Abstract
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.
Highlights
Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate as low as 5% from the time of diagnosis [1]
The high mortality rate is largely due to the limited availability of effective prognostic markers that would allow for early detection, as well as the highly invasive nature of pancreatic cancer, which leads to metastasis to distant organs [2]
Expression Profiling Interactive Analysis (GEPIA) platform. This In summary, our results indicated that SYT8 plays an important analysis revealed that SYT8 levels were significantly higher in role in both promoting cell invasion in vitro and tumor metastasis tumor tissues when compared with non-tumor healthy tissues in vivo
Summary
Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate as low as 5% from the time of diagnosis [1]. Estrogen-related receptor alpha (ERRα) is a nuclear receptor (NR) with high sequence similarity to the estrogen receptor, but with a poor affinity towards estrogen binding, and is widely expressed in metabolically active cells [22, 23]. It has diverse roles such as in cardiac maturation and regulation of mitochondrial biogenesis [24, 25]. We identified SIRT1 as an interacting suggested that SYT8 directly regulates cell survival and tumor component of ERRα using the ToppGene Suite portal
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