Abstract
Abstract
Stomach adenocarcinoma is among the most prevalent malignant gastrointestinal tumors worldwide. Ferroptosis, a relatively new form of programmed cell death, has garnered significant attention for its role in cancer molecular mechanisms and therapeutic strategies. Therefore, it is particularly important to explore the mechanism of key molecules in ferroptosis in stomach adenocarcinoma. In our study, CUGBP Elav-like family member 2 (CELF2) was identified as being lowly expressed in stomach adenocarcinoma tumor tissues at both the mRNA and protein levels. Next, CELF2 effectively inhibited the growth and migration of stomach adenocarcinoma cells both in vitro and in vivo. RNA sequencing (RNA-seq) analysis of AGSCELF2 and AGSNC cells showed that the functions of differentially expressed genes were enriched in the glutathione metabolism and ferroptosis pathways. CELF2 increased the levels of key ferroptosis markers, including reactive oxygen species, malondialdehyde, Fe2+, and 4-hydroxynonenal, while reducing glutathione levels. Furthermore, CELF2 enhanced the susceptibility of stomach adenocarcinoma tumor cells to ferroptosis. Interestingly, the expression levels of CELF2 and solute carrier family 7 member 11 (SLC7A11) were negatively correlated in RNA-seq data and The Cancer Genome Atlas database. RNA immunoprecipitation and RNA pull-down assays confirmed the interaction between CELF2 and SLC7A11. Overexpression (OE) of SLC7A11 reversed the effects of CELF2 on stomach adenocarcinoma growth and ferroptosis levels. Moreover, the ferroptosis inhibitor ferrostatin-1 effectively rescued the inhibitory effect of CELF2 OE on the proliferation of tumor cells. CELF2 is a tumor suppressor that promotes the level and susceptibility of ferroptosis in stomach adenocarcinoma cells by targeting SLC7A11.
Implications:
This study offers valuable molecular insights for the development of ferroptosis-targeted therapies for stomach adenocarcinoma.