LncRNA CCAT2通过调控CD44的剪接模式影响胃癌细胞的表型改变及其在胃癌进展中的作用

胃癌是严重威胁我国民众健康的重大疾病，CD44作为肿瘤干细胞(CSCs)的标志物之一，其功能调控在胃癌发生发展中发挥着重要作用。前期工作中我们筛选获得了5个在胃癌中高表达且具有临床诊断功能的LncRNA分子。生物信息学结果显示其中的CCAT2可能是CD44的上游作用元件，CCAT2通过影响CD44的剪接模式及亚型分布，调控胃癌细胞的生物学性状和命运转归。本研究将围绕CCAT2/ESRPs/CD44v通路展开研究，构建胃癌相关LncRNA调节网络，探寻影响胃癌病程动态演化的关键靶标分子；以其为切入点，从多个维度干扰胃癌细胞的生物学行为，并最终达到消灭胃癌肿瘤干细胞(GCSCs)，减轻肿瘤负荷的目的。研究结果在理论和技术上的突破将为重新认识胃癌转移、复发提供新的思路，同时也为胃癌早期诊断，筛选治疗策略、评估预后等提供更多的理论依据。

Gastric cancer (GC) serves as a kind of regional diseases, which has posed severe threatens to health of Chinese individuals and exerted great burdens to the development of society and economy. Despite amazingly rapid development of diagnostic and therapeutic methods, existing clinical regimens remain unsatisfactory. Diagnosis and intervention at early stage will play the vital roles in controlling the mortality of GC, so it is considerably urgent to explore diagnostic biomarkers and individual therapeutic targets with optimal clinical values. CD44, a classical biomarker of gastric cancer stem cells (GCSCs), has been proved to act as an important role in the genesis and development of GC. Additionally, various CD44 isoforms have their own regulatory mechanisms and potential application in GC. Previously, we screened out five long non-coding RNAs (LncRNAs) with high expressions in blood. The optimal performance of this diagnostic panel endows lncRNAs with excellent potential of clinical translation. LncRNA CCAT2, one of the five lncRNAs, was significantly correlated with multiple clinicopathological characteristics, which preliminarily indicated the close relationship between CCAT2 and GC development. Further bioinformatics analysis revealed that CCAT2 might be an upstream regulating element of CD44. Another study showed that unbalance of CD44 and microRNA facilitated the conversion of GC cells to GCSCs. Therefore, the scientific question is that CCAT2 can regulate biological characteristics, fate determination and stemness maintenance of GC cells through influencing splicing methods and isoform distribution of CD44. Appropriate interference of CCAT2 may lead to changes of CD44 isoforms, reversing the rapid process of malignancy. This conversion may also reduce chances of metastasis and resistance caused by GCSCs to maximize the efficacy of adjuvant therapy. This study focuses on CCAT2/ESRPs/CD44v pathway in GC. Construction of the lncRNA network will contribute to the detailed identification of mechanisms concerning cancer genesis and development. We aim to find the critical molecules in GC. The interference of these targets may inhibit the biological characteristics through multiple ways, eliminating GCSCs and alleviating cancer burdens. Our study strives to scientifically combine the basic researches with clinical practice. The theoretical and technological breakthrough will broaden horizons of origins of GC metastasis and recurrence. Meanwhile, these achievements will provide solid foundation for early diagnosis, selection of therapeutic regimens and prognostic evaluation.