核孔复合物蛋白TPR促进肝癌发生发展的作用及其分子机制研究

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is one of the most fatal disease in China. Gain of chromosome 1q21.1–32.1 is the most frequent amplifying region in HCC, and is closely associated with hepatocarcinogenesis. Nuclear pore complex-associated protein TPR is located in recurrently altered region 1q31.1. TPR functions as a scaffolding element essential for normal nucleocytoplasmic transport of proteins and mRNAs. However, molecular and cellular mechanisms underlying the role of TPR in HCC remain unclear. Our preliminary studies revealed that TPR expression was significantly increased in HCC tissue compared to paracancerous tissue, and the expression level of TPR was closely correlated with tumor size and prognosis of patients with HCC. Downregulation of TPR with siRNA significantly inhibited the cell viability while promoted cell apoptosis and senescence. Afterwards, we found that TPR expression was regulated by transcriptional regulator YAP (Yes-associated protein) and TEAD1 (TEA Domain Transcription Factor 1), which act downstream nuclear effectors of the Hippo pathway. Further studies showed that supportive role of TPR in HCC was probably associated with mitochondrial function. To uncover the TPR dependent pathway in HCC process, we will go further to clarify how TPR expression is modulated by genetics and elucidate how TPR promotes hypermetabolism and high activity of proliferation. This study will provide new ideas and targets to improve the diagnosis and treatment of HCC from the way of nucleocytoplasmic transport.

肝细胞癌(HCC)是原发性肝癌最常见的类型，致死率极高。1q21.1–32.1染色体区域扩增在HCC患者中的发生频率最高，且与HCC早期发生密切相关。核孔复合物蛋白TPR位于DNA拷贝数扩增的高频区1q31.1，作为支架元件调节胞核–胞浆之间的蛋白质和mRNAs运输，而TPR在HCC中的作用及相关分子机制仍不清楚。我们初步研究发现，TPR在肝癌组织中的表达显著高于癌旁组织，其表达水平与肿瘤大小及病人预后显著相关；下调TPR表达，能够抑制肝癌细胞活力，促进细胞凋亡和衰老；TPR的在HCC中高表达受Hippo信号通路下游转录因子YAP/TEAD1调控；TPR促进HCC发展可能与线粒体功能有关。本课题将进一步明确TPR在肝癌中高表达的调控机理，从胞核–胞浆物质转运的角度深入研究TPR促进肝癌发生发展的具体分子机制，为改善HCC的诊疗提供新思路和干预靶点。

核蛋白易位启动子区域蛋白TPR在肿瘤的发生发展过程中发挥着重要的作用，而TPR在肿瘤中的作用及相关分子机制至今为止仍不清楚。在前期的研究中，通过cBioPortal数据库，我们全面分析了TPR基因变异情况。结果显示，TPR在胰腺癌、肝癌、肺腺癌、前列腺癌和膀胱癌等大多数肿瘤中都存在基因拷贝数扩增。通过对GEO和TCGA全基因组测序数据的分析发现，TPR在消化系统肿瘤肝癌组织和胰腺癌组织中的表达显著高于相应癌旁组织，且与预后密切相关。通过一系列的实验，我们推测TPR可能通过调控肿瘤细胞的复制压力来影响肿瘤的生长。进一步的研究发现TPR与PRMT2 (Protein Arginine Methyltransferase 2)存在相互作用，TPR能够增强肿瘤细胞的核苷酸代谢，从而促进癌细胞的生长。之后申请人拟在TPR敲除模型小鼠中进行验证，并结合临床样本分析TPR的临床意义及其作为治疗靶点的可能性。本课题将从肿瘤的代谢重编程方面着手为改善肝癌和胰腺癌的诊疗提供新的思路和方法。