PCBP1促进肿瘤细胞凋亡和增殖抑制以及阻止肿瘤发生、转移的分子机理

Our previous results showed that a metastasis-promoting phosphatase PRL-3 is translationally suppressed by Poly C Binding Protein 1 (PCBP1).In addition, Overexpression of PCBP1 in tumor cells suppressed tumorigenesis in mouse model, meanwhile knock down of PCBP1 enhanced tumor formation. Analysis of clinical patient samples demonstrated that PCBP1 expression was downregulated or diminished in various types of cancer, which is negatively correlated to the corresponding types of tumorigenesis.Taken together with the above results, we proposed that PCBP1 would be a tumor suppression gene that could induce tumor cell apoptosis and block cell cycle progression through the yet unknown mechanisms. To confirm this hypothesis,we conducted some experiments and the results indicated that PCBP1 can induce tumor cell apoptosis. Following those results,this project will further investigate the function of PCBP1 in tumorigenesis and metastasis by involving in cell cycle regulation ,cell apoptosis, cell adhesion and cell motility and invasion, and try to find novel therapeutic molecule targets, and the regulational relationship between the novel targets and PCBP1.Therefore, we believe this project would shed lights on the mechanism of tumorigenesis resulted from PCBP1 dysfunctional expression, and it would be of help to the patients with PCBP1 expression silence related cancers,as long as it is funded.

申请人首先报道了肿瘤生长转移基因-小分子磷酸酶PRL-3被Poly C Binding Protein 1（PCBP1）在翻译水平上抑制表达时，首次发现PCBP1具有在小鼠中抑制肿瘤生成的功能。我们临床病样分析也表明PCBP1在多类肿瘤中表达水平下调或消失，与这些肿瘤发生呈负相关。由此，我们推断PCBP1具有抑制肿瘤发生、转移的功能，但目前国内外尚未有相关报道。我们预实验结果已经证明PCBP1可以促进肿瘤细胞凋亡。本项目拟从PCBP1的作用途径直接入手，全面详细探索PCBP1抑制肿瘤细胞增殖，促进肿瘤细胞凋亡，抑制肿瘤发生、转移的作用途径及相关分子信号传导通路，以期发现新的靶标分子；并从生化机理上深入研究这些靶标分子受PCBP1调控的详细机理。最后结合进一步临床病样分析，揭示PCBP1抑制肿瘤发生的作用机制，为全面诊断和治疗由 PCBP1表达沉默所导致的肿瘤奠定基础。

我们在申请本项目时已经报道了肿瘤生长转移基因PRL-3在翻译水平上被Poly C Binding Protein 1（PCBP1）抑制表达时首次发现PCBP1具有在小鼠中抑制肿瘤生成的功能，提示PCBP1可能是一个新的肿瘤抑制基因。我们临床病样分析也表明PCBP1在多类肿瘤中表达水平下调或消失，与这些肿瘤发生呈负相关。但当时国内外尚未有相关报道。于是我们申请了本项目，通过4年多研究，我们已经发现，PCBP1可以在饥饿条件下抑制肿瘤细胞自噬作用，导致肿瘤细胞缺乏内在营养供给来促进肿瘤细胞凋亡。同时还探明PCBP1可以通过结合细胞周期抑制因子P27 mRNA的3'UTR 区域通过稳定其RNA稳定性而增加p27蛋白表达，从而抑制肿瘤发生、转移；同时结合进一步临床病样分析，揭示PCBP1表达下调，是大多数肿瘤发生的一个普遍规律。此外，我们还发现PCBP1可以通过调控只是关键因子P62同时进行抑制自噬发生。上述研究结果部分已经在国际专业期刊发表；其余的正在整理和发表过程当中。因此通过本资助项目，我们首次揭示了一个全新的肿瘤抑制基因PCBP1，并明确了其作用机制方式。我们的研究结果可以提示将细胞周期抑制剂和促进自噬抑制剂和常规临床化疗用药联合使用来抑制由PCBP1表达下调导致的肿瘤治疗提供参考依据，也可为全面诊断由 PCBP1表达沉默所导致的肿瘤提供诊断依据。