长非编码RNA DTS1通过调控SMARCA5蛋白促进胃癌细胞进入药物耐受状态的机制研究

进入药物耐受状态（drug-tolerant state, DT状态）促使癌细胞通过多样的机制获得稳定耐药能力。但与这一状态相关的基因表达调控过程仍然不清楚。长非编码RNA（long noncoding RNA, lncRNA）能够在基因表达调控的各个层面以灵活多样的机制发挥调控作用。在前期工作中，我们发现lncRNA DTS1（Drug-tolerant state associated lncRNA 1）对于胃癌细胞进入DT状态至关重要。过表达DTS1能够增加DT状态细胞的形成，而下调DTS1表达则能够抑制细胞进入DT状态。并且，DTS1很可能通过结合并调控SMARCA5蛋白——多种染色质重塑复合物的催化亚基而发挥作用。本项目拟通过深入研究以DTS1和SMARCA5蛋白为核心的基因表达调控通路，增加对DT状态相关的基因表达调控过程的认知，为胃癌的药物治疗提供新的思路。

Drug-tolerant state is a transition process through which cancer cells ultimately acquire stable drug resistance through diverse mechanisms. However, the mechanisms of gene regulation underlying the process remain largely unknown. Long noncoding RNA (lncRNA), a key regulator of gene expression, plays crucial roles in multiple steps of gene regulation by diverse mechanisms. By analyzing drug-tolerant gastric cancer cells with whole transcriptome RNA-seq, we found that the expression of lncRNA DTS1 (Drug-tolerant state associated lncRNA 1) was activated under drug-tolerant state, and overexpression of DTS1 increased the formation of drug-tolerant cells while knockdown of DTS1 prevents cells from entering drug-tolerant state. Moreover, DTS1 is likely to exert its function by modulating SMARCA5 protein- a catalytic subunit of multiple chromatin-remodeling complexes. In this project, we are going to reveal the gene regulatory network of DTS1 and SMARCA5 in the drug-tolerant state of gastric cancer cells, which will contribute to our understanding of drug-tolerant state and be meaningful for drug treatment in gastric cancer.