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Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma

Oncogene volume 38, pages 3119–3133 (2019)Cite this article

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Abstract

Esophageal squamous cells carcinoma (ESCC) is a major common thoracic tumor characterized by distinctly high incidences and mortality rates. Despite advances in multimodality therapy, the mortality rate of ESCC remains high and understanding of molecular alterations leading to the development and progression of ESCC is still very limited. In this study, a new tumor suppressor candidate, cell adhesion molecule with homology to L1CAM (CHL1), located at 3p26 which was frequently deleted in ESCC was identified. Reduced expression of CHL1 correlated with poor differentiation, increased invasion, and lymph-node metastasis, advanced tumor stage, and decreased overall survival. Methylation-specific PCR and FISH assays revealed that down-regulation of CHL1 in both ESCC cell lines and clinical samples were associated with promoter hypermethylation and loss of heterozygosity. Functional studies using lentiviral-based overexpression and knockdown systems provided direct support of CHL1 to function as an important tumor suppressor with both anti-proliferation and anti-metastasis abilities, through Merlin and SEMA3B-Np1-mediated inhibition of AKT signaling pathway. Further characterization of CHL1 may provide a novel therapeutic target in ESCC treatment.

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Acknowledgements

This work was supported by grants from National Key R&D Program of China (2017YFC1309000), Shenzhen Peacock Team Project (KQTD2015033117210153), National Natural Science Foundation of China (81472250, 81602061, and 81772554), the Hong Kong Research Grant Council grants including GRF (HKU/7668/11 M and 767313), CRF (C7038-14G and C7027-14G), Health and Medical Research Fund (04150826), and Natural Science Foundation of Henan Province (182300410376, 182300410297, and 162300410300). Professor XY Guan is Sophie YM Chan Professor in cancer research.

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  1. These authors contributed equally: Hong Tang, Lingxi Jiang, Cailei Zhu

Authors and Affiliations

  1. Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China

    Hong Tang, Yufeng Wu, Suxia Luo & Qiming Wang

  2. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Hong Tang, Lingxi Jiang, Cailei Zhu, Raymond Liu, Qian Yan, Juan Chen, Victor Ho-Fun Lee & Xin-Yuan Guan

  3. Shanghai Key Laboratory of Gastric Neoplasms, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lingxi Jiang

  4. Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China

    Ming Liu

  5. Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China

    Yongxu Jia & Yanru Qin

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Correspondence to Suxia Luo, Qiming Wang or Xin-Yuan Guan.

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Tang, H., Jiang, L., Zhu, C. et al. Loss of cell adhesion molecule L1 like promotes tumor growth and metastasis in esophageal squamous cell carcinoma. Oncogene 38, 3119–3133 (2019). https://doi.org/10.1038/s41388-018-0648-7

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