title: Piccolo mediates EGFR signaling and acts as a prognostic biomarker in esophageal squamous cell carcinoma.
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.
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan, China.|Guangdong Koheala Precision Medicine Institute, Guangzhou, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: R
authors.initials: R
authors.lastname: Hong
authors.affiliation: Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: N
authors.initials: N
authors.lastname: Lu
authors.affiliation: Guangdong Koheala Precision Medicine Institute, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.|Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan, China.|Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital &Institute, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000502:physiology*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D000077156:Gefitinib; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000502:physiology*; D011379:Prognosis; D016016:Proportional Hazards Models; D055550:Protein Stability; D021381:Protein Transport; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003598:Cytoskeletal Proteins; D009479:Neuropeptides; C498630:PCLO protein, human; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib