SEC23A confers ER stress resistance in gastric cancer by forming the ER stress-SEC23A-autophagy negative feedback loop

BackgroundSec23 homolog A (SEC23A), a core component of coat protein complex II (COPII), has been reported to be involved in several cancers. However, the role of SEC23A in gastric cancer remains unclear.MethodsThe expression of SEC23A in gastric cancer was analyzed by using qRT-PCR, western blotting and IHC staining. The role of SEC23A in ER stress resistance was explored by functional experiments in vitro and vivo. The occupation of STAT3 on the SEC23A promoter region was verified by luciferase reporter plasmids and CHIP assay. The interaction between SEC23A and ANXA2 was identified by Co-IP and mass spectrometry analysis.ResultsWe demonstrated that SEC23A was upregulated in gastric cancer and predicted poor prognosis in patients with gastric cancer. Mechanistically, SEC23A was transcriptional upregulated by ER stress-induced pY705-STAT3. Highly expressed SEC23A promoted autophagy by regulating the cellular localization of ANXA2. The SEC23A-ANXA2-autophay axis, in turn, protected gastric cancer cells from ER stress-induced apoptosis. Furthermore, we identified SEC23A attenuated 5-FU therapeutic effectiveness in gastric cancer cells through autophagy-mediated ER stress relief.ConclusionWe reveal an ER stress-SEC23A-autophagy negative feedback loop that enhances the ability of gastric cancer cells to resist the adverse survival environments. These results identify SEC23A as a promising molecular target for potential therapeutic intervention and prognostic prediction in patients with gastric cancer.

Automated summary

SEC23A is upregulated in gastric cancer and indicates poor prognosis. It promotes autophagy by regulating ANXA2 cellular localization, and protects gastric cancer cells from ER stress-induced apoptosis. Moreover, SEC23A attenuates the effectiveness of 5-FU therapy in gastric cancer cells through autophagy-mediated ER stress relief. These findings suggest SEC23A as a potential therapeutic target and prognostic predictor in gastric cancer.