Abstract
Pancreatic cancer (PC) is recognized as the most aggressive and deadliest malignancy because it has the highest mortality of all cancers in humans. Mutations in multiple tumor suppressors and oncogenes have been documented to be involved in pancreatic cancer progression and metastasis. The upregulation of tetraspanin 1 (TSPAN1), a transmembrane protein, has been reportedly observed in many human cancers. However, the role of TSPAN1 and its underlying molecular mechanisms in PC progression have not been fully elucidated. In this study, we validated the oncogenic role of TSPAN1 in PC, showing that TSPAN1 reinforces cell proliferation, migration, invasion and tumorigenesis. To investigate the upregulation of TSPAN1 in PC, we showed that miR-216a is the upstream negative regulator of TSPAN1 via direct binding to the TSPAN1 3'-untranslated region. Through RNA-Seq analysis, we for the first time revealed that TSPAN1 expression transcriptionally regulates ITGA2, which is involved in the actin cytoskeleton pathway. The stimulated cell proliferation and invasion initiated by TSPAN1 overexpression could be abolished by knockdown of ITGA2 in PC cells. Furthermore, TSPAN1 epigenetically regulates the expression of ITGA2 by modulating the levels of TET2 DNMT3B and DNMT1, resulting in hypomethylation of the CpG island of the ITGA2 promoter. In conclusion, the newly identified miR-216a/TSPAN1/ITGA2 axis is involved in the modulation of PC progression and represents a novel therapeutic strategy for future pancreatic cancer treatment.