PRL-3通过调控Sox12表达促进乙肝相关肝癌侵袭转移的机制研究

PRL-3 is closely related to malignant biological behavior of many malignant tumors. However, the role of PRL-3 in hepatocellular carcinoma remains unknown. Our preliminary data showed that PRL-3 was up-regulated in HCC tissues and portal vein tumor thrombus. High PRL-3 expression was correlated with HCC with cancer thrombus and HBV infection. Patients with high-level PRL-3 expression have lower overall survival. Base on this finding, our preliminary research also found: ① PRL-3 can promote HCC migration and invasion. ② HBx can increase the expression of PRL-3 and CREB/NF-κB/AP1, all of which are important nuclear transcription factors, may participate in this regulation. ③ PRL-3 may regulate the expression of Sox12 through its phosphatase domain in HCC. Hence we suspect there exists a HBx-mediated positive feedback signaling pathway, called PRL3-Src-ERK-(CREB/NF-κB/AP1)-PRL3, which can constantly stimulate the expression of PRL-3. The overexpression of PRL-3 then upregulates Sox12 expression, and promotes HCC metastasis. Our project will include reasonable experiment scheme in combination with abundant preliminary experiment data and clinical material. Our research will provide scientific evidence in developing effective treatment against HBV related HCC.

PRL-3与多种恶性肿瘤的生物学行为密切相关，但其在肝细胞癌（HCC）中的具体作用机制目前仍不清楚。我们前期研究发现PRL-3在HCC组织和门脉癌栓中高表达，且PRL-3高表达与HCC伴发癌栓、HBV感染相关，高表达PRL-3的患者预后更差。在此基础上，我们发现：①PRL-3可促进HCC细胞的迁移与侵袭；②HBV病毒X蛋白（HBx）可通过激活PRL-3启动子促进其表达，并且CREB、NF-κB、AP1等转录因子可能参与HBx对PRL-3的调控；③PRL-3可能通过其磷酸酶结构域调控Sox12在HCC中的表达。综合以上前期研究，我们推测：HCC中存在由HBx介导的PRL3-Src-ERK-(CREB/NF-κB/AP1)-PRL3正反馈信号通路，使PRL-3过表达，进而上调Sox12，促进侵袭转移。本项目拟通过严谨的实验验证该科学假设，研究成果将为寻找HBV相关HCC的治疗靶点提供科学依据。

我们前期研究发现PRL-3在HCC组织和门脉癌栓中高表达，且PRL-3高表达与HCC伴发癌栓、HBV感染相关，高表达PRL-3的患者预后更差。越来越多的证据表明蛋白质酪氨酸磷酸酶（PTP）是癌症的合适治疗靶标， PRL-3作为PTP重要一员，PRL-3在乙肝相关肝细胞癌（HCC）中的具体作用机制及是否有望成为治疗靶标仍不清楚。. 在本项目研究中我们发现：①公共数据库的HCC样本和我们中心的队列样本中PRL-3均呈表达上调， 且其高表达与不良预后有关。② 确定HCC中拷贝数的增加和染色体8q24.3的扩增与PRL-3过表达呈正相关。 PRL-3的过表达促进了HCC细胞的增殖，迁移和粘附，而其丢失则具有相反的作用。③在肝癌中，黏着斑激酶（FAK）与PRL-3共扩增并共表达。并且PRL-3还促进FAK的磷酸化，随后介导HCC细胞中PRL-3的致癌功能。④我们还鉴定了TGFB1为PRL-3的下游分子，而且正是TGF-β信号传导介导了PRL-3诱导FAK活化。⑤此外，还观察到p38和PI3K/AKT途径介导PRL-3诱导的TGFB1表达和随后的FAK激活，而FAK的激活又刺激了p38和PI3K/AKT途径的激活，这就形成了一个由PRL-3触发的AKT/p38/TGFB1/FAK正反馈环路。. 本项目通过严谨的实验验证该正反馈环路的存在，该研究成果对PRL-3有望作为HCC的治疗靶点提供了科学依据。