Abstract
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 NFκB transcriptional activity and this RT-induced NFκB were required/adequate for MMP9 maintenance. RT-triggered NFκB-dependent MMP9 actuated a second-signaling feedback to NFκB, facilitating a NFκB-MMP9-NFκB positive feedback cycle (PFC). Critically, MMP9-NFκB feedback is mediated by MMP9-dependent activation of IKKβ 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 NFκB 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 NFκB-binding sites, demonstrating that MMP9 regulates these molecules by activating NFκB. Collectively, these data suggest that RT-triggered NFκB-dependent MMP9 actuates feedback to NFκB though IKKβ- and ERK1/2-dependent IκBα 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.
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This study is funded by the Department of Radiation Oncology at OUHSC, National Institutes of Health, NIH-P20GM103639, and Oklahoma Center for the Advancement of Science and Technology, OCAST-HR19-045.
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NA contributed to the conception and design of the experiments. DS, SA, RM, MN, and NA performed the experiments and contributed to the acquisition of the data. NA, SA, and MN contributed to data analysis and interpretation of the data. NA and DS drafted the manuscript, and MN helped in revising it critically. All authors read and approved the final manuscript.
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Highlights
• Radiation-induced NFκB is required and adequate for the maintenance of MMP9 in NB.
• RT-triggered NFκB-dependent MMP9 actuates a second-signaling feedback to NFκB.
• MMP9-NFκB second signaling feedback is mediated by MMP9-dependent activation of IKKβ and ERK activity.
• NFκB-MMP9-NFκB feedback–dependent acquired maintenance of MMP9 after therapeutic pressure could contribute heavily for tumor evolution.
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Somasundaram, D.B., Aravindan, S., Major, R. et al. 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. Cell Biol Toxicol 39, 1053–1076 (2023). https://doi.org/10.1007/s10565-021-09663-4
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DOI: https://doi.org/10.1007/s10565-021-09663-4