Nkx2-8 downregulation promotes angiogenesis and activates NF-Œ∫B in esophageal cancer
Authors: Jueheng Wu
Hui Gong
Mengfeng Li
Chuyong Lin
Jun Li
Aibin Liu
Xi Lin
Libing Song
Journal: Cancer Research (2013)
Discipline: CLINICAL MEDICINE
Keywords: Angiogenesis; Esophageal squamous cell carcinoma; VEGF-C; Nkx2-8; Prognostic factor
Affiliations: 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.

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-Œ∫B activity by restraining nuclear localization of NF-Œ∫B p65 via downregulation of AKIP1, a NF-Œ∫B p65 binding partner, and also by directly targeting the AKIP1 promoter. We confirmed evidence for the importance of the Nkx2-8/AKIP1/NF-Œ∫B 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-Œ∫B activation and ESCC angiogenesis. 

Retracted: No

PubPeer comments:
 Image reuse in two papers.  , 
 #1 Dear Lecithocera Eumenopisuff1a Thanks for pointing this out. The tube formation experiments were done by the same first author nearly at the same time. We will check the original data carefully. Jun Li , 
 Dear authors, thank you for your response. However, you need recheck the data both carefully and thoroughly. Figure 3B contains two images which appear to overlap.  , 
 More in figure 3B, if you rotate one of the images. It appears to be stretched a bit compared to the others.  , 
 Dear Lecithocera Eumenopis and Dendrodoa Grossulariauff1a thank you for pointing these errors. We will recheck all the data both carefully and thoroughly, and also repeated these experiments to make corrigendum as soon as possible. Jun Li , 
 15 April 2022 Editor s Note. https: aacrjournals.org cancerres article 82 8 1670 694357 Editor-s-Note-Nkx2-8-Downregulation-Promotes The editors are publishing this note to alert readers to a concern about this article (1). The editors were made aware of duplications in Fig. 3A and B. Specifically, in Fig. 3A, the authors used the incorrect image for the ESCC Kyse510 Nkx2u20138 RNAi#1 group, which was duplicated from Fig. 8A in ref. 2. In Fig. 3B, regions from the same image were used in the Kyse510 Vector, Kyse30 Scrambled vector, and Kyse510 Scrambled vector groups. Also in Fig. 3B, regions from the same image were used in the Kyse30 Nkx2u20138-RNAi#2 and Kyse510 Nkx2u20138-RNAi#2 groups. Because satisfactorily corrected figures could not be provided, the editors are publishing this note to alert readers to these concerns. References 1. Lin C , Song L , Gong H , Liu A , Lin X , Wu J , et al . Nkx2u20138 downregulation promotes angiogenesis and activates NF-u03baB in esophageal cancer. Cancer Res 2013;73:3638u201348. 2. Jiang L , Lin C , Song L , Wu J , Chen B , Ying Z , et al . MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-u03baB Iu03baBu03b1 negative feedback loop. J Clin Invest 2012;122:33u201347. , 
 #6 Newly detected figure reuse: in Fig. 3B, regions from the same image were used in the Kyse30 Nkx2u20138-RNAi#2 and Kyse510 Nkx2u20138-RNAi#2 groups  ,