Jo Dong Hyun, Lee Kyungmin, Kim Jin Hyoung, Jun Hyoung Oh, Kim Younghoon, Cho Young-Lai, Yu Young Suk, Min Jeong-Ki, Kim Jeong Hun
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.
Oncotarget. 2017 Feb 28;8(9):15441-15452. doi: 10.18632/oncotarget.14487.
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.
视网膜母细胞瘤是儿童最常见的眼内癌，发病率为1/20000活产儿。目前，视网膜母细胞瘤患儿采用卡铂、长春新碱和依托泊苷等药物进行化疗。不幸的是，如果传统治疗失败，应摘除患眼以防止肿瘤扩散至邻近组织并发生转移。本研究旨在探讨L1在视网膜母细胞瘤黏附介导的增殖和化疗耐药中的作用。L1在30个视网膜母细胞瘤组织和2个视网膜母细胞瘤细胞系中表达存在差异。此外，在每个肿瘤样本中，视网膜母细胞瘤肿瘤中L1阳性细胞的比例与视网膜母细胞瘤分化肿瘤的特征性结构——Flexner-Wintersteiner菊形团的数量呈负相关。使用L1缺失和过表达细胞进行的体外实验表明，L1通过调节细胞周期相关蛋白，同时调节Akt、细胞外信号调节激酶和p38信号通路，增加了视网膜母细胞瘤细胞黏附介导的增殖。此外，L1通过上调凋亡和多药耐药相关基因，增加了对卡铂、长春新碱和依托泊苷的耐药性。在小鼠原位移植模型中，体内肿瘤形成和化疗耐药性也与L1水平呈正相关。通过这种方式，L1增加了视网膜母细胞瘤黏附介导的增殖和化疗耐药性。针对L1的靶向治疗可能对视网膜母细胞瘤肿瘤的治疗有效，尤其是对那些快速增殖且对传统化疗药物耐药的肿瘤。
