The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression

Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins a1, av, ß1, and ß5 in cells with high TRPM2 expression. Transcription factors HIF-1a, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of a1, av, and ß1 membrane localization and co-immunoprecipitation confirmed the presence of a1ß1, avß1, and avß5 complexes. Inhibitors of a1ß1, avß1, and avß5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells highly expressing TRPM2 through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing the rationale for TRPM2 inhibition in anti-neoplastic therapy. Overall design: Two samples were analyzed in duplicate: SHSY5Y KO+V5 and SHSY5Y KO+M2