Background: Gastric cancer (GC) is one of the most common cancers and the second leading cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) are associated with GC development and progression. However, the functional roles and underlying mechanism of LINC01433 on GC progression remain elusive.
Methods: Firstly, the expression of LINC01433 was examined in 76 pairs of primary GC and corresponding adjacent non-tumorous tissues. Next, overexpression and knockdown experiments were conducted in GC cells to explore the effect of LINC01433 on the malignant behaviors of GC cells. Then, the interaction between LINC01433 and YAP was detected by RNA immunoprecipitation (RIP) and RNA pull-down assays.
Results: We found that LINC01433 was significantly upregulated in GC tissues and cell lines and correlated with poor prognosis. Through gain- and loss-of-function experiments, we demonstrated that LINC01433 promoted proliferation, migration, invasion and chemotherapy resistance in GC cells. Further mechanistic investigation revealed that LINC01433 could stabilize oncoprotein YAP through enhancing the interaction between deubiquitinase USP9X and YAP. LINC01433 decreased the phosphorylation of YAP via suppressing YAP-LATS1 association. Intriguingly, YAP directly bound to LINC01433 promoter region and activated its transcription. Thus, LINC01433 and YAP formed a positive feedback loop.
Conclusion: Collectively, our study demonstrates that the positive feedback loop between LINC01433 and YAP promotes GC progression, and implies that the LINC01433-YAP feedback loop may be a promising therapeutic target for GC treatment.
Keywords: protein stability, USP9X, YAP, LATS1