Circular RNA nuclear receptor interacting protein 1 promoted biliary tract cancer epithelial-mesenchymal transition and stemness by regulating the miR-515-5p/AKT2 axis and PI3K/AKT/mTOR signaling pathway

Biliary tract cancer (BTC) is a devastating malignancy that is notoriously difficult to diagnose and is associated with high mortality. Circular RNA (circRNA) is a class of endogenous non-coding RNA which has been regarded as the key regulator of tumor initiation and progression, including BTC. Circular RNA nuclear receptor interacting protein 1 (circ_NRIP1), as a circular RNA, is abnormally expressed in many human tumors and exhibits diverse functions in cancer progression. However, its biological significance in BTC has not been thoroughly investigated. In this research, we elucidated that circ_NRIP1 was notably overexpressed in both BTC tissues and cells. We further established a correlation between circ_NRIP1 expression and clinicopathological features in BTC patients, highlighting its clinical relevance. Through functional assays, we observed that knockdown of circ_NRIP1 significantly inhibited tumor cell proliferation, invasion, stemness maintenance, and epithelial-mesenchymal transition, indicating its active involvement in promoting BTC progression. Additionally, it attenuated growth of xenograft and metastasis models. Mechanically, we revealed that circ_NRIP1 served as the competing endogenous RNA to sequester miR-515-5p through complementary base pairing mechanism, thereby upregulated AKT2 expression and indirectly activated PI3K/AKT/mTOR signaling pathway. Generally, targeting the circ_NRIP1/miR-515-5p/AKT2 axis and aberrant activation of the PI3K/AKT/mTOR pathway may hold promising therapeutic strategies for BTC. Our research contributes to a better understanding of the underlying biological basis of BTC and paves the way for the development of innovative treatment approaches.