长链非编码RNA-CCPLINC抑制大肠癌的转移及机制研究

Colorectal cancer is a very common cancer with high morbidity and mortality. Long non coding (lnc) RNA plays a vital role in human cancer initiation and development. Recently, competing endogenous RNA has drawn much attention—lncRNA regulates mRNA through competitively binding to common miRNAs. Our previous data demonstrated that lncRNA-BX648207 significantly correlated with the survival of colorectal cancer patients, thus we named it CCPLINC(colorectal cancer predictive long intergenic non coding RNA). CCPLINC was down regulated in colorectal cancer tissues, and it suppressed the proliferation and invasion of colorectal cancer cells. CCPLINC could inhibit the expression of miR-19a-5p, which was associated with colorectal cancer metastasis, and correlated with the expression of target gene PTEN. Therefore, we hypothesize that "CCPLINC-miR-19a-5p-PTEN" mode could suppress colorectal cancer metastasis. We will discuss the anti-metastasis function of CCPLINC in colorectal cancer, demonstrate the way that CCPLINC actively compete with PTEN for miR-19a-5p, analysize the significance of CCPLINC in clinical diagnosis and treatment in vitro, in vivo experiments and patient samples.

大肠癌的发生率和死亡率居高不下。长链非编码(long non coding, lnc)RNA 在人类肿瘤的进展中扮演重要角色。近年来竞争性内源RNA受到关注——lncRNA与mRNA竞争结合miRNA，从而相互调控。我们前期研究中发现lncRNA-BX648207的表达与大肠癌的预后显著相关，因此将其命名为CCPLINC。CCPLINC在大肠癌组织中表达下降，并显著抑制大肠癌细胞的增殖和侵袭能力。CCPLINC表达升高可下调大肠癌转移相关miR-19a-5p，CCPLINC与靶基因PTEN的表达呈正相关性。因此我们提出“CCPLINC-miR-19a-5p-PTEN”的调控模式可抑制大肠癌转移。本研究将从细胞实验、临床标本和动物实验等方面探讨CCPLINC抑制大肠癌转移的功能，阐明CCPLINC与PTEN竞争结合miR-19a-5p的确切方式，并分析CCPLINC作为临床诊治新靶点的意义。

大肠癌是一个关键社会问题，居世界癌症相关死亡率的第三位。长链非编码（long non-coding，lnc）RNA在人类肿瘤的发生发展和化疗耐药中发挥重要作用。我们前期通过基因表达谱数据库分析表明lncRNA-BX648207与大肠癌预后良好相关，因此我们将其命名为大肠癌预后相关长链非编码RNA（colorectal cancer predictive long intergenic non coding RNA）。.在癌症组织中，肿瘤细胞被一群其他细胞，比如肿瘤相关成纤维细胞及淋巴细胞包绕，这些非肿瘤细胞构成了一个肿瘤微环境，并且不同种类细胞之间通过各种方式相互作用，最终影响肿瘤的生长，转移和对化疗的反应。此课题着重研究CCPLINC如何影响肿瘤细胞的恶行行为及肿瘤微环境细胞之间的相互作用。通过原位杂交技术我们发现CCPLINC主要在肿瘤细胞中表达，CCPLINC与大肠癌病人良好预后相关。肿瘤细胞中CCPLINC的低表达会抑制T淋巴细胞的增殖并增加调节性T细胞的比例，从而抑制肿瘤免疫。我们同时显示lncRNA关键上游调控基因p53突变体可通过上调ERP29的表达从而导致肿瘤化疗耐药。