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RETRACTED ARTICLE: CREB3L4 promotes angiogenesis and tumor progression in gastric cancer through regulating VEGFA expression

Cancer Gene Therapy volume 29, pages 241–252 (2022)Cite this article

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This article was retracted on 07 April 2023

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Abstract

Tumor angiogenesis is a key step in the progression of gastric cancer (GC) that delivers essential nutrients and oxygen to tumor cells and distant sites. The cyclic AMP responsive element-binding protein 3-like 4 (CREB3L4) is a transcription factor highly expressed in multiple human cancers. This study aimed to investigate the regulatory effects of CREB3L4 on GC progression and angiogenesis. CREB3L4 was overexpressed in GC tissues and cell lines, and was positively correlated with advanced tumor stage and poor survival in GC patients. The upregulation of CREB3L4 in GC cells increased cell viability, promoted cell proliferation, reduced apoptosis, enhanced cell migration and invasion, and induced the formation of tubule-like endothelial structures, whereas CREB3L4 knockdown impeded tumor cell growth, attenuated cell motility, and prevented human umbilical vein endothelial cells from forming tubule-like structures. In addition, mice inoculated with CREB3L4-deficient GC cells showed significantly suppressed tumor growth compared to the group harboring wild-type tumors. Further analysis revealed that CREB3L4 expression was positively correlated with the level of vascular endothelial growth factor A (VEGFA) in gastric tumors. CREB3L4 regulated the transcription activity of VEGFA by binding to its promoter. The downregulation of VEGFA eliminated CREB3L4-induced GC cell growth and movement, and the formation of endothelial structures; while VEGFA upregulation greatly induced the growth and movement of GC cells with CREB3L4 deficiency. In conclusion, CREB3L4 promoted gastric tumor progression and endothelial angiogenesis by transcriptionally activating the VEGFA promoter, suggesting that therapeutic potential of the CREB3L4/VEGFA axis in GC treatment.

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Fig. 1: Expression of CREB3L4 in GC tissues and its correlation with the prognosis and survival of GC patients.
Fig. 2: Effect of CREB3L4 expression on GC cell survival and proliferation.
Fig. 3: Effect of CREB3L4 expression on migration and invasion of GC cells and angiogenesis of endothelial cells.
Fig. 4: Correlations of CREB3L4 expression with VEGFA expression and angiogenesis in tumor tissues.
Fig. 5: The transcription activity of VEGFA is regulated by CREB3L4.
Fig. 6: CREB3L4 mediates GC cell proliferation, migration, invasion, and angiogenesis via VEGFA.
Fig. 7: Effect of CREB3L4 knockdown on GC tumorigenesis in vivo.

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All data generated or analyzed during this study are included in this published article.

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Authors and Affiliations

  1. Department of Digestive Internal Medicine, Gaozhou People’s Hospital, Gaozhou City, Guangdong Province, China

    Nannan Wang & Zuoguang Lin

  2. Department of Digestive Internal Medicine, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning city, Guangxi Province, China

    Yuanneng Chen

  3. Department of the First School of Clinical Medicine Surgery, Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, China

    Chengwei Shi

  4. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, China

    Huaxia Xie

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Contributions

N.W. and Y.C. designed the study and supervised the data collection, C.S. analyzed and interpreted the data, Z.L. and H.X. prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

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Correspondence to Huaxia Xie.

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All procedures performed in studies involving human participants were in accordance with the standards upheld by the Ethics Committee of Gaozhou People’s hospital. All animal experiments were approved by the Ethics Committee of The first affiliated hospital of Zhejiang Chinese medical university.

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Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

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This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1038/s41417-023-00613-2

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Wang, N., Chen, Y., Shi, C. et al. RETRACTED ARTICLE: CREB3L4 promotes angiogenesis and tumor progression in gastric cancer through regulating VEGFA expression. Cancer Gene Ther 29, 241–252 (2022). https://doi.org/10.1038/s41417-021-00305-9

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