TRPC3 promotes tumorigenesis of gastric cancer via the CNB2/GSK3β/NFATc2 signaling pathway

The transient receptor potential canonical (TRPC) channels have been implicated in various types of malignancies including gastric cancer (GC). However, the detailed mechanisms of TRPC channels underlying cell proliferation and apoptosis of GC cells remain largely unknown. Here, we report that TRPC3 was highly expressed in clinical GC specimens and correlated with GC malignant progression and poor prognosis. Forced expression of TRPC3 in GC cells enhanced both receptor-operated Ca2+ entry (ROCE) and store-operated Ca2+ entry (SOCE) and promoted the nuclear factor of activated T cell 2 (NFATc2) nuclear translocation by AKT/GSK-3β and CNB2 signaling. Pharmacological inhibition of TRPC3 or CRISPR/Cas9-mediated TRPC3 knockout effectively inhibited the growth of GC cells both in vitro and in vivo. These effects were reversible by the rescue of TRPC3 expression. Furthermore, we confirmed the role of TRPC3 and the ROCE-AKT/GSK3β-CNB2/NFATc2 signaling cascade in regulating cell cycle checkpoint, apoptosis cascade, and intracellular ROS production in GC. Overall, our findings suggest an oncogenic role of TRPC3 in GC and may highlight a potential target of TRPC3 for therapeutic intervention of GC and its malignant progression. •TRPC3 expression is up-regulated in GC cells associated with the severity of malignancy and poor prognosis.•TRPC3 up-regulation enhances cell proliferation, cell cycle, ROS, and apoptosis resistance contributed to tumorigenesis.•TRPC3 up-regulation enhances ROCE in GC cells to activate CNB2/GSK3β/NFATc2 pathway and excitation-transcription cascade.•Knockdown of TRPC3 suppresses GC development, raising the TRPC3-dependent pathway as a potential target for GC treatment.