Fu Zhiping, Liang Xing, Shi Ligang, Tang Liang, Chen Danlei, Liu Anan, Shao Chenghao
Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
Cell Death Discov. 2021 Dec 14;7(1):390. doi: 10.1038/s41420-021-00779-4.
Pancreatic cancer is a highly lethal malignancy due to failures of early detection and high metastasis in patients. While certain genetic mutations in tumors are associated with severity, the molecular mechanisms responsible for cancer progression are still poorly understood. Synaptotagmin-8 (SYT8) is a membrane protein that regulates hormone secretion and neurotransmission, and its expression is positively regulated by the promoter of the insulin gene in pancreatic islet cells. In this study, we identified a previously unknown role of SYT8 in altering tumor characteristics in pancreatic cancer. SYT8 levels were upregulated in patient tumors and contributed towards increased cell proliferation, migration, and invasion in vitro and in vivo. Increased SYT8 expression also promoted tumor metastasis in an in vivo tumor metastasis model. Furthermore, we showed that SYT8-mediated increase in tumorigenicity was regulated by SIRT1, a protein deacetylase previously known to alter cell metabolism in pancreatic lesions. SIRT1 expression was altered by orphan nuclear receptor ERRα and troponin-1 (TNNI2), resulting in cell proliferation and migration in an SYT8-dependent manner. Together, we identified SYT8 to be a central regulator of tumor progression involving signaling via the SIRT1, ERRα, and TNNI2 axis. This knowledge may provide the basis for the development of therapeutic strategies to restrict tumor metastasis in pancreatic cancer.
胰腺癌是一种高度致命的恶性肿瘤，原因在于患者早期检测失败且转移率高。虽然肿瘤中的某些基因突变与疾病严重程度相关，但癌症进展的分子机制仍知之甚少。突触结合蛋白8（SYT8）是一种调节激素分泌和神经传递的膜蛋白，其表达在胰岛细胞中受胰岛素基因启动子的正向调控。在本研究中，我们发现了SYT8在改变胰腺癌肿瘤特征方面此前未知的作用。患者肿瘤中SYT8水平上调，在体外和体内均促进了细胞增殖、迁移和侵袭。在体内肿瘤转移模型中，SYT8表达增加也促进了肿瘤转移。此外，我们表明，SYT8介导的致瘤性增加受SIRT1调节，SIRT1是一种蛋白质脱乙酰酶，此前已知其可改变胰腺病变中的细胞代谢。孤儿核受体ERRα和肌钙蛋白-1（TNNI2）改变了SIRT1的表达，从而以SYT8依赖的方式导致细胞增殖和迁移。我们共同确定SYT8是肿瘤进展的核心调节因子，涉及通过SIRT1、ERRα和TNNI2轴的信号传导。这一知识可能为开发限制胰腺癌肿瘤转移的治疗策略提供基础。
