Defining the Role of Sphingosine Kinase 2 (SphK2) in Gastric Signet Ring Cell Carcinoma (GSRCC)

Gastric signet ring cell carcinoma (GSRCC) is a particularly aggressive subtype of gastric cancer (GC) that is defined by its distinct signet ring cell morphology. GSRCC is associated with being more common in younger patients, its advanced stages by the time of diagnosis, and a poor prognosis compared to other GC subtypes. Additionally, GSRCC is somewhat resistant to standard chemotherapy treatments, highlighting the need for novice approaches to its treatment. Sphingosine kinase 2 (SphK2), a tumor promoting enzyme has emerged as a potential therapeutic target due to its role in boosting cancer cell proliferation, migration, and survival. This study aimed to investigate the role of SphK2 in GSRCC using shRNA-mediated knockdown (KD). We generated stable SphK2 KD AGS and KATO III GSRCC cell lines using lentiviral shRNA transduction. The efficacy of shRNA targeting was confirmed by antibiotic screening and western blot analysis, demonstrating a significant reduction in SphK2 protein levels. The effects of SphK2 loss on cell proliferation, migration, and invasion were assessed using in vitro assays, including MTT assays to measure cell viability and proliferation, wound healing assays to evaluate cell migration, and transwell assays to assess invasive capacity. Our results demonstrate that SphK2 loss significantly reduces GSRCC cell proliferation, migration, and invasion compared to control cells. These findings highlight the potential of targeting SphK2 as a novel therapeutic strategy for GSRCC, warranting further investigation into the efficacy of SphK2 inhibitors, such as Opaganib, in preclinical and clinical settings.