长非编码RNA-AK098783介导EZH2调控SFRP1对结直肠癌转移的作用机制研究

Distant metastasis is an important prognostic factor of colorectal cancer , but its inherent mechanism is still unclear. We focused on epigenetic regulatory mechanisms of cancer metastasis. Tissue samples were screened by microarray to identify the lncRNAs that mediated the metastasis process of colorectal cancer(CRC). we found AK098783, a lncRNA that can promote cell motility in vitro, was closely related to the metastases and poor prognosis of patients with CRC by research on large scale clinical specimens. it is valuable for clinical application transformation. Further study shows that AK098783 can inhibit the expression of SFRP1 by bind to histone methyltransferases EHZ2, then activate WNT singnaling pathway to promote the metastasis of CRC cells. Based on our previous study. We attempt to verify the regulation mechanisms and roles of AK098783 that involved in CRC metastases and WNT pathway activation both in vivo and in vitro. We also try to elucidate the pathways and targets that AK098783 elaborate its function and effect. Finally, we will identify the fine interaction model between the molecules that related with AK098783.

结直肠癌远处转移是影响患者预后的重要因素，其内在的机制尚不够清晰。申请人关注于肠癌转移的表观遗传学调控机制，通过组织标本中筛选影响肠癌转移过程的长链非编码RNA，我们聚焦于AK098783，在体外实验中该分子能够促进细胞运动迁移，在大样本的组织标本检测和统计分析中，我们确认AK098783与转移的发生及患者预后密切相关，具有临床转化价值。进一步研究还表明，AK098783能结合组蛋白甲基化修饰酶EZH2，抑制WNT信号负调节分子SFRP1表达，进而激活WNT信号，促进肠癌细胞迁移。本项目拟在此基础上结合体内、体外模型，多角度验证AK098783在结直肠癌转移调控中的作用方式和调节WNT信号的分子机制，解析其发挥功能效应的途径及作用靶点，鉴定分子相互作用的精细模式。

恶性肿瘤的远处转移是影响患者预后的重要因素，其内在的机制尚不够清晰。申请人关注于消化道肿瘤转移的表观遗传学调控机制，通过组织标本中筛选影响大肠癌转移过程的长链非编码RNA，我们聚焦于AK098783这一lncRNA分子，在体外实验中该分子能够促进细胞运动迁移，在大样本的组织标本检测和统计分析中，我们确认AK098783与转移的发生及患者预后密切相关，具有临床转化价值。初步的研究结果表明，AK098783可以调控WNT信号通路，为深入探讨调控大肠癌转移的分子机制，我们通过TCGA大数据分析结合文献检索，发现RNA结合蛋白FXR1在大肠癌、食管癌中明显高表达，FXR1表达水平与大肠癌、食管癌的不良预后及转移密切相关，但后续的试验结果并未证实FXR1可以与AK098783相互作用。在此基础上，本课题组对FXR1临床应用价值，以及促进肿瘤转移的机制进行了深入的研究。结合体内、体外模型，多角度验证FXR1在结直肠癌及食管癌转移调控中的作用方式和调节下游信号的分子机制，解析其发挥功能效应的途径及作用靶点，鉴定分子相互作用的精细模式。