长链非编码RNA TXNDC3-1调控肝癌细胞增殖的机制研究

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, however, the biology of this kind of tumor still remains poorly understood. Our preliminary study found TXNDC3-1, one of the lncRNA aberrantly expressed in HCC and associated with cell cycle, is significantly down-regulated in HCC tissues and cell lines. CDCA3 was identified as a target gene of TXNDC3-1，More importantly, its expression level is associated with tumor size when we analyzed the relationship between TXNDC3-1 and clinical characteristics. Multivariate analysis showed that TXNDC3-1 was an independent risk factor affecting postoperative survival time in HCC patients. In this study, we will take a further step to investigate the underlying mechanism of TXNDC3-1’s tumor suppressor role in HCC at the molecular, cell, tissue and animal level. The present study will identify a novel target for therapeutic intervention in HCC.

肝癌是世界范围内最常见的恶性肿瘤之一，但人们对其具体分子机制仍缺乏全面了解。我们前期研究发现lncRNA TXNDC3-1与细胞周期及细胞增殖密切相关，其在肝癌组织及细胞系中显著低表达。细胞周期调控因子CDCA3为TXNDC3-1的下游靶基因，TXNDC3-1组织表达水平与肿瘤大小显著相关，并可作为独立的肝癌手术后预后的分子标志物，但其具体作用机制有待进一步探究。我们推测，TXNDC3-1可通过细胞周期相关信号通路抑制肝癌细胞增殖。为验证这一假说，我们将采用Q-PCR、RNA pull down、RIP、蛋白质谱、RNA-Seq等手段，从分子、细胞、临床样本以及动物整体水平等多方面探讨TXNDC3-1在肝癌细胞增殖中的重要作用。本课题将深入探讨TXNDC3-1调控肝癌细胞的分子机制及其意义，为肝癌的诊断提供新的候选标志物，为肝癌靶向治疗提供新的思路和科学依据

肝细胞癌（HCC）的分子机制仍然知之甚少。在本项目的资助下，我们研究了与细胞分裂周期相关的3（CDCA3）表达状态，并表征了HCC中与CDCA3相关的长非编码RNA（lncRNA）。我们发现CDCA3是HCC中潜在的致癌因子，并首次报道了一种可以抑制CDCA3的新的长链非编码RNA lncCDCA3L (原名TXNDC3-1) 。LncCDCA3L在HCC中显着下调，其表达水平与肿瘤大小相关，并且可以作为影响HCC患者术后生存时间的独立危险因素。从机制上讲，lncCDCA3L可以通过基于发夹结构基序的新方式直接与1423-1455区域的CDCA3 mRNA结合来抑制CDCA3蛋白水平并抑制肝癌发生。.我们的研究共同揭示了lncCDCA3L如何抑制HCC细胞的致瘤特性并以CDCA3依赖性方式在HCC中表现出肿瘤抑制剂特征的分子机制。这里的研究结果支持lncCDCA3L可用作HCC患者的候选预后生物标志物。