C15orf39, a downstream effector of PI3K/AKT signaling, promotes gastric carcinogenesis and correlates with patient outcomes.

The phosphatidylinositol-3-kinases (PI3K) signaling pathway is highly complex and well-known to exert oncogenic roles in multiple cancer types. Exploring new factors involved in this pathway may offer the potential for improving the early diagnosis and treatment strategies for cancers. Here we used gastric cancer (GC) as a model to identify co-regulated effectors downstream of three catalytic subunits of PI3K through high-throughput sequencing in PIK3CA, PIK3CB, and PIK3CD knockdown GC cells. C15orf39, a new uncharacterized gene, was selected due to the most significant expression change. qRT-PCR and immunohistochemistry analyses revealed that C15orf39 was frequently upregulated in GC tissues and strongly correlated with poor clinical outcomes in GC patients. Gain- and loss-of-function studies demonstrated that C15orf39 promoted GC cell proliferation, migration, and drug resistance. Mechanistically, C15orf39 promoted GC progression possibly via modulating cell mitosis and cell cycle. FOXK2, a transcription factor activated by PI3K/AKT signaling, could bind to the promoter of C15orf39 and positively regulate C15orf39 expression. These findings unveiled a new PI3K/AKT/FOXK2/C15orf39 signaling axis that promotes GC development and progression. C15orf39 may become a potential biomarker for early diagnosis and personalized treatment to improve the prognosis of GC patients.