression increased HCC cell growth in vitro and xenograft tumor growth in vivo. Knockdown of SNORD126 suppressed cell growth. However, sequence properties of SNORD126 and the molecular mechanism underlying its effects remain unknown. We hypothesize that SNORD126’s pro-oncogenic effect is mediated by downstream genes. We will identify the key region by construction of mutations and functional verification. The gene expression microarray and KEGG signaling pathway analysis will be performed to identify the downstream targets of SNORD126, and in which pathway SNORD126 participates. The therapeutic effect will be evaluated in HCC patient-derived xenograft (PDX) tumor models using antisense oligonucleotides against SNORD126. Our proposal explores new insights into the role of C/D box snoRNAs, and provides a potential target for cancer therapy.

我们前期检测人肝癌样本发现一个显著高表达的C/D box型小核仁RNA (snoRNA): SNORD126，明确其亚细胞定位、结合蛋白等特性，肝癌细胞实验和细胞株裸鼠成瘤实验显示：SNORD126促进肝癌生长。综合snoRNA基本生物特性、前期结果和SNORD126结构预测，推测：SNORD126通过调控下游基因的表达进而发挥促肝癌生长功能。本项目中，我们将1)构建SNORD126序列突变体后，检测其亚细胞定位、对细胞生长的影响等，明确其关键序列；2)通过基因表达谱芯片实验发现其调控的靶基因，阐明SNORD126促肝癌生长机理；3)在肝癌病人来源肿瘤异种移植小鼠(PDX)模型上，观察用反义寡聚核苷酸下调SNORD126的效果和对肿瘤生长的抑制作用，探索SNORD126作为肝癌治疗靶点的可行性。本研究有望拓展对C/D box snoRNA的认识，为以snoRNA为靶标的癌症治疗提供新思路。

小核仁RNA参与了多种肿瘤的形成，本项目重点探索SNORD126促进肝癌生长的分子机制及其关键序列，明确其作为潜在治疗靶点的效果。结果表明：SNORD126促进肿瘤细胞生长的机制是通过上调FGFR2的表达而激活PI3K-AKT信号通路；mTOR抑制剂雷帕霉素可以抑制SNORD126引起的肿瘤生长；C’2和D结构域是SNORD126发挥功能的关键序列。同时发现SNORD126也通过调控PI3K-AKT信号通路促进脂肪细胞分化，为snoRNA在肿瘤之外的生理过程中的作用提供了新的实验证据。