PRL-3对肿瘤干细胞形成,导致肿瘤复发、转移的作用机理

It is well known that tumor metastasis and drug resistance is mainly due to the existence of tumor stem cell.We have reported that aberrant expression of phosphatase PRL-3 enhaces tumor metastasis in various tumors,which is related to metastasis, relapse and the poor prognosis.Thus we suspected that PRL-3 would play key roles in tumor stem cell formation,resulting in the drug resistance and relapse. Our primary results demonstrated that PRL-3 is involved in signaling transductions of tumor stem cell formation by regulating the expression of key stem cell molecules,including Nanog,CD24,RAP2C and other transcription factors,which consequently made tumor cells transformed into tumor stem cells.This project will further characterize the roles of PRL-3 in induction of tumor stem cell and the underlying detailed mechanisms, to find novel core molecules that control tumor stem cell switched from normal tumor cells; Taken together with results of the xenograft model and clinical samples, the co-relationship between PRL-3 and its downstream core molecules in induction of tumor stem cells, maligancy,drug sensitivity,relapse and final survival will be analyzed to confirm PRL-3's function. Furthermore, the regulation network of PRL-3 to the core molecules,such as CD24,PAP2C and Nanog, etc. will be investigated as well.We belive this study will make the practical basis of novel tumor stem cell marker,PRL-3 and find the new tumor stem cell related core molecules for tumor therapy in future,and also expand our knowledge of the origin of tumor stem cell.

肿瘤干细胞是肿瘤复发转移和耐药的重要原因之一。我们多次报道磷酸酶PRL-3 促进多种肿瘤转移,并和不良预后高度相关，暗示PRL-3也可能促进了这些肿瘤干细胞的形成和维持，导致肿瘤耐药和复发转移。我们前期探索研究发现PRL-3参与了肿瘤干细胞形成的信号传导，并调控了干细胞关键因子Nanog、CD24、RAP2C及其它重要转录因子的表达，使肿瘤细胞获得干细胞特征。本研究将进一步详细探讨PRL-3诱导肿瘤细胞转化为肿瘤干细胞的具体生化机制和信号传导途径，期望发现新的肿瘤干细胞形成关键因子；通过肿瘤模型和临床样本，分析鉴定所发现的关键因子对肿瘤干细胞形成、耐药性和复发转移的影响；进一步探讨PRL-3与这些关键因子，如CD24、RAP2C、Nanog等在肿瘤干细胞形成中的互作调控机制，为将PRL-3 作为一个新的肿瘤干细胞标记和治疗靶点，发现新的肿瘤耐药、复发转移相关的治疗靶标分子奠定理论实践基础。

肿瘤干细胞在多种类型的肿瘤组织中发现和证实，是肿瘤发生、转移和化疗抗性的主要驱动力。但是，肿瘤细胞向肿瘤干性细胞转换的分子机制迄今还不清楚。磷酸酶PRL-3已被证明与肿瘤细胞的间质细胞向表皮细胞转化相关，因这个细胞转化过程通常与干细胞形成相关，由此我们研究了PRL-3在肿瘤干细胞形成中的作用，而申请了本研究项目。我们研究发现，在卵巢癌细胞中，PRL-3可以促进肿瘤细胞向肿瘤干细胞的转化过程，这个方式主要是通过上调关键干性因子SOX2导致；从机制上来看，PRL-3是通过上调表达SOX2的转录因子MEF2A造成SOX2表达上调。进一步发现，原来PRL-3和竞争性结合去乙酰化酶HDAC4造成其降解，而导致MEF2A 的乙酰化修饰增加，促进了与SOX2启动子结合；同时使得组蛋白乙酰化增加而使得染色体局部松散，导致SOX2转录活化。本研究首次揭示了PRL-3的表观遗传调控功能对肿瘤干细胞的形成的作用。临床病样分析同样验证了上述结果，为肿瘤复发、耐药提供了理论参考依据。. 同时，我们还发现PRL-3上调可以导致大肠癌细胞增加对葡萄糖的摄取能力，明确了PRL-3上调是肿瘤细胞偏向糖酵解过程的一个主要因子；在斑马鱼胚胎发育过程中，PRL-3上调可以导致自发性脊索瘤发生。