FN1 Shapes the Behavior of Papillary Thyroid Carcinoma through Alternative Splicing of EDB Region

Papillary thyroid cancer (PTC) is often characterized by the indolent behavior with slow cell proliferation, however, small tumors still have a tendency to metastasize to the cervical lymph node, and the molecular mechanisms underlying that remain poorly understood. FN1 is an extracellular matrix (ECM) protein with the controversial role in tumors, containing three alternative splicing domains. In this study, FN1 was as the hottest gene of PTC and distinctive expression in PTC cells. The alternatively splicing EDB region of FN1 was exclusively expressed in tumors, which impacted on integrin β1 (ITGB1) bonding FN1 and it secretion process, resulting in completely distinct roles of two isoforms of FN1 including and skipping EDB domain. EDB(-)FN1 intracellularly inhibited tumor proliferation, whereas extracellular EDB(+)FN1 activated migration, invasion and lymphoangiogenesis in vitro and in vivo. Mechanistically, EDB(-)FN1 upregulated p21 in p53 signaling pathway, however, EDB(+)FN1 secretes into ECM promoted VEGFC expression. Collectively, FN1 is a potential determinant behind the characteristic behavior of PTC with its two isoforms playing distinct roles owing to the alternative splicing of EDB domain.