title: PSCA acts as a tumor suppressor by facilitating the nuclear translocation of RB1CC1 in esophageal squamous cell carcinoma.
abstract: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. By high-throughput transcriptome sequencing (RNA-Seq) profiling of three pairs of primary ESCCs and their corresponding non-tumorous tissues, we identified that prostate stem cell antigen (PSCA), a gene that encodes a glycosylphosphatidylinositol-anchored protein, is significantly downregulated in ESCC. Here, we reported decreased expression of PSCA in 188/218 (86.2%) of primary ESCC cases and was negatively regulated by its transcription factor sex-determining region Y-box5 that was significantly associated with the poor differentiation (P = 0.003), increased lymph node metastasis (P < 0.0001), advanced stage (P = 0.007), and disease-specific survival (P < 0.0001), but not associated with the recently reported transcrible rs2294008 (C > T) polymorphism in ESCC. Functional studies showed that PSCA could arrest cell cycle progression and promote cell differentiation independent of the start codon polymorphism. Further mechanistic studies revealed that retinoblastoma 1-inducible coiled-coil 1 (RB1CC1), a key signaling node to regulate cellular proliferation and differentiation, interacted specifically with PSCA in ESCC cells. Binding of PSCA and RB1CC1 in cytoplasm resulted in stabilization and translocation of RB1CC1 into nucleus, thereby activating key factors involved in cell cycle arrest and differentiation. Collectively, our data provide a novel molecular mechanism for the tumor suppressor role of PSCA and may help design effective therapy targeting PSCA-RB1CC1 pathway to control esophageal cancer growth and differentiation.
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077, China.|State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China.
authors.forename: Li-Yi
authors.initials: LY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology , Macau 999078 , China.
authors.forename: Jian-Lin
authors.initials: JL
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China.|Department of Gastric and Pancreatic Surgery, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China.
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Qiu
authors.affiliation: Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China.
authors.forename: Sui-Sui
authors.initials: SS
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China.
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Zhu
authors.affiliation: Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China.
authors.forename: Victor Ho-Fun
authors.initials: VH
authors.lastname: Lee
authors.affiliation: Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University , Zhengzhou 450000 , China.
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University , Guangzhou 510000 , China.
authors.forename: Hai-Bo
authors.initials: HB
authors.lastname: Liu
authors.affiliation: Laboratory of Surgery, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou 510000 , China and.
authors.forename: Jiong
authors.initials: J
authors.lastname: Bi
authors.affiliation: Department of Clinical Oncology, University of Hong Kong , Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077 , China.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Room 56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong 999077, China.|State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University, Guangzhou 510000, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Shenzhen Key Laboratory of Translational Medicine of Tumor and Cancer Research Centre, School of Medicine, Shenzhen University , Shenzhen 518000 , China.
authors.forename: Li
authors.initials: L
authors.lastname: Fu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071183:Autophagy-Related Proteins; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D004938:Esophageal Neoplasms / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D058851:GPI-Linked Proteins / Q000378:metabolism; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D000071183:Autophagy-Related Proteins; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; C407704:RB1CC1 protein, human; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases