circHMGCS1与RNA结合蛋白HuR相互作用参与恶性胶质瘤干细胞的干性维持及其机制研究

Malignant Glioma accounted for the largest class of primary brain tumor, and its high malignant degree、therapy resistance and high recurrence rate are widely accepted to be leaded by the exist of glioma stem-like cells (GSCs) . However, the mechanism of GSCs maintain is still unclear. In our preliminary study, we used the in vitro differentiation model from human neural progenitor cells (hNPCs) to mature glia cells, and identified a circRNA, circHMGCS1, which was highly expressed in hNPCs but was gradually down-regulated in mature glia cells. In further research, we found that: 1) circHMGCS1 was elevated in glioma, and its high expression level of was positively correlated with malignant degree; 2) circHMGCS1 can maintain the expression of stemness relative transcription factor SOX2. Moreover, knockdown expression of circHMGCS1 inhibited the neurosphere formation, and increased the sensitivity to TMZ treatment; 3) circHMGCS1 interacted with RNA binding protein HuR which maintains the stemness of GSCs. So we present our scientific hypothesis: circHMGCS1 regulates SOX2 stability by interacting with RNA binding protein HuR to function in maintaining stemness of GSCs. In this study, we will further investigate the interaction mechanism between circHMGCS1 and HuR, and perform the in vivo experiment to verify our hypothesis. It’s very helpful to comprehend the molecular mechenism of radiotherapy and chemotherapy resistance of GBM, and find new therapy target to malignant glioma.

脑胶质瘤是占比最大的一类原发脑瘤，放化疗效果差且复发率高，目前广泛认为与一群高度去分化且具有自我更新能力的胶质瘤干细胞相关，但其干性维持的分子机制仍不明确。前期研究中，我们在神经母细胞（hNPCs）诱导神经胶质细胞的体外分化模型中鉴定到一环状RNA，circHMGCS1，其在神经母细胞中高表达，而随着分化逐渐降低。进一步研究发现：1）circHMGCS1在脑胶质瘤中高表达，且与临床分级正相关；2）circHMGCS1与干性转录因子SOX2表达正相关，敲低能显著抑制球囊形成、增加对替莫唑胺敏感性；3）circHMGCS1可与具有肿瘤干细胞维持功能的RNA结合蛋白HuR相互作用。由此提出科学假设：circHMGCS1与HuR相互作用，参与恶性胶质瘤干细胞干性维持并促进抗药性。本课题将从相互作用机制和小鼠颅内成瘤实验进行研究。这将有助于阐明脑胶质瘤发生和放化疗抵抗分子机制，为临床诊疗提供新思路。

神经胶质瘤是中枢神经系统（CNS）中最常见，最具侵略性的原发性恶性肿瘤，环状RNA在其中的作用还有很多未解之谜。circ-MAPK4是通过调节miR-125a-3p的p38 / MAPK信号通路在神经胶质瘤细胞存活和凋亡中发挥关键作用，可以为神经胶质瘤的治疗提供一条新思路。在另一个研究中，结直肠癌患者的主要死亡原因是转移。越来越多的证据表明，circRNA在癌症的发生和发展中起着关键作用。然而，协调癌症转移的circRNAs的潜在分子机制仍然不明确，需要进一步澄清。因此，我们在结直肠癌模型中探讨circRNA的功能。circHERC4通过miR-556-5p/CTBP2/E-cadherin途径在促进肿瘤侵袭性方面发挥关键作用，是该疾病的预后生物标志物，提示CircHERC4可能是大肠癌患者可开发的治疗靶点。