SP1-Induced LncRNA ZFAS1 Contributes to Cell Proliferation and Migration in Gastric Cancer through AKT/mTOR Signaling.

Background:

Objectives: This study aimed to investigate the role of lncRNA ZFAS1 in gastric cancer progression, focusing on its regulation by SP1 and its impact on the AKT/mTOR signaling pathway. By exploring ZFAS1's effects on cell proliferation, migration, and apoptosis, we sought to uncover its molecular mechanisms and potential as a therapeutic target.

Materials and methods: We evaluated ZFAS1 expression in gastric cancer cells (SGC7901) by RT-qPCR and compared it with GES-1 cells. The LnCAR database provided insight into ZFAS1 levels in STAD compared to normal tissue. To knockdown ZFAS1 in SGC7901 cells, we transfected the cells with si-ZFAS1 #1-3 (small interfering RNAs targeting ZFAS1), and si-ZFAS1-2 was found to have the highest knockdown efficiency. Then, the effect of ZFAS1 knockdown on cell invasion, migration and proliferation was evaluated using transwell invasion, wound healing assays, CCK8 and flow cytometry. In addition, ZFAS1 promoter regions were examined using the JASPAR database and subsequent ChIP assays to understand SP1 transcription factor binding. The effect of ZFAS1 on the AKT/mTOR pathway was clarified using Western blotting.

Results: SGC7901 cells were shown to have increased ZFAS1 expression, which was linked to a poor prognosis for gastric cancer. Knockdown of ZFAS1 in SGC7901 cells inhibited cell invasion, migration and proliferation and induced apoptosis. In addition, SP1 was found to upregulate ZFAS1 transcription by binding to its promoter region. ZFAS1 knockdown resulted in a significant reduction of AKT/mTOR pathway components, including p-AKT, AKT, p-mTOR, and mTOR. When the AKT activator SC79 was introduced, the repressive effects of ZFAS1 knockdown on cell invasion, migration, proliferation, and AKT/mTOR signaling were partially reversed.

Conclusions: Our results highlight the pivotal role of ZFAS1 in gastric cancer cell malignancy, which inhibits the activation of the AKT/mTOR pathway. The regulatory involvement of SP1 in ZFAS1 transcription provides a novel understanding of the molecular mechanisms driving cancer progression and offers potential therapeutic avenues by suggesting that further research could focus on developing targeted therapies that modulate ZFAS1 expression or activity, which may lead to more effective treatment options for gastric cancer patients in the future.