lncRNA-CRCAL在结直肠癌早期诊断及发生发展中的机制研究

Colorectal Cancer is one of the most frequent malignancies in China and all over the world. Recent studies have shown that long noncoding RNAs (lncRNAs) play critical roles in multiple biological processes, including carcinogenesis, migration and invasion. By analyzing public database and using bioinformatic analysis, we identified lncRNA-CRCAL as a differentially expressed lncRNA in colorectal cancer tissues compared to their matched normal tissue counterparts, and we identified it as a potential target gene of p53. We also identified lncRNA-CRCAL as a GRWD1 binding lncRNA. We will perform functional study of lncRNA-CRCAL through overexpression or knockdown of it and further verify this regulatory mechanism in cancer cells. Then we will elucidate its effects in cell proliferation, apoptosis, migration and invasion in colorectal cancer cell lines and in nude mice. Finally, we will examine the levels of lncRNA-CRCAL in plasma samples of colorectal cancer patients and healthy controls as well as in cancerous and the corresponding normal tissues of patients with colorectal cancer. Overall the purpose of this study is to investigate the regulatory mechanism of lncRNA-CRCAL in colorectal cancer development and evaluate its potential capacity in disease prognosis.

结直肠癌是目前世界上最常见的恶性肿瘤之一，发病率呈逐年上升趋势，约有20%的新发结直肠癌病例在确诊时已发生远处转移。因此，发现其早期诊断标志物及研究其发病机制具有重要临床价值。lncRNA被发现在肿瘤发生发展中发挥重要调控作用，参与诸多肿瘤生物学过程。本课题组前期通过公共数据库和生物信息学分析，发现一个全新的在结直肠癌组织中显著高表达的lncRNA-CRCAL，并利用数字PCR检测发现其在结直肠癌患者血浆外泌体中呈显著高表达。我们另外发现CRCAL受到p53的调控作用，并可与GRWD1蛋白结合，推测以此影响p53通路活性，并与p53形成反馈调节回路。本课题拟采用数字PCR方法明确血浆外泌体源性CRCAL在诊断结直肠癌中的临床价值，系统性的探索CRCAL在结直肠癌中的生物学功能并研究其参与调控肿瘤恶性表型的具体机制，为结直肠癌的早期诊断提供新的标志物，为阐明结直肠癌的发病机制提供新线索。

结直肠癌是目前世界上第三大常见癌症，也是人类最致命的恶性肿瘤之一。揭示结直肠癌潜在的分子机制并寻找新的治疗和预后靶标对于结直肠癌患者的治疗至关重要。Lnc RNA是长度大于200核苷酸的非编码RNA，在肿瘤的发生、发展等各个阶段发挥着重要的作用。本项目在前期基础上，明确lncRNA PiHL（CRCAL）在结直肠癌组织高表达，揭示PiHL通过依赖或者部分依赖野生型p53蛋白的方式促进结直肠癌细胞的增殖、促进细胞在S期的积累，抑制细胞的凋亡；同时，在动物水平验证PiHL以p53依赖的方式调控结直肠癌进展；验证了PiHL结合GRWD1蛋白、RPL11蛋白在结直肠癌进展中的发挥作用。并结合研究发现，明确 PiHL 参与结直肠癌细胞奥沙利铂耐药，探讨PiHL参与结直肠癌细胞奥沙利铂耐药机制。本研究有助于进一步认识结直肠癌的分子机制，为结直肠癌的防治提供新的实验依据和理论基础。