IKBB tumor suppressive role in nasopharyngeal carcinoma via NF-κB-mediated signalling

Abstract

Tumor suppressor genes (TSGs) play a prominent role in cancer and are important in the development of nasopharyngeal carcinoma (NPC), which is endemic in Southern China as well as Southeast Asia. Apart from TSGs, aberrant signalling pathways are also commonly associated with tumor progression. Unsurprisingly, the NF-κB pathway is frequently associated with angiogenesis and promoting tumor growth and development. Functional complementation studies using microcell-mediated chromosome transfer helped to identify IKBB as a putative TSG in NPC. IKBB, an inhibitor of NF-κB, has recently been shown to be inversely associated with tumor growth and metastasis via inactivation of the NF-κB pathway, but its suppressive role is still only poorly understood. This study takes the lead in revealing the suppressive role of IKBB in NPC. IKBB is silenced in the majority of NPC tumor tissues in all stages. Its suppressive role is substantiated by perturbation in tumor formation, cell migration and angiogenesis. Interestingly, IKBB not only affects the 'seed', but also influences the 'soil' by downregulating the transcriptional level of proangiogenic factors Rantes, Upar, IL6, and IL8. For the first time, our data establish the importance of a novel tumor suppressive IKBB gene in abrogating angiogenesis in NPC via the NF-κB signalling pathway, which is likely mediated by crosstalk with the Akt/Gsk3β signalling pathway. What's new? The distinct ethnic and geographic incidence patterns of nasopharyngeal carcinoma (NPC) occur on a background of complex genetic alteration, with the loss of tumor suppressor genes thought to be of particular consequence. The present study suggests that the loss of IKBB, a putative tumor suppressor in NPC, is critical in the progression of the disease. Experiments show that, acting through the NF-κB/Akt/Gsk3β signalling pathway, IKBB expression suppressed cell migration and angiogenesis. In vivo, IKBB attenuated tumor growth, with important modulatory effects on the tumor microenvironment. IKBB expression was diminished in the majority of patient samples.