SNORA71A Downregulation Enhances Gemcitabine Sensitivity in Gallbladder Cancer Cells by Inducing Ferroptosis Through Inhibiting the AKT/NRF2/GPX4 Pathway.

Abstract

Previous findings have indicated a marked upregulation of SNORA71A in gallbladder cancer (GBC) tissues compared to normal samples. However, the precise role and molecular mechanisms of SNORA71A in GBC remain largely unknown. Moreover, gemcitabine (GEM) drug resistance has been found to lead to unfavorable outcomes and recurrence in GBC patients. Therefore, this study aims to investigate the impact of SNORA71A on GBC and explore its potential effects on the sensitivity of GBC cells to GEM. RT-qPCR was conducted to assess SNORA71A level in matched normal and GBC tissues. Cell proliferation was examined through CCK-8 and 5-ethynyl-2'-deoxyuridine (EdU) assays. Additionally, the expression of proteins in GBC cells was analyzed using western blot assay. The level of SNORA71A was notably higher in GBC tissues relative to normal tissues. SNORA71A overexpression led to increased GBC cell proliferation and invasion. Conversely, SNORA71A deficiency strongly suppressed GBC cell proliferation and invasion and triggered cell apoptosis and ferroptosis. Additionally, downregulation of SNORA71A obviously enhanced the antiproliferative and anti-invasive effects of GEM on GBC cells, whereas these changes were reversed by inhibiting ferroptosis. Furthermore, deficiency of SNORA71A further augmented the GEM-induced downregulation of p-Akt, Nrf2, and GPX4 in NOZ cells; however, these effects were reversed by ferroptosis inhibition. Collectively, these findings suggested that downregulation of SNORA71A may increase the sensitivity of GBC cells to GEM by triggering ferroptosis through inhibiting the AKT/NRF2/GPX4 signaling pathway.