化疗耐药仍是胃癌等恶性肿瘤临床治疗失败的主要原因，长链非编码RNA(lncRNA)参与调控基因表达及代谢重编程等诸多分子事件，但其在耐药中的作用及其机制仍需深入探讨。Linc00942在胃癌耐药细胞中高表达；活化细胞自噬可下调其表达；自噬调控蛋白p62结合并招募linc00942进行自噬依赖性降解；敲减Linc00942的表达可促进MSI2蛋白的蛋白酶体依赖性降解，并逆转胃癌化疗耐药。因此，我们推测受细胞自噬性降解调控的linc00942可能通过结合并抑制MSI2的泛素化依赖性降解来促进胃癌化疗耐药。本项目拟通过分析细胞自噬调节linc00942代谢稳态平衡的作用及其机制，探索linc00942影响MSI2蛋白表达的分子机理，解析linc00942在胃癌化疗耐药中的调控功能及机制，从而揭示非编码RNA代谢稳态的新调控方式及胃癌化疗耐药的本质和规律，为改善胃癌临床诊治提供科学依据和理论支撑。

Chemoresistance remains the uppermost disincentive for cancer treatment. However, the functions of long non-coding RNAs (lncRNAs) in chemoresistance are largely unclarified. We screened chemoresistance-related lncRNAs in preliminary investigations and identified Linc00942, as one of the most upregulated lncRNA. Knockdown of its expression restored the sensitivity to multiple chemotherapeutic drugs such as cisplatin, doxorubicin and 5-fluorouracil. As we previously reported, autophagy was blocked in chemoresistant gastric cancer cells. Interestingly, autophagy activation reduced Linc00942 expression. SQSTM1/p62, the critical adaptor protein to transport cargoes to-be-degraded to autophagosomes, directly bound to Linc00942 and promoted its RNautophagy-dependent degradation. Moreover, we identified MSI2 as one downstream protein target interacted with Linc00942 by antibody array-based screening. Knockdown of Linc00942 expression activated ubiquitination-dependent proteasomal degradation of MSI2 protein, eventually promoting chemoresistance. Therefore, we postulated that.RNautophagy-dependent degradation of Linc00942 restores chemoresistance by derepressing ubiquitination dependent degradation of MSI2 protein. To prove it, we will perform a serial of experiments to analyze the regulation of linc00942 homeostasis by autophagy, the influence of Linc00942 on ubiquitination dependent degradation of MSI2 protein and their relevance to chemoresistance. By doing so, we believe that the project will provide a deeper insight to understand chemoresistance and novel rational foundation to improve the clinical efficacy of chemotherapy for gastric and probably other cancers.