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CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2

Oncogene volume 37, pages 1075–1085 (2018)Cite this article

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A Correction to this article was published on 28 September 2021

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Abstract

Cullin 4B (CUL4B) is a scaffold protein overexpressed in several solid malignancies. It is known to silence tumor suppressor through post-transcriptional manner. However, its clinical significance and underlying molecular mechanisms in gastric cancer (GC) remain largely unknown. In this study, we found that CUL4B was significantly overexpressed in GC tissues and its overexpression was correlated with lymph node metastasis and poor prognosis. Through gain- and loss-of-function experiments, we showed that CUL4B promotes GC cell invasion and epithelial–mesenchymal transition (EMT) in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we identified HER2 as a downstream target gene of CUL4B in GC. CUL4B unregulated HER2 expression via transcriptionally repressing miR-125a. Intriguingly, HER2 inhibitors significantly reversed CUL4B-induced EMT in vitro and partially blocked GC metastasis in tumor xenografts with CUL4B overexpression. Finally, we suggested the involvement of the PI3K/AKT pathway in CUL4B-induced HER2 upregulation in GC. In all, we proposed a model for a CUL4B-miR-125a-HER2 oncoprotein axis, which provided novel insight into how HER2 was activated and contributed to GC progression and metastasis.

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Acknowledgements

We thank Baichun Jiang for technical assistance. This work was supported by National Natural Science Foundation of China (Grants No. 81672554 and 81472417 to BH, 31371369 and 31671427 to YZ).

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Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, Shandong University QiLu Medical College, School of Basic Medical Sciences, Jinan, Shandong, China

    M Qi, M Jiao, X Li, J Hu, M Zhao, R Zhang, H Liu, L Zhang & B Han

  2. Department of Pathology, Shandong University Qilu hospital, Jinan, China

    M Qi, L Liu & B Han

  3. Department of Pathology, Binzhou People’s Hospital, Binzhou, China

    X Li

  4. Research Center for Medicinal Biotechnology, Key Laboratory for Rare and Uncommon Diseases of Shandong Province, Shandong Academy of Medicinal Sciences, Jinan, China

    L Wang

  5. Ministry of Education and Department of Molecular Medicine and Genetics, The Key Laboratory of Experimental Teratology, Shandong University QiLu Medical College, School of Basic Medical Sciences, Jinan, China

    Y Zou, J Mi & Y Gong

  6. Department of Pathology, Affiliated Hospital of Binzhou Medical College, Binzhou, China

    M Zhao

  7. Department of Pathology, Xintai Traditional Chinese Medicine Hospital, Taian, China

    R Zhang

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  1. M Qi
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Correspondence to B Han.

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Qi, M., Jiao, M., Li, X. et al. CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2. Oncogene 37, 1075–1085 (2018). https://doi.org/10.1038/onc.2017.380

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  • DOI: https://doi.org/10.1038/onc.2017.380

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