Identification and Validation a Necroptosis‑related Prognostic Signature and Associated Regulatory Axis in Stomach Adenocarcinoma

Background: Gastric cancer (GC) ranks fifth in global cancer incidence and third in cancer-related mortality. The prognosis of GC patients was poor. Necroptosis is a type of regulated cell death mediated by RIP1, RIP3, and MLKL. Necroptosis was found to be involved in antitumor immunity in the cancer immunotherapy.

Methods: LASSO Cox regression analysis was performed to construct a prognostic signature. Bioinformatics analysis was performed to construct a lncRNA-miRNA-mRNA regulatory axis. qRT-PCR was performed to verify the expression and prognosis of hub gene in STAD.

Results: Most of necroptosis regulators were upregulated, while the mRNA level of TLR3, ALDH2, and NDRG2 was downregulated in STAD versus gastric tissues. The genetic mutation and copy number variation of necroptosis regulator in STAD were also summarized. GO and KEGG pathways analysis revealed that these necroptosis regulators were mainly involved in programmed necrotic cell death and TNF signaling pathway. A necroptosis‑related prognostic signature based on four genes (EZH2, PGAM5, TLR4, and TRAF2) had a good performance in predicting the prognosis of STAD patients. We also identified lncRNA SNHG1/miR-21-5p/TLR4 regulatory axis in the progression in STAD. Verification study suggested that the hub gene TLR4 upregulated in STAD and correlated with a poor overall survival. Moreover, Cox regression analysis revealed that TLR4 expression and clinical stage were independent factors affecting the prognosis of STAD patients.

Conclusion: We performed a comprehensive bioinformatics analysis and identified a necroptosis‑related prognostic signature and a lncRNA SNHG1/miR-21-5p/TLR4 regulatory axis in STAD. Further study should be performed to confirm our result.