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

W Zhang; R Hong; L Xue; Y Ou; X Liu; Z Zhao; W Xiao; D Dong; L Dong; M Fu; L Ma; N Lu; H Chen; Y Song; Q Zhan

doi:10.1038/onc.2017.15

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

Oncogene. 2017 Jul 6;36(27):3890-3902. doi: 10.1038/onc.2017.15. Epub 2017 Mar 6.

Authors

W Zhang^{1

2

3}, R Hong⁴, L Xue⁵, Y Ou^{1

6}, X Liu^{1

7}, Z Zhao¹, W Xiao¹, D Dong¹, L Dong¹, M Fu¹, L Ma¹, N Lu⁵, H Chen³, Y Song¹, Q Zhan^{1

2

8}

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.
² Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan, China.
³ Guangdong Koheala Precision Medicine Institute, Guangzhou, China.
⁴ Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
⁵ Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
⁶ Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
⁷ Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
⁸ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital &Institute, Beijing, China.

PMID: 28263981
DOI: 10.1038/onc.2017.15

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.

MeSH terms

Animals
Antibodies, Monoclonal / pharmacology
Antineoplastic Agents / pharmacology
Biomarkers, Tumor / metabolism*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / secondary
Cell Line, Tumor
Cell Proliferation / drug effects
Cytoskeletal Proteins / physiology*
Disease-Free Survival
ErbB Receptors / metabolism*
Esophageal Neoplasms / genetics
Esophageal Neoplasms / metabolism*
Esophageal Neoplasms / mortality
Esophageal Neoplasms / pathology
Female
Gefitinib
Gene Expression
Humans
Inhibitory Concentration 50
Kaplan-Meier Estimate
Lymphatic Metastasis
Male
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Mutation
Neoplasm Transplantation
Neuropeptides / physiology*
Prognosis
Proportional Hazards Models
Protein Stability
Protein Transport
Quinazolines / pharmacology
Signal Transduction

Substances

Antibodies, Monoclonal
Antineoplastic Agents
Biomarkers, Tumor
Cytoskeletal Proteins
Neuropeptides
PCLO protein, human
Quinazolines
EGFR protein, human
ErbB Receptors
Gefitinib