Abstract 176P
Background
This study aims to systematically explore the specific functions and potential mechanisms of DHX9 in the development of gastric cancer (GC), assess the clinical application value of DHX9 and its target genes as new therapeutic targets for GC.
Methods
This study identified differentially expressed transcriptional regulators in 94 cases of GC and adjacent tissues. By constructing GC cell lines with stable knockdown and overexpression of DHX9, we studied the key roles of DHX9 in malignant phenotypes such as cell proliferation, cell cycle, apoptosis, migration, and invasion. Rescue experiments were conducted to verify the potential mechanisms of DHX9 and its target genes in the development of GC. Furthermore, we evaluated the anti-tumor effects and safety of inhibitors in GC cell and cell-derived xenografts.
Results
In the present study, we found that the expression of the transcriptional regulator DHX9 was significantly higher in GC tissues than in adjacent tissues (p = 2.7e-8). The difference in expression was more pronounced in signet ring cell carcinoma (p = 0.013) and was closely associated with poor prognosis (p = 0.049). ChIP sequencing results showed that DNA binding sites of DHX9 included genes such as TRIM73, MICA and AURKA. KEGG analysis indicated that the differentially expressed genes were mainly enriched in TNF, PI3K-Akt and thyroid hormone synthesis signaling pathways. Overexpression of DHX9 in AGS cell line significantly upregulated 379 genes, including SNORD3C, EID3 and AURKA. Further rescue experiments and western blot analysis confirmed that DHX9 and AURKA exerted pro-proliferative and anti-apoptotic effects by activating PI3K/AKT and TNF signaling pathways. Moreover, animal experiments showed that overexpression of DHX9 significantly enhanced the tumorigenic capacity of cell line-derived xenografts.
Conclusions
This study reveals that high expression of DHX9 in GC is significantly associated with poor prognosis. DHX9 exerts pro-cancer effects by regulating the expression of AURKA and subsequently activating downstream PI3K/AKT and TNF signaling pathways. DHX9 and AURKA can serve as novel biomarkers for GC survival and prognosis, and provide potential therapeutic targets for GC patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.