L1CAM通过cyclinD1依赖途径促进胰腺癌放疗后报复性再增殖机制的研究

Retaliatory proliferation of cancer cell played an important role in tumor recurrence after radiotherapy. High expression of L1CAM in dying pancreatic cancer cell was confirmed through high-throughput compound gene chip screening in a pancreatic cancer cell growth model after radiotherapy established in our previous research. It also showed that high expression of L1CAM could promote pancreatic cancer cell proliferation and cyclinD1 was found as a downstream target of L1CAM. However, the mechanism of phenomenon was unclear. The latest research had shown that L1CAM could regulate stat3 gene, which binding sites was existed in the promoter region of cyclinD1 predicted by bioinformatics algorithms. These findings suggested that L1CAM may regulate cyclinD1 expression through stat3 pathway. To investigate the effect of L1CAM promoting pancreatic cancer cell proliferation through cyclinD1 overexpression modulated by stat3 signaling pathway after radiation, following work will be carried out: 1) To clarify that cyclinD1 was involved in inducing tumor cell repopulation mediated by L1CAM in pancreatic cancer cell after radiotherapy; 2) To identify that L1CAM could regulate the expression of cyclinD1 through modulating stat3 pathway. These results will help unravel the molecular mechanisms behind L1CAM mediated tumor cell proliferation and may provide a novel anti-cancer molecular target in pancreatic cancer.

放疗后胰腺癌细胞报复性再增殖是引起肿瘤耐受复发的关键因素。本课题前期通过建立胰腺癌放疗后再增殖模型、并应用基因芯片扫描及分子生物学技术发现濒死胰腺癌细胞中L1CAM可能促进胰腺癌细胞再增殖，并可能调控下游cyclinD1表达，而其作用具体机制不清。最近研究表明L1CAM能够调控stat3基因与靶基因启动子结合，而生物信息学预测到cyclinD1启动子区域存在stat3结合位点，提示L1CAM可能通过stat3途径调节cyclinD1的表达。本课题拟以cyclinD1和stat3为切入点，探讨L1CAM促进放疗后肿瘤再增殖的机制。拟：1）观察濒死细胞中L1CAM是否通过cyclinD1促进放疗后胰腺癌细胞再增殖；2）验证放疗后濒死细胞中L1CAM是否通过激活stat3通路调控cyclinD1的表达。本研究将阐明放疗后L1CAM促进肿瘤细胞再增殖的机制，为胰腺癌放疗后再增殖的治疗提供新思路。

放疗后胰腺癌细胞报复性再增殖是引起肿瘤耐受复发的关键因素,而其作用具体机制不清。本课题前期通过建立胰腺癌放疗后再增殖模型。我们的实验结果证实L1CAM-stat3信号通路在此过程不是主要的信号通路，通过对放疗前和放疗后全基因组的生物信息学分析和进一步的实验证实发现放疗后长链非编码RNAPVT1在胰腺癌细胞过度表达，这在文献中未见报道。本课题研究证实PVT1的表达与放疗后胰腺癌细胞放疗耐受有关，PVT1高表达组的胰腺癌细胞增殖活性高，放疗的治疗效果差，通过Q-PCR的方法进一步检测PVT1影响放疗后肿瘤增殖的机制，本研究表明PVT1高表达影响肿瘤细胞核酸代谢的指标PRPS2，及EZH2，进而促进放疗后肿瘤细胞的再增殖。另外我们利用不同类型的软骨肉瘤和骨肉瘤的石蜡标本，应用Q-PCR及荧光原位杂交的方法在软骨肉瘤中发现PVT1高表达。我们首先发现PVT1在软骨肉瘤中与肿瘤细胞的增殖有关。其与软骨肉瘤患者预后的关系有待进一步的分析。继续研究相关的下游基因如PRPS2，EZH2在以上肿瘤中高表达，其与软骨肉瘤患者预后的关系有待进一步的分析。同时本研究发现PRPS2在骨肉瘤的表达，分析并证实PRPS2与骨肉瘤患者差的预后相关，文章已在投稿。总之，长链非编码RNAPVT1与胰腺癌的放疗后耐受密切相关，它可能通过PRPS2通路促进放疗后胰腺癌细胞的增殖；另外，我们的研究证实在骨肉瘤和软骨肉瘤中PVT1和PRPS2高表达，其中PRPS2与骨肉瘤差的预后相关，这将为骨肉瘤的治疗和预后监测提高新的靶点。

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