lncRNA575经MMP3持续活化ROS促进胰腺癌侵袭转移的分子机制

Previous studies have confirmed lncRNA575 participated in the tumorigenesis, and its targets are involved in MMP3、QKI、RBM38 etc. We found that: 1) lncRNA575 expression levels are negatively associated with pancreatic carcinoma histological grade、TNM stage and patients, survival time; 2) The expression of MMP3 is significantly over-expressed in pancreatic carcinoma tissues compared to normal pancreatic controls, while there are no obvious differences in QKI、RBM38 etc; 3) lncRNA575 is positively correlated with EMT acceleration; 4) I have published one SCI paper (IF=5.016), which has confirmed that EMT acceleration existed in pancreatic carcinoma. The known that EMT acceleration promoted by Twist which accept continuous activation via ROS, and EMT can promoted the invasion/metastasis of tumor. We speculate: The invasion/metastasis of pancreatic carcinoma promoted by lncRNA575 which induce continuous activation of ROS via MMP3. We are planning to investigate: 1) To detect lncRNA575 expression in large pancreatic carcinoma samples, and analyze the correlation with clinical data; 2)To Measure the expression of MMP3、downstream molecules、EMT and invasion/metastasis of tumor in cell lines and animal model; 3) Reversly validate the mechanism by siRNA interference in cell lines and animal model. The study is expected to clarify the molecular mechanisms of pancreatic carcinoma promoted by lncRNA575 which induce continuous activation of ROS via MMP3, and provide new ideas for the treatment of pancreatic carcinoma.

研究提示lncRNA575参与肿瘤发生发展过程，其靶点有MMP3、QKI、RBM38等。我们发现：lncRNA575表达量与胰腺癌分期分级、预后呈负相关；与正常胰腺相比，胰腺癌高表达MMP3，而QKI、RBM38等无明显差异；lncRNA575与EMT加速呈正相关；已发表一篇SCI论著（IF=5.016）证实胰腺癌中存在EMT加速。已知MMP3靶点ROS可激活Twist加速EMT，EMT可促进肿瘤侵袭转移。推测：lncRNA575经MMP3持续活化ROS致Twist高表达，加速EMT，促进胰腺癌侵袭转移。拟研究：大样本检测胰腺癌中lncRNA575表达，分析与临床资料的相关性；在细胞及动物模型中检测MMP3及下游分子表达、EMT发生及肿瘤侵袭转移情况；采用siRNA干扰在细胞及动物模型中进行反向验证。有望阐明lncRNA575经MMP3促进胰腺癌侵袭转移的分子机制，为胰腺癌诊治提供新思路。

早期复发、转移、耐药是胰腺癌极差预后的主要原因。我们既往研究表明，非编码RNA在胰腺癌发生发展过程中发挥着重要作用，但准确的表达谱以及详尽的分子机制尚不清楚。结合我们新近的研究发现：多个miRNAs参与调控胰腺癌的增殖、侵袭转移以及耐药，而lncRNA、circRNA可通过“海绵效应”吸附miRNA调控下游靶点。本项目旨在阐明lncRNA、circRNA在胰腺癌组织中的表达谱、功能作用及相关分子机制，为探索胰腺癌诊治新策略提供理论依据。. 本项目主要利用胰腺癌临床标本系统研究非编码RNA（CircRNA/LncRNA/miRNA）在胰腺癌中表达情况以及功能作用；对lncRNA575和HOTAIR与胰腺癌患者的临床资料和生存预后的相关性进行了详细的分析；结合之前的研究基础，深入探讨了circRNA通过“海绵吸附”效应调控miRNA的表达进而影响胰腺癌发生发展的过程；针对circRNA与miRNA，鉴定了多个具有明显表达差异性的circRNAs与miR-15a/miR-506具有多个互补结合位点；基于miRNA在胰腺癌中的重要功能作用，系统地总结分析了胰腺癌中复杂的miRNA调节网络。. 通过本课题的研究发现胰腺癌中非编码RNA（CircRNA/LncRNA/miRNA）的异常表达是影响胰腺癌进展和患者生存预后的重要因素；胰腺癌中lncRNA575和HOTAIR的异常表达与胰腺癌分期分级、预后生存时间密切相关，与患者年龄、性别无关；胰腺癌中circRNAs异常表达与胰腺癌的发生发展密切相关，可通过“海绵吸附”效应调控miR-15a/miR-506的表达从而影响胰腺癌的进展；准确鉴定了多个具有明显表达差异性的circRNAs与miR-15a/miR-506的多个互补结合位点；系统地总结了胰腺癌中发挥重要功能作用的miRNA以及胰腺癌中复杂的miRNA调节网络。. CircRNA/LncRNA/miRNA可能为临床上预测胰腺癌患者预后以及探索诊治新策略提供了潜在靶点。. 发表了5篇与本课题相关的SCI文章，基于本课题研究成果申请并获得一项课题基金资助。