Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Oncogene. 2021 Dec;40(49):6666-6679. doi: 10.1038/s41388-021-01838-x. Epub 2021 Oct 12.
Copy number alterations are crucial for gastric cancer (GC) development. In this study, Tocopherol alpha transfer protein-like (TTPAL) was identified to be highly amplified in our primary GC cohort (30/86). Multivariate analysis showed that high TTPAL expression was correlated with the poor prognosis of GC patients. Ectopic expression of TTPAL promoted GC cell proliferation, migration, and invasion in vitro and promoted murine xenograft tumor growth and lung metastasis in vivo. Conversely, silencing of TTPAL exerted significantly opposite effects in vitro. Moreover, RNA-sequencing and co-immunoprecipitation (Co-IP) followed by liquid chromatograph-mass spectrometry (LC-MS) identified that TTPAL exerted oncogenic functions via the interaction of Nicotinamide-N-methyl transferase (NNMT) and activated PI3K/AKT signaling pathway. Collectively, TTPAL plays a pivotal oncogenic role in gastric carcinogenesis through promoting PI3K/AKT pathway via cooperating with NNMT. TTPAL may serve as a prognostic biomarker of patients with GC.
拷贝数改变对于胃癌（GC）的发生至关重要。在本研究中，我们在原发性 GC 队列（30/86）中发现Tocopherol alpha transfer protein-like（TTPAL）高度扩增。多变量分析表明，高 TTPAL 表达与 GC 患者的不良预后相关。TTPAL 的异位表达促进 GC 细胞在体外的增殖、迁移和侵袭，并促进小鼠异种移植肿瘤生长和肺转移。相反，TTPAL 的沉默在体外表现出明显相反的作用。此外，RNA 测序和免疫共沉淀（Co-IP）后进行液相色谱-质谱（LC-MS）鉴定表明，TTPAL 通过与烟酰胺-N-甲基转移酶（NNMT）相互作用和激活 PI3K/AKT 信号通路发挥致癌作用。总之，TTPAL 通过与 NNMT 合作促进 PI3K/AKT 通路在胃癌发生中发挥关键致癌作用。TTPAL 可能作为 GC 患者的预后标志物。
