title: L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma.
abstract: Retinoblastoma is the most common intraocular cancer in children, affecting 1/20,000 live births. Currently, children with retinoblastoma were treated with chemotherapy using drugs such as carboplatin, vincristine, and etoposide. Unfortunately, if conventional treatment fails, the affected eyes should be removed to prevent extension into adjacent tissues and metastasis. This study is to investigate the roles of L1 in adhesion-mediated proliferation and chemoresistance of retinoblastoma. L1 was differentially expressed in 30 retinoblastoma tissues and 2 retinoblastoma cell lines. Furthermore, the proportions of L1-positive cells in retinoblastoma tumors were negatively linked with the number of Flexner-Wintersteiner rosettes, a characteristic of differentiated retinoblastoma tumors, in each tumor sample. Following in vitro experiments using L1-deleted and -overexpressing cells showed that L1 increased adhesion-mediated proliferation of retinoblastoma cells via regulation of cell cycle-associated proteins with modulation of Akt, extracellular signal-regulated kinase, and p38 pathways. In addition, L1 increased resistance against carboplatin, vincristine, and esoposide through up-regulation of apoptosis- and multidrug resistance-related genes. In vivo tumor formation and chemoresistance were also positively linked with the levels of L1 in an orthotopic transplantation model in mice. In this manner, L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma. Targeted therapy to L1 might be effective in the treatment of retinoblastoma tumors, especially which rapidly proliferate and demonstrate resistance to conventional chemotherapeutic drugs.
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.|Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Jo
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyoung Oh
authors.initials: HO
authors.lastname: Jun
authors.affiliation: Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Dongguk University, Seoul, Republic of Korea.
authors.forename: Young-Lai
authors.initials: YL
authors.lastname: Cho
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.affiliation: Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea.
authors.forename: Jeong-Ki
authors.initials: JK
authors.lastname: Min
authors.affiliation: Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.|Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea.|Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D019572:Retinal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D012175:Retinoblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D039842:Neural Cell Adhesion Molecule L1
keywords: L1; adhesion-mediated proliferation; cell adhesion molecules; chemoresistance; retinoblastoma