The malignancy of chordomas is enhanced via a circTLK1/miR-16-5p/Smad3 positive feedback axis.

CircRNAs play crucial roles in various malignancies via an increasing number of reported regulatory mechanisms, including the classic sponging mechanism between circRNAs and micro RNAs (miRNAs). We performed bioinformatic analyses and identified circTLK1 as a regulator of malignant chordoma progression. Moreover, we observed that circTLK1 showed high expression in chordoma cells and tissues, while circTLK1 interference suppressed chordoma cell proliferation and invasion. In addition, circTLK1 directly interacted with miR-16-5p, which has previously been shown to repress chordoma, and circTLK1 knockdown suppressed Smad3 expression. Chromatin immunoprecipitation sequencing further demonstrated that Smad3 acts as a positive regulator by interacting with TLK1, thereby mediating the circTLK1/miR-16-5p/Smad3 positive feedback axis. Taken together, our findings suggested that the disruption of the circTLK1/miR-16-5p/Smad3 positive feedback pathway, particularly via the Smad3 inhibitor SIS3, could be a promising therapeutic strategy.