长链非编码RNA-CTSLP4异常低表达促进胃癌侵袭转移的作用及其分子调控机制研究

Abnormal expression of long non-coding RNA is closely related to tumor progression. Previously, we found that HP infection resulted in the downregulated expression of LncRNA-CTSLP4 in gastric cancer, and overexpression of LncRNA-CTSLP4 inhibited the ability of invasion and metastasis of gastric cancer cells. LncRNA-CTSLP4 can bind to HSP90a and participate in the regulation of EGFR and AKT expression and activation. Based on the previous work, we propose the following hypothesis: CagA from HP inhibits the expression of LncRNA-CTSLP4 by activation of FOXA1 in gastric cancer cells. The downregulated expression of LncRNA-CTSLP4 results in a decrease of LncRNA-HSP90a complex and an increase of FOXK1 targeted gene-EGFR, which leads to an excessive activation of the AKT/NF-kB pathway that promotes the metastasis of gastric cancer. This study aims to: 1. analyze the expression of LncRNA-CTSLP4 in gastric cancer tissues and the clinical significance; 2. define the role of LncRNA-CTSLP4 in gastric cancer progression; 3. illustrate the mechanism and structure basis of LncRNA-CTSLP4 in gastric cancer cells; 4. explore the mechanism underlying the downgregulated expression of LncRNA-CTSLP4 in gastric cancer. Thus, our study clarifies the role of LncRNA-CTSLP4 in gastric cancer progression, and further annotated the genome structure and function from the perspective of RNA, and these findings should thereby ultimately contribute to the development of novel idea and target for clinical treatment of gastric cancer metastasis.

长链非编码RNA的表达异常与肿瘤进展密切相关。我们前期发现HP感染诱导胃癌中LncRNA-CTSLP4低表达；CTSLP4过表达后抑制胃癌细胞侵袭转移；CTSLP4与HSP90a结合调控EGFR和AKT表达和活化。在前期基础上，我们提出如下科学假说：胃癌中HP来源的CagA蛋白激活FOXA1，抑制CTSLP4表达，竞争性结合HSP90a减少，HSP90a与FOXK1形成复合体，FOXK1降解减少和靶基因EGFR合成增多，导致AKT/NF-κB通路的过度激活，促进胃癌转移。本项目将探讨1.胃癌组织中CTSLP4的表达和临床意义；2.CTSLP4在胃癌进展中的作用；3.CTSLP4的作用机制和结构基础；4.胃癌中CTSLP4低表达的调控机制。通过以上研究进一步阐明CTSLP4在胃癌进展中的作用和调控机制，从RNA的角度注释基因组的结构与功能，并为临床胃癌转移的防治提供一种新的思路和靶点。

长链非编码RNA(Long non-coding RNA, LncRNA)是一类调控型大分子非编码RNA，其表达异常与肿瘤进展密切相关。本项目研究发现：1.Lnc-CTSLP4在胃癌组织和胃癌细胞中表达显著低于对应癌旁非肿瘤组织及永生化胃上皮细胞，胃癌组织中Lnc-CTSLP4表达水平与肿瘤浸润深度，有无淋巴结转移以及TNM分期呈负相关，且Lnc-CTSLP4的低表达与胃癌患者的不良预后密切相关。2.Lnc-CTSLP4可以抑制胃癌细胞的体外侵袭、迁移、上皮-间充质转化和小鼠腹腔种植与播散能力。3.Lnc-CTSLP4可以与Hsp90α结合，进而阻断Hsp90α与HNRNPAB的结合，促进HNRNPAB的泛素化降解。4.HNRNPAB可以结合Snail的启动子区域并促进Snail的转录，促进胃癌细胞的上皮-间充质转化。5.HNRNPAB在胃癌组织高表达，与胃癌患者不良预后密切相关。6.幽门螺杆菌感染激活FOXA1抑制胃癌细胞中LncRNA-CTSLP4异常低表达。该项目研究结果揭示了LncRNA-CTSLP4通过结合Hsp90α阻断HNRNPAB/Snail信号通路抑制胃癌转移的作用机制及其低表达的调控机制，为临床上对胃癌转移进行防治提供新的靶点。