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Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma

Oncogene volume 36, pages 3890–3902 (2017)Cite this article

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Abstract

The presynaptic cytomatrix protein Piccolo, encoded by PCLO, is frequently mutated and amplified in esophageal squamous cell carcinoma (ESCC), but its exact roles in ESCC remain unclear. Here we report that Piccolo expression correlates significantly with clinical stage, patient survival and tumor embolus. Functional studies demonstrate that PCLO knockdown remarkably attenuates ESCC malignancy in vitro and in vivo, and ectopic EGFR expression partially compensates for Piccolo loss. PCLO knockdown promotes ubiquitination and degradation of EGFR, which is associated with the negative regulatory effect of Piccolo on E3 ligase Siah1. An anti-Piccolo monoclonal antibody inhibited tumor proliferation in a mouse model of ESCC. These results demonstrate that Piccolo contributes to tumor aggressiveness in ESCC, likely by stabilizing EGFR and promoting EGFR-dependent signaling. Our results further suggest that Piccolo may represent a novel prognostic biomarker and therapeutic target for patients with ESCC.

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Acknowledgements

We appreciated Jie Chen and Tian Lan for revising this manuscript and offering constructive advices. This work is supported by the National 973 Program (2015CB553904) and National Natural Fund of China (81230047 and 81321091).

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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    W Zhang, Y Ou, X Liu, Z Zhao, W Xiao, D Dong, L Dong, M Fu, L Ma, Y Song & Q Zhan

  2. Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan, China

    W Zhang & Q Zhan

  3. Guangdong Koheala Precision Medicine Institute, Guangzhou, China

    W Zhang & H Chen

  4. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China

    R Hong

  5. Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    L Xue & N Lu

  6. Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China

    Y Ou

  7. Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China

    X Liu

  8. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China

    Q Zhan

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Correspondence to Q Zhan.

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Zhang, W., Hong, R., Xue, L. et al. Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma. Oncogene 36, 3890–3902 (2017). https://doi.org/10.1038/onc.2017.15

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  • DOI: https://doi.org/10.1038/onc.2017.15

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