lncRNA-COL1A1-014调控CXCL12-CXCR4及TAMs参与胃癌进程的作用及分子机制研究

The lack of clear molecular markers and drug targets lead to diffiulty early diagnosis and intervention of gastric adenocarcinoma.We focused the changes of mRNA and non-coding RNA (ncRNA) expression level in the development of gastric adenocarcinoma, hoping to find biomarkers for early diagnosis and targets for intervention therapy of gastric adenocarcinoma. Through the screening of lncRNA, microRNAs, and mRNA related to gastric adenocarcinoma using gene chip technology, after the preliminary verification on the clinical samples and cells, we have summarized COL1A1-014 is overexpression in gastric tissues and cells, COL1A1-014 canregulate its target genes CXCL12 based on ceRNA mechanism in gastric adenocarcinoma, they are closely related to the occurrence and development process and gastric cancer.This project is based on our previous study and the latest research progression, CXCL12 could regulate TAMs in tumor microenvironment of gastric cancer and downstream effector molecules, to reveal the molecular mechanism of COL1A1-014 targeted CXCL12-CXCR4 biological axis, regulating the TAMs and downstream effector molecules in microenvironment of gastric cancer, from the perspective of endogenous competition process, to clarify the biological function of COL1A1-014 in gastric carcinoma. The study is expected to find potential biomarkers for the diagnosis and prognosis of gastric cancer, as well as drug targets.

胃癌由于缺乏明确的分子标志物及药靶导致早期诊断和干预困难。课题组在胃癌生物标志物及治疗靶标方面，针对胃癌发生发展进程中基因谱及非编码RNA（ncRNA）表达水平的变化进行研究，发现lncRNA COL1A1-014在胃癌组织和胃癌细胞中显著异常高表达，并可通过内源性竞争机制靶向调控胃癌细胞中趋化因子CXCL12的表达，与胃癌发生发展进程密切相关。本项目在课题组前期研究的基础上，结合国内外关于CXCL12可通过调控胃癌微环境中肿瘤相关巨噬细胞（TAMs）及下游效应分子的最新研究进展，拟探索COL1A1-014靶向调控胃癌中CXCL12-CXCR4生物学轴、调节胃癌微环境中TAMs及血管生成参与胃癌进程的分子机制，阐明COL1A1-014在胃癌进程中的功能及作用。研究有望发现胃癌潜在的诊断和预后生物标志物及药物治疗靶标。

胃癌是全球范围内最常见的恶性肿瘤之一，在东亚尤其高发，病例总数约占全球的50%，胃癌的治疗靶点研究迫在眉睫。巨噬细胞是胃癌微环境的重要组成部分，其中，M2 型巨噬细胞可通过降低炎症反应，促进血管发生等促进肿瘤进程，被称为肿瘤相关巨噬细胞（TAMs）。本项目探索了长链非编码RNA （lncRNA）COL1A1-014靶向调控胃癌中CXCL12-CXCR4生物学轴、调节胃癌微环境中TAMs参与胃癌进程的分子机制。研究发现，COL1A1-014在胃癌中显著高表达，其可能通过竞争性结合miR-1273h-5p，间接抑制靶基因CXCL12表达参与胃癌进程；COL1A1-014在体外可以显著促进胃癌细胞增殖、凋亡、克隆形成能力以及迁移、侵袭，在体内可促进裸鼠移植瘤生长。miR-1273h-5p作为COL1A1-014的microRNA反应元件（MREs），在胃癌中的表达水平显著降低，并具有抑癌基因的作用；COL1A1-014的靶基因CXCL12可促进M2型巨噬细胞在胃癌中的募集，显著减低M1型巨噬细胞激活因子IL-12水平，升高M2型巨噬细胞激活因子IL-4、IL-10、TGF-β水平，促进胃癌中M2型巨噬细胞的分化。此外，靶向胃癌中非编码RNA及其相关生物轴开展了小分子化合物的筛选研究，发现了血根碱（SAN）等小分子化合物在胃癌治疗中具有较好的潜力。本项目阐明了COL1A1-014/miR-1273h-5p/CXCL12-CXCR4生物轴在胃癌进程中的功能及作用，为胃癌潜在的诊断和预后生物标志物及药物治疗靶标研究提供了重要线索。