title: Nkx2-8 downregulation promotes angiogenesis and activates NF-κB in esophageal cancer.
abstract: 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-κB activity by restraining nuclear localization of NF-κB p65 via downregulation of AKIP1, a NF-κB p65 binding partner, and also by directly targeting the AKIP1 promoter. We confirmed evidence for the importance of the Nkx2-8/AKIP1/NF-κB 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-κB activation and ESCC angiogenesis.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Departments of Biochemistry, Microbiology, and Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Aibin
authors.initials: A
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002642:Chick Embryo; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D034622:RNA Interference; D051996:Transcription Factor RelA / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: C471621:AKIP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; D009687:Nuclear Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051996:Transcription Factor RelA; D014157:Transcription Factors; D042582:Vascular Endothelial Growth Factor C