26257

NKX2-8

NKX2.8|NKX2H|Nkx2-9;NK2 homeobox 8;NKX2-8;NK2 homeobox 8

NK-2 homolog 8|NK-2 homolog H|NK2 transcription factor related, locus 8|homeobox protein NK-2 homolog H|homeobox protein Nkx-2.8

14q13.3

protein-coding

Angiogenesis is a major clinical feature of esophageal squamous cell carcinoma (ESCC), an aggressive disease of increasing incidence in developed countries. In ESCCs, the proangiogenic factor VEGF-C is an independent prognostic factor for ESCC, where understanding the mechanisms of VEGF-C upregulation may cue possible therapeutic insights. Here, we report that expression of the transcription factor Nkx2-8 is downregulated in ESCCs where it inversely correlates with progression and VEGF-C upregulation. Patients with ESCCs with lower Nkx2-8 expression exhibited reduced overall survival. Modulating expression of Nkx2-8 up or down inhibited or enhanced, respectively, proangiogenic activity in vitro and in vivo. Mechanistic investigations showed that Nkx2-8 repressed NF-kappaB activity by restraining nuclear localization of NF-kappaB p65 via downregulation of AKIP1, a NF-kappaB p65 binding partner, and also by directly targeting the AKIP1 promoter. We confirmed evidence for the importance of the Nkx2-8/AKIP1/NF-kappaB axis identified in ESCC cell models through an immunohistochemical analysis of a large cohort of human ESCC specimens. Taken together, our results showed that Nkx2-8 functions as a tumor suppressor in ESCCs, the downregulation of which contributes to NF-kappaB activation and ESCC angiogenesis.