Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
Cancer Res. 2019 Jul 1;79(13):3332-3346. doi: 10.1158/0008-5472.CAN-18-2986. Epub 2019 Apr 24.
Copy number alterations are crucial for the development of colorectal cancer. Our whole-genome analysis identified tocopherol alpha transfer protein-like (TTPAL) as preferentially amplified in colorectal cancer. Here we demonstrate that frequent copy number gain of TTPAL leads to gene overexpression in colorectal cancer from a Chinese cohort ( = 102), which was further validated by a The Cancer Genome Atlas (TCGA) cohort ( = 376). High expression of TTPAL was significantly associated with shortened survival in patients with colorectal cancer. TTPAL promoted cell viability and clonogenicity, accelerated cell-cycle progression, inhibited cell apoptosis, increased cell migration/invasion ability , and promoted tumorigenicity and cancer metastasis . TTPAL significantly activated Wnt signaling and increased β-catenin activation and protein expression of cyclin D1 and c-Myc. Coimmunoprecipitation followed by mass spectrometry identified thyroid receptor-interacting protein 6 (TRIP6) as a direct downstream effector of TTPAL. Depletion of TRIP6 significantly abolished the effects of TTPAL on cell proliferation and Wnt activation. Direct binding of TTPAL with TRIP6 in the cytoplasm inhibited ubiquitin-mediated degradation of TRIP6 and, subsequently, increased levels of TRIP6 displaced β-catenin from the tumor suppressor MAGI1 via competitive binding. This sequence of events allows β-catenin to enter the nucleus and promotes oncogenic Wnt/β-catenin signaling. In conclusion, TTPAL is commonly overexpressed in colorectal cancer due to copy number gain, which promotes colorectal tumorigenesis by activating Wnt/β-catenin signaling via stabilization of TRIP6. TTPAL overexpression may serve as an independent new biomarker for the prognosis of patients with colorectal cancer. SIGNIFICANCE: TTPAL, a gene preferentially amplified in colorectal cancer, promotes colon tumorigenesis via activation of the Wnt/β-catenin pathway.
拷贝数改变对于结直肠癌的发生发展至关重要。我们的全基因组分析鉴定出生育酚 alpha 转移蛋白样（TTPAL）在结直肠癌中优先扩增。在这里，我们证明了 TTPAL 的频繁拷贝数增益导致了来自中国队列的结直肠癌中的基因过表达（= 102），这在癌症基因组图谱（TCGA）队列（= 376）中得到了进一步验证。TTPAL 的高表达与结直肠癌患者的生存时间缩短显著相关。TTPAL 促进细胞活力和集落形成能力，加速细胞周期进程，抑制细胞凋亡，增加细胞迁移/侵袭能力，并促进肿瘤发生和癌症转移。TTPAL 显著激活了 Wnt 信号通路，并增加了 β-连环蛋白的激活和细胞周期蛋白 D1 和 c-Myc 的蛋白表达。免疫沉淀结合质谱分析鉴定出甲状腺受体相互作用蛋白 6（TRIP6）是 TTPAL 的直接下游效应物。TRIP6 的耗竭显著消除了 TTPAL 对细胞增殖和 Wnt 激活的影响。TTPAL 在细胞质中与 TRIP6 的直接结合抑制了泛素介导的 TRIP6 降解，随后，TRIP6 水平的增加将 β-连环蛋白从肿瘤抑制因子 MAGI1 上置换出来，通过竞争性结合。这一系列事件允许 β-连环蛋白进入细胞核，并通过稳定 TRIP6 促进致癌性 Wnt/β-连环蛋白信号通路。总之，由于拷贝数增加，TTPAL 在结直肠癌中普遍过表达，通过稳定 TRIP6 激活 Wnt/β-连环蛋白信号通路促进结直肠肿瘤发生。TTPAL 过表达可能成为结直肠癌患者预后的独立新标志物。意义：TTPAL 是结直肠癌中优先扩增的基因，通过激活 Wnt/β-连环蛋白通路促进结肠肿瘤发生。
