MMP-9 reinforces radiation-induced delayed invasion and metastasis of neuroblastoma cells through second-signaling positive feedback with NFκB via both ERK and IKK activation

Neuroblastoma (NB) progression is branded with hematogenous metastasis and frequent relapses. Despite intensive multimodal clinical therapy, outcomes for patients with progressive disease remain poor, with negligible long-term survival. Therefore, understanding the acquired molecular rearrangements in NB cells with therapy pressure and developing improved therapeutic strategies is a critical need to improve the outcomes for high-risk NB patients. We investigated the rearrangement of MMP9 in NB with therapy pressure, and unveiled the signaling that facilitates NB evolution. Radiation-treatment (RT) significantly increased MMP9 expression/activity, and the induced enzyme activity was persistently maintained across NB cell lines. Furthermore, RT-triggered NF kappa B transcriptional activity and this RT-induced NF kappa B were required/adequate for MMP9 maintenance. RT-triggered NF kappa B-dependent MMP9 actuated a second-signaling feedback to NF kappa B, facilitating a NF kappa B-MMP9-NF kappa B positive feedback cycle (PFC). Critically, MMP9-NF kappa B feedback is mediated by MMP9-dependent activation of IKK beta and ERK phosphotransferase activity. Beyond its tumor invasion/metastasis function, PFC-dependent MMP9 lessens RT-induced apoptosis and favors survival pathway through the activation of NF kappa B signaling. In addition, PFC-dependent MMP9 regulates 19 critical molecular determinants that play a pivotal role in tumor evolution. Interestingly, seven of 19 genes possess NF kappa B-binding sites, demonstrating that MMP9 regulates these molecules by activating NF kappa B. Collectively, these data suggest that RT-triggered NF kappa B-dependent MMP9 actuates feedback to NF kappa B though IKK beta- and ERK1/2-dependent I kappa B alpha phosphorylation. This RT-triggered PFC prompts MMP9-dependent survival advantage, tumor growth, and dissemination. Targeting therapy-pressure-driven PFC and/or selective inhibition of MMP9 maintenance could serve as promising therapeutic strategies for treatment of progressive NB.

Automated summary

This study investigates the acquired molecular rearrangements in neuroblastoma cells under therapy pressure, particularly focusing on MMP9. It finds that radiation treatment significantly increases MMP9 expression/activity and triggers NF kappa B-dependent MMP9, which then actuates a positive feedback cycle promoting survival advantage and tumor growth. This feedback is mediated by the activation of IKK beta and ERK phosphotransferase activity. Targeting therapy-pressure-driven MMP9 maintenance could be a promising therapeutic strategy for progressive neuroblastoma.