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Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies. [ABSTRACT FROM AUTHOR]

The emergence of multiple drug resistance (MDR) is the main cause of chemotherapy failure in gastric cancer. In this study, to generate MDR gastric cancer cell lines, we exposed MKN45 and AGS gastric cancer cells to cisplatin, fluorouracil, and adriamycin. Through transcriptome sequencing, we found that interferon regulatory factor-1 (IRF-1) was expressed at significantly lower levels in the MDR cell lines than in the parental cell lines. We then established stable clones of MKN45 and SGC7901 cells with a doxycycline-inducible IRF-1 expression system and confirmed that IRF-1 overexpression efficiently reversed the MDR. Further analyses indicated that IRF-1 suppresses P-glycoprotein (P-gp) expression in vitro and in vivo, leading to an increase in chemotherapy drug retention. The results showed that IRF-1 bound to the promoter regions of P-gp gene and inhibited P-gp transcription. IFN-γ induced IRF-1-mediated downregulation of P-gp in gastric cancer cells. Finally, we demonstrated that the clinical correlation between IRF-1 and P-gp expression and that IRF-1 serves as an independent prognostic factor for patients with gastric cancer. We conclude that IRF-1 reverses the MDR trait of gastric cancer by downregulating P-gp, and this mechanism has potential treatment implications and is clinically actionable. [ABSTRACT FROM AUTHOR]