L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma
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Dong Hyun Jo1,2,3,*, Kyungmin Lee4,5,*, Jin Hyoung Kim1,3, Hyoung Oh Jun1,3, Younghoon Kim6, Young-Lai Cho7, Young Suk Yu1,8, Jeong-Ki Min4,5, Jeong Hun Kim1,2,3,8
1Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
3Tumor Microenvironment Research Center, Global Core Research Center, Seoul National University, Seoul, Republic of Korea
4Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
5Department of Biomolecular Science, University of Science & Technology, Daejeon, Republic of Korea
6Department of Pathology, College of Medicine, Seoul National University, Seoul, Republic of Korea
7Department of Chemistry, Dongguk University, Seoul, Republic of Korea
8Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
*These authors have contributed equally to this work
Jeong-Ki Min, email: [email protected]
Jeong Hun Kim, email: [email protected]
Keywords: retinoblastoma, L1, cell adhesion molecules, adhesion-mediated proliferation, chemoresistance
Received: August 31, 2016 Accepted: December 13, 2016 Published: January 04, 2017
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.
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