Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Oncogene. 2019 Apr;38(17):3119-3133. doi: 10.1038/s41388-018-0648-7. Epub 2019 Jan 8.
Esophageal squamous cells carcinoma (ESCC) is a major common thoracic tumor characterized by distinctly high incidences and mortality rates. Despite advances in multimodality therapy, the mortality rate of ESCC remains high and understanding of molecular alterations leading to the development and progression of ESCC is still very limited. In this study, a new tumor suppressor candidate, cell adhesion molecule with homology to L1CAM (CHL1), located at 3p26 which was frequently deleted in ESCC was identified. Reduced expression of CHL1 correlated with poor differentiation, increased invasion, and lymph-node metastasis, advanced tumor stage, and decreased overall survival. Methylation-specific PCR and FISH assays revealed that down-regulation of CHL1 in both ESCC cell lines and clinical samples were associated with promoter hypermethylation and loss of heterozygosity. Functional studies using lentiviral-based overexpression and knockdown systems provided direct support of CHL1 to function as an important tumor suppressor with both anti-proliferation and anti-metastasis abilities, through Merlin and SEMA3B-Np1-mediated inhibition of AKT signaling pathway. Further characterization of CHL1 may provide a novel therapeutic target in ESCC treatment.
食管鳞状细胞癌（ESCC）是一种主要的胸部肿瘤，其发病率和死亡率都很高。尽管采用了多种方法治疗，但 ESCC 的死亡率仍然很高，而且对导致 ESCC 发生和发展的分子变化的了解仍然非常有限。在这项研究中，鉴定了一个位于 3p26 上的新的肿瘤抑制候选物，与 L1CAM（CHL1）具有同源性的细胞黏附分子，该基因在 ESCC 中经常缺失。CHL1 的表达降低与分化不良、侵袭性增加、淋巴结转移、肿瘤晚期和总生存率降低相关。甲基化特异性 PCR 和 FISH 检测显示，ESCC 细胞系和临床样本中 CHL1 的下调与启动子过度甲基化和杂合性丢失有关。使用基于慢病毒的过表达和敲低系统进行的功能研究直接支持 CHL1 通过 Merlin 和 SEMA3B-Np1 介导的 AKT 信号通路抑制发挥重要的肿瘤抑制作用，具有抗增殖和抗转移能力。进一步对 CHL1 的研究可能为 ESCC 的治疗提供一个新的治疗靶点。
