A novel thrombospondin-1 transcript exhibits distinctive expression and activity in thyroid tumorigenesis

Abstract

Abstract Thrombospondin 1 (TSP1) is known for its cell-specific functions in cancer progression, such as proliferation and migration. It contains 22 exons that may potentially produce several different transcripts. Here, we identified TSP1V as a novel TSP1 splicing variant produced by intron retention (IR) in human thyroid cancer cells and tissues. We observed TSP1V functionally inhibited tumorigenesis contrary to TSP1 wild-type (TSP1W), as identified by in vivo and in vitro. These activities of TSP1V caused by inhibiting p-Smad and p-FAK. RT-PCR and minigene experiments revealed that some phytochemicals/non-steroidal anti-inflammatory drugs (NSAIDs) enhanced IR. We further found that RNA binding motif protein 5 (RBM5) suppressed IR, induced by sulindac sulfide treatment. Sulindac sulfide also reduced p-RBM5 in a time dependent manner. On the other hand, trans-chalcone demethylated TSP1V, thereby preventing MeCP2 binding to TSP1V gene. In addition, TSP1V levels were significantly lower in patients with DTC, but not in those with BTN, indicating its potential application as a diagnostic biomarker in tumor progression.